Stroke Syndromes

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Stroke syndromes ‘This comprehensive work will provide its owner with a ready source of reference for a multitude of questions that might arise in the evaluation and localization of individual stroke patients’ (European Neurology) ‘A detailed compilation of descriptions that puts into one place a wealth of information on the clinical observations that can be collected into meaningful stroke syndromes’ (Vascular Medicine) ‘An excellent sourcebook for anyone interested in stroke’ (Neuroradiology) The first edition of Stroke Syndromes was widely welcomed as a new and authoritative reference in the assessment and diagnosis of stroke. This revised and updated edition remains the definitive guide to patterns and syndromes in stroke. A comprehensive survey of all types of neurological, neurophysiological and other clinical dysfunction due to stroke, the book is organized to make pattern recognition easier. It contains descriptions of clinical problems encountered in stroke patients and their differential diagnosis, and will enable clinicians to differentiate between possible locations on the basis of symptoms and signs. A companion volume Uncommon Causes of Stroke completes this highly authoritative reference work, which clinicians in neurology will find essential to the understanding and diagnosis of stroke. Julien Bogousslavsky is Professor and Chair in the University Department of Neurology, and Professor of Cerebrovascular Diseases, University of Lausanne, Switzerland. He was Cofounder of the European Stroke Conference and of the journal Cerebrovascular Diseases. Louis R. Caplan is Professor of Neurology at Harvard Medical School and Chief of the Stroke Service, Beth Israel Deaconess Medical Center, Boston. He is Vice-President of the American Neurological Association.

Stroke syndromes Second edition

Edited by

Julien Bogousslavsky University of Lausanne, Switzerland

and

Louis R. Caplan Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA

                                                     The Pitt Building, Trumpington Street, Cambridge, United Kingdom    The Edinburgh Building, Cambridge CB2 2RU, UK 40 West 20th Street, New York, NY 10011-4211, USA 10 Stamford Road, Oakleigh, VIC 3166, Australia Ruiz de Alarcón 13, 28014 Madrid, Spain Dock House, The Waterfront, Cape Town 8001, South Africa http://www. cambridge.org © Cambridge University Press, 1995, 2001 This book is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 1995 Reprinted 1996, 1998 Second edition 2001 Printed in the United Kingdom at the University Press, Cambridge Typeface Utopia 8.5/12pt.

System QuarkXPress™ [  ]

A catalogue record for this book is available from the British Library Library of Congress Cataloguing in Publication data Stroke syndromes / edited by Julien Bogousslavsky, Louis Caplan – 2nd ed. p.

cm.

Includes bibliographical references and index. ISBN 0 521 77142 0 (hb) 1. Cerebrovascular disease – Diagnosis. 2. Diagnosis, Differential. 3. Symptoms. I. Bogousslavsky, Julien. II. Caplan, Louis R. [DNLM: 1. Cerebrovascular Accident – diagnosis. 2. Syndrome. WL 355 S9213735 2000] RC388.5 .S8567 616.8⬘1–dc21

2000 00-058499

ISBN 0 521 77142 0 hardback ISBN 0 521 80258 X boxed set (with Uncommon causes of stroke)

Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Nevertheless, the authors, editors and publisher can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

To Lucie Belime-Laugier and Carl and Bess Caplan. Who have passed on but remain as an eternal inspiration.

To our patients. They have taught us much about stroke, dealing with adversity, courage, and the meaning of health, life, and death. We shall always be in their debt.  

Contents

List of contributors Preface

page x xvii

PA RT I CL I N I C A L M A N I F E S TAT I O N S 11

Stroke onset and courses Haruko Yamamoto, Masayasu Matsumoto, Kazuo Hashikawa and Masatsugu Hori

3

12

Clinical types of transient ischemic attacks Graeme J. Hankey

8

13

Hemiparesis and other types of motor weakness 22 Teresa Pinho e Melo and Julien Bogousslavsky

14

Sensory abnormality Jong Sung Kim

34

15

Cerebellar ataxia Dagmar Timmann and Hans Christoph Diener

48

16

Headache: stroke symptoms and signs Conrado J. Estol

60

17

Eye movement abnormalities Charles Pierrot-Deseilligny

76

18

Cerebral visual dysfunction Jason J.S. Barton and Louis R. Caplan

87

19

Visual symptoms (eye) Shirley H. Wray

111

10

Vestibular syndromes and vertigo Marianne Dieterich and Thomas Brandt

129

11

Auditory disorders in stroke Robert A. Levine and Rudolf Häusler

144

12

Abnormal movements Joseph Ghika and Julien Bogousslavsky

162

vii

viii

Contents

13

Seizures and stroke Anne L. Abbott, Christopher F. Bladin and Geoffrey A. Donnan

14

Disturbances of consciousness and sleep– wake functions Claudio Bassetti

182

PA RT I I VA S C U L A R TO P O G R A PH I C SYNDROMES 29

Arterial territories of human brain Laurent Tatu, Thierry Moulin, Julien Bogousslavsky and Henri Duvernoy

375

30

Superficial middle cerebral artery syndromes Jean-Philippe Neau and Julien Bogousslavsky

405

31

Lenticulostriate arteries Patrick Pullicino

428

32

Anterior cerebral artery John C.M. Brust, Tohru Sawada and Seiji Kazui

439

33

Anterior choroidal artery territory infarcts Philippe Vuadens and Julien Bogousslavsky

451

34

Thalamic infarcts and hemorrhages Alain Barth, Julien Bogousslavsky and Louis R. Caplan

461

35

Caudate infarcts and hemorrhages Chin-Sang Chung, Hye-Seung Lee and Louis R. Caplan

469

192

15

Aphasia and stroke Andrew Kertesz

211

16

Agitation and delirium John C.M. Brust and Louis R. Caplan

222

17

Frontal lobe stroke syndromes Paul J. Eslinger and Raymond K. Reichwein

232

18

Memory loss José M. Ferro and Isabel P. Martins

242

19

Neurobehavioural aspects of deep hemisphere stroke José M. Ferro

252

20

Right hemisphere syndromes Stephanie Clarke

264

21

Poststroke dementia Didier Leys and Florence Pasquier

273

36

Posterior cerebral artery Claudia J. Chaves and Louis R. Caplan

479

22

Disorders of mood behaviour Florence Ghika-Schmid and Julien Bogousslavsky

285

37

Large and panhemispheric infarcts Stefan Schwarz, Stefan Schwab and Werner Hacke

490

23

Agnosias, apraxias and callosal disconnection syndromes Patrik Vuilleumier

38 302

Multiple, multilevel and bihemispheric infarcts Emre Kumral

Muscle, peripheral nerve and autonomic changes Thierry Kuntzer and Bernard Waeber

323

24

25

Dysarthria Paola Santalucia and Edward Feldmann

334

26

Dysphagia and aspiration syndromes Mark J. Alberts and Jennifer Horner-Catt

341

27

Respiratory dysfunction François Vingerhoets and Julien Bogousslavsky

353

28

Clinical aspects and correlates of stroke recovery 363 Marta Altieri, Vittorio Di Piero, Edoardo Vicenzini and Gian Luigi Lenzi

499

39

Midbrain infarcts Marc Hommel and Gérard Besson

512

40

Pontine infarcts and hemorrhages Chin-Sang Chung and Louis R. Caplan

520

41

Medullary infarcts and hemorrhages Bo Norrving

534

42

Cerebellar stroke syndromes Pierre Amarenco

540

43

Extended infarcts in the posterior circulation (brainstem/cerebellum) Barbara E. Tettenborn

557

44

Border zone infarcts E. Bernd Ringelstein and Florian Stögbauer

564

45

Classical lacunar syndromes John M. Bamford

583

Contents

46

Putaminal hemorrhages Kazuo Minematsu and Takenori Yamaguchi

590

47

Lobar hemorrhages Carlos S. Kase

599

48

Intraventricular hemorrhages Peter C. Gates

612

49

Subarachnoid hemorrhage syndromes Jan van Gijn and Gabriel J.E. Rinkel

618

50

Brain venous thrombosis syndromes Caroline Arquizan, Jean-François Meder and Jean-Louis Mas

626

Carotid occlusion syndromes François Nicoli and Julien Bogousslavsky

651

51

52

Cervical artery dissection syndromes Tobias Brandt, Erdem Orberk and Werner Hacke

53

Syndromes related to large artery thromboembolism within the vertebrobasilar system Louis R. Caplan

54

Spinal stroke syndromes Matthias Sturzenegger

Index

660

667 691

705

ix

Contributors

Anne L. Abbott (née Harris) Neurology Department Repatriation Campus Austin and Repatriation Medical Centre Locked Bag 1 Heidelberg West Victoria 3081 Australia Mark J. Alberts Division of Neurology Department of Medicine, PO Box 2900 Duke University Medical Center Durham, NC 27710 USA Marta Altieri Università degli studi di Roma Department of Neurological Science V Cattedra di Clinica Neurologica V. le dell’Università, 30 00185 Rome Italy Pierre Amarenco Neurology Services Saint-Antoine Hospital Rue du Fbg St-Antoine 184 F-75571 Paris France Caroline Arquizan Neurology Services Sainte Anne Hospital 1 Rue Cabanis 75674 Paris Cedex 14 France

x

Contributors

John M. Bamford St James’s University Hospital Beckett Street Leeds LS9 7TF UK

Tobias Brandt Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany

Alain Barth Inselspital Neurological Clinic and Poliklinik 3010 Berne Switzerland

John C.M. Brust Department of Neurology Harlem Hospital Center 506 Lenix Avenue New York, NY 10037 USA

Jason J.S. Barton Beth Israel Deaconess Medical Center East Campus 330 Brooklyn Avenue Boston, MA 02215 USA Claudio Bassetti Inselspital Hospital of L’lle Neurological Clinic and Poliklinik CH 3010 Bern-Schweiz Switzerland Gérard Besson Central University Hospital of Grenoble Department of Clinical and Biological Neurosciences Neurological Services BP 217X 38043 Grenoble Cedex 9 France

Louis R. Caplan Beth Israel Deaconess Medical Center East Campus 330 Brooklyn Avenue Boston, MA 01125 USA Claudia J. Chaves Beth Israel Deaconess Medical Center East Campus 330 Brooklyn Avenue Boston, MA 01125 USA Chin-Sang Chung Department of Neurology Samsung Medical Center Sungkyunkwan University School of Medicine 50 ILWON-dong Kangnam-ku Seoul, South Korea 135–710

Christopher F. Bladin Neurology Department Box Hill Hospital Nelson Road Box Hill, Victoria 3128 Australia

Stephanie Clarke Division of Neuropsychology CHUV-Nestle CH-1011 Lausanne Switzerland

Julien Bogousslavsky Department of Neurology University of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland

Hans C. Diener Neurological Clinic University Clinic Essen Hufelandstr. 55 D-45122 Essen Germany

Thomas Brandt Department of Neurology Klinikum Grosshadern Ludwig Maximilians University Munich Marchioninistr. 15 D-81377 Munich 70 Germany

Marianne Dieterich Department of Neurology Klinikum Grosshadern Ludwig Maximilians University Munich Marchioninistr. 15 D-81377 Munich 70 Germany

xi

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Contributors

Geoffrey A. Donnan Department of Neurology and Neurosciences Neurosciences Building Repatriation Campus Austin and Repatriation Medical Centre Locked Bag 1 Heidelberg West Victoria 3081 Australia Henri Duvernoy Anatomy Laboratory Central University Hospital Jean Minjoz Hospital 25030 Besancon France Paul J. Eslinger Hershey Medical Center 500 University Drive Hershey, PA 17033 USA Conrado J. Estol Centre for Neurological Treatment and Rehabilitation Pacheco de Melo 1860 Buenos Aires 1128 Argentina Edward Feldmann Department of Clinical Neurosciences Brown University School of Medicine 110 Lockwood Street 324 Providence, RI 02903 USA José M. Ferro University of Lisbon Faculty of Medicine Av. Prof. Egas Moniz 1699 Lisbon Codex Portugal Peter C. Gates Department of Neuroscience Greelong Hospital Geelong Victoria 3220 Australia

Joseph Ghika Department of Neurology University of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland Florence Ghika-Schmid Department of Neurology University of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland Werner Hacke Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany Graeme J. Hankey Royal Perth Hospital Neurology Box X2213 GPO Perth 6847 Western Australia Kazuo Hashikawa Division of Strokology Department of Internal Medicine and Therapeutics (A8) Osaka University Graduate School of Medicine 2-2, Yamadaoko, Suita Osaka 565-0871 Japan Rudolf Häusler Department of ENT Department of Otorhinolaryngology Head and Neck and Cranio-MaxilloFacial Surgery University Hospital of Berne University of Berne 3010 Berne Switzerland

Contributors

Marc Hommel Central University Hospital of Grenoble Department of Clinical and Biological Neurosciences Neurological Services BP 217X 38043 Grenoble Cedex 9 France Masatsugu Hori Division of Strokology Department of Internal Medicine and Therapeutics (A8) Osaka University Graduate School of Medicine 2-2, Yamadaoko, Suita Osaka 565-0871 Japan Jennifer Horner-Catt Department of Speech and Language Therapy University of Canterbury Private Bag 4800 Christchurch New Zealand Carlos S. Kase Department of Neurology Boston University School of Medicine 715 Albany Street Robinson Building 605 Boston, MA 02118-2526 USA Seiji Kazui National Cardiovascular Center Fujishirodai 5-7-1, Suita Osaka 565-8565 Japan Andrew Kertesz St Jospeh’s Health Centre Department of Clinical Neurological Sciences University of Western Ontario 268 Grosvenor Street London, Ontario Canada NA 4V2

Jong Sung Kim Department of Neurology Asan Medical Center Song-Pa PO Box 145 Seoul 138-600 South Korea Emre Kumral Stroke and Neuropsychology Unit Department of Neurology School of Medicine Ege University Bornova Izmir 35100 Turkey Thierry Kuntzer Service de Neurologie CHUV BH 07/306 CH-1011 Lausanne Switzerland Hye-Seung Lee Department of Neurology Samsung Medical Center Sungkyunkwan University School of Medicine 50 ILWON-dong Kangnam-ku Seoul South Korea 135-710 Gian Luigi Lenzi Department of Neurological Sciences University of Rome La Sapienza Via Cavour, 325 00184 Rome Italy Robert A. Levine Eaton Laboratory of Auditory Physiology Massachusetts Eye and Ear Infirmary Harvard University Boston, MA USA Didier Leys Neurology Services Salengro Hospital Rue Oscar Lambret 59037 Lille France

xiii

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Contributors

Isabel P. Martins Department of Neurology Santa Maria Hospital Av. Prof. Egas Moniz P-1699 Lisbon Portugal

François Nicoli Neurology Services Pr. JL Gastaut Sainte Marguerite Hospital F-13009 Marseilles France

Jean-Louis Mas Neurology Services Centre Raymond Garcin-1 CHSA Sainte Anne Hospital 1 Rue Cabanis 75674 Paris Cedex 14 France

Bo Norrving Department of Neurology University Hospital S-22185 Lund Sweden

Masayasu Matsumoto Division of Strokology Department of Internal Medicine and Therapeutics (A8) Osaka University Graduate School of Medicine 2-2, Yamadaoko, Suita Osaka 565-0871 Japan Jean-François Meder Radiology Services Centre Raymond Garcin-CHSA Sainte Anne Hospital 1 Rue Cabanis 75674 Paris Cedex 14 France Kazuo Minematsu Cerebrovascular Division Department of Medicine National Cardiovascular Center Fujishirodai 5-7-1, Suita Osaka 565-8565 Japan Thierry Moulin Neurology Services Central University Hospital Jean Minjoz Hospital 25030 Besancon France Jean-Philippe Neau Clinical Neurology Services Jean Bernard Hospital BP 577 86021 Poitiers France

Erdem Orberk Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany Florence Pasquier University of Lille Lille France Vittorio Di Piero Università degli studi di Roma Department of Neurological Science V Cattedra di Clinica Neurologica V. le dell’Università, 30 00185 Rome Italy Charles Pierrott-Deseilligny Clinique Paul Castaigne Clinic Neurology Services Hospitals Group Pitié-Salpêtrière 47–83 Boulevard de l’Hôpital 75651 Paris Cedex 13 France Teresa Pinho e Melo University of Lisbon Neurology Clinic Santa Maria Hospital Av. Prof Egas Moniz P-1699 Lisbon Portugal Patrick Pullicino Department of Neurology Buffalo General Hospital 100 High Street Buffalo, NY 14203 USA

Contributors

Raymond K. Reichwein Section of Neurology H037 Hershey Medical Center 500 University Drive Hershey, PA 17033 USA E. Bernd Ringelstein Neurology Clinic Westfälische Wilhelms-University Münster Albert Schweitzer Str. 33 D-48129 Münster Germany Gabriel J.E. Rinkel University Department of Neurology University Medical Centre Box 85500 3508 GA Utrecht The Netherlands Paolo Santalucia Department of Clinical Neurosciences Brown University School of Medicine 110 Lockwood Street 324 Providence, RI 02903 USA Tohru Sawada National Cardiovascular Center Fujishirodai 5-7-1, Suita Osaka 565-8565 Japan Stefan Schwab Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany Stefan Schwarz Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany Florian Stögbauer Neurology Clinic Westfälische Wilhelms-University Münster Albert Schweitzer Str. 33 D-48129 Münster Germany

Matthias Sturzenegger Inselspital Neurological Clinic and Policlinic 3010 Berne Switzerland Laurent Tatu Neurology Services Central University Hospital Jean Minjoz Hospital 25030 Besancon France Barbara E. Tettenborn Kantonsspital St Gallen CH-9007 St Gallen Switzerland Dagmar Timmann Neurological Clinic Universitätsklinikum Essen Hufelandstr. 55 D-45122 Essen Germany Jan van Gijn Department of Neurology University Medical Centre PO Box 85500 3508 GA Utrecht The Netherlands Edoardo Vicenzini Università degli studi di Roma Department of Neurological Science V Cattedra di Clinica Neurologica V. le dell’Università, 30 00185 Rome Italy François Vingerhoets Department of Neurology, University of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland Philippe Vuadens Department of Neurology Unversity of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland

xv

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Contributors

Patrik Vuilleumier University of Davis Neurology Department 127 VA Medical Center Building E 150 Muir Road Martinez, CA 94553 USA

Takenori Yamaguchi Cerebrovascular Division Department of Medicine National Cardiovascular Center Fujishirodai 5-7-1, Suita Osaka 656-8565 Japan

Bernard Waeber Division of Clinical Pathophysiology CHUV BH 19/640 CH-1011 Lausanne Switzerland

Haruko Yamamoto Pharmaceuticals and Medical Devices Evaluation Center National Institute for Health Services MHW 3-8-21 Toranomon Minato-ku Tokyo 105-8409 Japan

Shirley H. Wray Harvard Medical School Department of Neurology Director, Unit for Neurovisual Disorders Massachusetts General Hospital Boston, MA 02114 USA

Preface

The success of Stroke syndromes over the 5 years elapsed since its publication is the reason for this second edition. Indeed, numerous comments made to us by colleagues, from trainees to international experts, have confirmed to us the interest and importance of a book deeply rooted in the clinical practice with stroke patients – especially in the era of starwars medicine aiming to help examination of these patients and facilitate diagnosis of their condition. The best compliment to medical teachers is when their work is liked by students and junior residents. However, we thought that there was room for improvement, and we have tried to reshape Stroke syndromes, so that some omissions have been filled, and so that it is still more userfriendly. Besides, we have divided the initial book into two volumes, the first focusing on syndromes and their brain and vascular correlates, the second on the particular vascular etiologic syndromes which formed Part III of the first edition. However, the book, still meant as a guide, remains what it was, ‘a bound source and store of patterns and syndromes for non-experts in stroke to refer to when they encounter an unfamiliar pattern’, of three different types: ii(i) patterns of symptoms and signs; i(ii) lesion patterns found in patients with infarcts and hemorrhages in various loci and various vascular territories; (iii) patterns and syndromes that occur in unusual conditions that are known to cause stroke but that are not encountered very often. We thank all authors who have agreed to adapt, rewrite and modify their initial chapters, as well as the numerous new contributors. Five years ago, we were grateful for the availability of fax machines, allowing rapid Lausanne–Boston communications, while now we are grateful for the availability of email; we also wrote that, for stroke management, ‘the window of opportunity is short, probably less than

xvii

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Preface

24 hours, while we know today that it is below 6 hours in most instances. Many other advances have been achieved. With this in mind, we hope that this completely updated and rewritten edition will continue to be of help in the care of patients with stroke. Julien Bogousslavsky, Lausanne Louis R. Caplan, Boston

Part I.i

Clinical manifestations

1

Stroke onset and courses Haruko Yamamoto, Masayasu Matsumoto, Kazuo Hashikawa and Masatsugu Hori Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan

Introduction The onset and early natural course of stroke gives critical information about the stroke mechanism (Caplan, 1993). For example, the deficit which is maximal at onset and not associated with headache is most compatible with an embolic mechanism, while a stuttering onset with improvement followed by worsening in the deficit would be against cerebral hemorrhage, but most compatible with a thrombotic process. The gradual development of a progressive focal deficit, accompanied by gradually developing symptoms of increased intracranial pressure, may suggest cerebral hemorrhage (Caplan, 1993). Despite the clinical importance of understanding the time course, there have not been many stroke databanks referring to it. In the Harvard Cooperative Stroke Registry, speed of onset was classified into four subtypes, and recorded for each type of stroke (Mohr et al., 1978). A similar classification of speed of onset has been used in the Lausanne Stroke Registry (Bogousslavsky et al., 1988). Table 1.1 shows the speed of onset for each subtype of stroke reported in these two registries. One may see the similarity of speed of onset in each subtype of stroke between the data from the two stroke registries, despite the different criteria to identify stroke subtype.

Onset and time course in early phase of stroke Ischemic stroke Anterior circulation damage Jones and Millikan (1976) reported the temporal profile of 179 patients with acute carotid ischemic stroke. In their study, 39% of patients had sudden onset and no change in the neurological deficit during the first 7 days after the

onset, while 35% of the patients showed improvement, 22% showed progression or remission and relapse of deficit, and 4% experienced later worsening of neurological deficit after a stable profile of at least 2 days. According to them, if hemiplegia develops within 3 hours of the onset and persists for 36 hours, there is more than a 90% chance that the patient will have a permanent incapacitating motor deficit. They also said that the combination of hemiplegia and any decrease in consciousness on admission predicted poor prognosis. However, they did not refer to the cause of stroke. Both the Harvard Cooperative Stroke Registry and the Lausanne Stroke Registry showed that sudden onset was observed most frequently in embolic infarction, followed by atherosclerotic infarction and lacunar infarction (see Table 1.1). There are reports which analyse speed of onset among infarction in a certain cerebral artery territory. In a report of 27 patients with anterior cerebral artery (ACA) infarction, 74% of them had sudden onset and the rest of them had smooth progressive onset over a few hours to 3 weeks (Bogousslavsky & Regli, 1990). The dominance of sudden onset may be related to the frequent embolic phenomenon from the internal carotid artery (ICA) or from the heart observed in 63% of the patients, although a study from Japan which evaluated angiographic abnormalities in 17 patients with solitary infarction in ACA territory revealed atherothrombosis as the cause of infarction in 59% (Kazui et al., 1993). Another paper from the Lausanne Stroke Registry mentioned large infarction in the middle cerebral artery (MCA) territory (Heinsius et al., 1998). According to this report, 73% of patients with large infarcts in MCA territory (infarction exceeding any one of the three main portions of MCA, that is, anterior superficial, posterior superficial, or deep white matter portion) had sudden onset of stroke. However, 40% of patients with infarction due to ICA dissection had

3

4

H. Yamamoto et al.

Table 1.1. Time course of onset for each type of stroke Speed of onset

Sudden

Stepwise or stutteringa

Smooth or graduala

Fluctuations

Atherosclerosis

HCSR LSR

40 66

34 27

13 —

13 7

Cardiac embolism

HCSR LSR

79 82

11 13

5 —

5 5

Lacune

HCSR LSR

38 54

32 40

20 —

10 6

Cerebral hemorrhage

HCSR LSR

34 44

3 52

63 —

0 4

Notes: Data are percentage of row. HCSR: Harvard Cooperative Stroke Registry, LSR: Lausanne Stroke Registry. a In LSR, only one subtype ‘progressive onset’ was applied for the two subtypes of ‘stepwise onset’ and ‘smooth onset’ in HCSR. Sources: Mohr et al. (1978); Bogousslavsky et al. (1988).

progressive onset, which was a significantly higher frequency compared with patients without dissection. Patients with ICA occlusion also showed higher frequency of progressive (34%) onset compared to patients without occlusion. Another paper from the Lausanne Stroke Registry about multiple infarction in the anterior circulation showed that 37 of 40 patients had sudden onset (Bogousslavsky et al., 1996). They reported various presumed causes of infarction, including major stenosis of ipsilateral ICA, cardiogenic embolism, granulomatous angitis, and ICA dissection. The above mentioned may suggest a tendency of sudden onset for infarction with embolic cause and of gradual or progressive onset for infarction with vascular occlusive lesion. Yamawaki et al. (1998) studied retrospectively 523 consecutive patients with thrombotic infarction who were admitted in a stroke care unit within 7 days after onset, and showed that progressive neurological deterioration occurred in 18% of patients, which was more frequent in atherothrombotic infarction located in the corona radiata or pons compared with lacunar infarction. Yamamoto et al. also revealed the significantly higher frequency of progressive neurological deterioration in patients with large artery atherosclerosis compared to those with lacunar infarction (Yamamoto et al., 1998). Watershed infarction occurs in the border zones between two main artery territories after severe hypotension. It may also occur under the existence of severe occlusive lesion in major arteries including ICA and MCA. A study from the Lausanne Stroke Registry about unilateral watershed infarction in the anterior circulation reported that the onset was usually immediately complete (65%),

progressed briefly (31%), or fluctuated over 24 hours (4%) in 51 patients (Bogousslavsky & Regli, 1986). More interestingly, 29% of the patients had preceding ipsilateral transient ischemic attacks (TIAs).

Posterior circulation damage Non-sudden onset or progressive neurological deterioration has been found more frequently among infarction in posterior circulation than that in anterior circulation. Jones et al. (1980) reported 20 (54%) of 37 patients with posterior circulation infarction had non-sudden onset, while only 48 (27%) of 179 patients with anterior circulation infarction had non-sudden onset. They observed that it took a long time (up to 96 hours), for stabilization of the clinical symptoms in patients with posterior circulation infarction. A similar result was reported by another study (Patrik et al., 1980). In their paper, 56.4% of patients with posterior circulation infarction had progressing or fluctuating onset. One of their patients had progressive ataxia over 7 days. They also observed progressive neurologic impairment after the original deficit had been stabilized for 24 hours in a few patients. The stable interval time was up to 7 days. They warned that instability and late exacerbation after the stable interval time could be expected for 7 days after onset. Vuilleumier et al. (1995) studied 28 patients with infarction in the lower brainstem. In their paper, 46% of the patients had stepwise neurological deterioration during up to 14 days after the onset. Before the onset, 46% of all patients experienced one or several warning TIAs, which were imbalance and/or vertigo. A report of 45 patients with basilar artery embolism

Stroke onset and courses

found that most of them had sudden onset (41 patients, 91%), and 15 of them had complete loss of consciousness (Schwarz et al., 1997). However, four patients had slowly progressive onset despite proven embolic etiology. Stroke in posterior circulation is rather rare territory, but Neau and Bogousslavsky (1996) reported posterior choroidal artery territory infarction. According to them, ten patients, which was 1.5% of 740 patients with posterior circulation infarction, had ischemic lesion in the posterior choroidal artery territory. None of the patients had TIA prior to their infarcts. Stroke was stabilized within a few minutes in nine of ten patients, and progressed over half an hour in one patient. Small artery disease was the most common presumed cause of infarction.

Hemorrhagic stroke Neurological deterioration may be often observed in patients with cerebral hemorrhage. In a study from the Lausanne Stroke Registry, the rate of progressive deficit after onset was similar between cerebral infarction and cerebral hemorrhage, and in both was significantly higher than the rate of progressive deficit in cardiogenic cerebral embolism (Yamamoto et al., 1998). A study of 204 patients with intracerebral hemorrhage, who underwent an initial CT scan within 48 hours and a repeat CT within 120 hours of the onset, reported that enlargement of hematoma was common in the hyperacute stage but seemed extremely rare after 24 hours of onset. Clinical deterioration was observed significantly more frequently in the patient group with hematoma enlargement than that without (the odds ratio; 11.7, 95% confidence intervals; 5.0–27.8) (Kazui et al., 1996). A similar result was reported by another study of 103 patients with cerebral hemorrhage (Brott et al., 1997).

Progressive stroke Deterioration of neurological symptoms in the acute phase after the onset is not rare in patients with ischemic or hemorrhagic stroke. It has attracted clinicians’ attention for more than 40 years (Millikan & Siekert, 1955a,b), and called various terms, such as progressive stroke, stroke-inprogression, or stroke-in-evolution. However, the definition of ‘progressive stroke’ has never been generally accepted. Some reports used certain stroke scales, others chose clinical definition (Gautier, 1985). Trials for revealing risk factors, which may predict progressive stroke, have also reached to variable and controversial results. A report investigated predictors of progressive stroke in each stroke

subtype group, and revealed that different risk factors were related to progressive stroke in different subtype groups, that is, infarction in posterior circulation territory and reduced level of consciousness for large-artery atherosclerosis, while at age younger than 65, hypertension, lack of preceding TIA, reduced level of consciousness, and infarction not in superficial anterior circulation for lacunar infarction (Yamamoto et al., 1998). Another report evaluated only patients with supratentorial lacunar infarction in the internal capsule or the corona radiata, and found that diabetes mellitus and severity of motor deficit on admission were related independently to neurological deterioration (Nakamura et al., 1999). At this point, however, it remains difficult to predict progressive stroke from clinical factors alone. There have been studies trying to reveal mechanisms involved in progressive stroke. Thrombus propagation, narrowing of arterial stenosis, development of brain edema, etc. have been suggested as causes. One study showed sequential changes of angiographic findings, including arterial stenosis or thrombus displacement in patients who had progressive stroke (Irino et al., 1983), while other studies suggested that insufficient blood supply caused by poor collateral circulation development might commonly contribute (Fisher & Garcia, 1996; Toni, et al., 1995). Recently, delayed neuronal death, mediated by the accumulation of glutamate and other excitatory amino acids in extracellular spaces, was suggested to play a role in experimental focal ischemia (Asplund, 1993). A recent study of 128 patients with ischemic hemispheric stroke found that concentrations of glutamate in plasma and cerebrospinal fluid (CSF) within the first 24 hours from stroke onset were significantly higher in patients presented with progressive stroke than in those with stable stroke (Castillo et al., 1997). This study also revealed that a plasma glutamate concentration of more than 200 ␮mol/l and a CSF glutamate concentration of more than 8.2 ␮mol/l were independently and significantly associated with progression of neurological deficit, and both of them were good predictors of progression (positive predictive value; 97% for plasma, 94.3% for CSF). This study also found that high body temperature at admission was an independent risk factor for progression within the first 48 hours of ischemic hemispheric stroke. However, it is open for future research whether these findings could explain progression of neurological deficit of other subgroups of stroke, including lacunar infarction and cerebral hemorrhage. Progressive stroke is always a sign of poor outcome in any subtypes of stroke, and early prediction and effective therapy would be mandatory.

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H. Yamamoto et al.

Early spontaneous improvement In acute phase of stroke, not only deterioration but also amelioration of neurological deficit may be observed, although it would never occur in cerebral hemorrhage. In particular, this may be found in cases of cardiogenic brain embolism, usually within minutes to hours, in the form of abrupt onset of a major hemispheric syndrome followed by dramatic improvement or complete disappearance of the symptoms. Mohr et al. (1986) called this phenomenon ‘a spectacular shrinking deficit’. They assumed the mechanism to be rapid migration of an embolus from a large artery of the carotid system to its distal branches, and emphasized the phenomenon as a sign of cardiogenic embolism. A study of 118 patients with an initial major hemispheric syndrome found that 14 (12%) of them had spectacular shrinking deficit, and all but one were compatible for cardiogenic brain embolism (Minematsu et al., 1992). According to this study, recovery began from 15 minutes to 24 hours after stroke onset, and earlier onset of recovery, which means shorter duration of a major hemispheric syndrome, was significantly related to better outcome. Patients with recovery tended to be young, and had significantly fewer risk factors. The study also revealed more distal occlusion of intracerebral arteries in patients with recovery compared to those without recovery, suggesting distal migration of embolus. Another recent study investigated cerebral blood flow in acute phase of ischemic stroke with single-photon emission computed tomography (SPECT) (Barber et al., 1998). In this study, repeated SPECT images revealed that early reperfusion observed between the first SPECT scan (9.2 hours after onset of stroke) and the second SPECT scan (44.3 hours after onset of stroke) was associated with better outcome and smaller final infarct size, while non-nutritional or luxury reperfusion was not associated with either an improved or an adverse outcome. It may explain the difficulty of the timing of thrombolysis for tissue salvage. Toni et al. (1998) also suggested the existence of individual time frames for tissue recovery in their study of spontaneous improvement after ischemic stroke with serial transcranial Doppler ultrasonography. These studies agreed with the point that spontaneous neurological improvement in the acute phase may usually lead to better outcome.

Transient ischemic attack Reports of the frequency with which TIA patients suffer cerebral infarction range from 2% to 62%. When assessed

retrospectively, the range is from 9% to 74%. About 36% have infarction within the month and 50% within 12 months of onset of TIAs. It is estimated that about onethird of those who suffer recurrent TIAs continue to have attacks without developing permanent disability; another third eventually have cerebral infarction, and in the remainder the attacks stop spontaneously. So, TIA could be a clinical course before stroke. Five-year mortality rates in TIA patients average about 20% to 25%. However, the majority of causes of death are secondary to myocardial rather than to cerebral infarction. Prognosis of TIA depends on its etiology and concomitant diseases. In younger populations, etiologies such as valvular and congenital heart disease and hypotension are major contributors to TIA, while in the elderly, hypertension and atherosclerosis are major contributors to risk in the course and prognosis is poorest. In a report of 1093 patients admitted with TIA, repetitive attacks (three or more attacks in 24 hours) in the presumed subcortical region occurred in 50 patients (4.5% of all TIAs). The episodes were usually clustered in a relatively brief interval, for example, five episodes in 3 hours, and the maximum number of events was 13. However, in 33 patients with the repetitive attacks who underwent angiographic study or duplex ultrasound of ICA, only three patients had significant stenotic change in ICA. The attacks were resistant to various forms of therapies, including hemodilution with plasma expanders, anticoagulation with intravenous heparin, and antithrombotic medication with aspirin. Twenty-one patients (42%) developed a fixed neurological deficit, although most of them presented typical lacunar syndrome (Donnan et al., 1993). A study of 47 patients with repetitive TIAs presenting acutely with repetitive symptoms indicative of anterior circulation ischemia reported that 55% of all patients were found to have anatomically significant disease. In particular, 85% of the patients with signs or symptoms suggestive of cortical ischemia, amaurosis fugax, or both had ‘positive’ angiogram (75% or more carotid stenosis, less than 75% carotid stenosis associated with ulceration, or 75% or more middle cerebral stenosis) (Rothrock et al., 1988).

Conclusion Type of onset and early clinical course may contain rich information about pathophysiology of stroke. Understanding the stroke dynamics would be necessary for active treatment in the acute phase, including thrombolysis.

Stroke onset and courses

iReferencesi Asplund, K. (1993). Deterioration of acute stroke. In Thrombolytic Therapy in Acute Ischemic Stroke II, ed. G. J.del Zoppo, E. Mori & W. Hacke, pp. 119–28. Berlin: Springer-Verlag. Barber, P.A., Davis, S.M., Infeld, B. et al. (1998). Spontaneous reperfusion after ischemic stroke is associated with improved outcome. Stroke, 29, 2522–8. Bogousslavsky, J. & Regli, F. (1986). Unilateral watershed cerebral infarcts. Neurology, 36, 373–7. Bogousslavsky, J. & Regli, F. (1990). Anterior cerebral artery territory infarction in the Lausanne Stroke Registry. Clinical and etiologic patterns. Archives of Neurolology, 47, 144–50. Bogousslavsky, J., van Melle, G., & Regli, F. (1988). The Lausanne Stroke Registry: analysis of 1000 consecutive patients with first stroke. Stroke, 19, 1083–92. Bogousslavsky, J., Bernasconi, A., & Kumral, E. (1996). Acute multiple infarction involving the anterior circulation. Archives of Neurology, 53, 50–7. Brott, T., Broderick, J., Kothari, R. et al. (1997). Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke, 28, 1–5. Caplan, L.R. (1993). Stroke. A Clinical Approach, 2nd edn. Stoneham, MA: Butterworth-Heinemann. Castillo, J., Davalos, A., & Noya, M. (1997). Progression of ischaemic stroke and excitotoxic aminoacids. Lancet, 349, 79–83. Donnan, G.A., O’Malley, R.N., Quang, L., Hurley, S., & Bladin, P.F. (1993). The capsular warning syndrome: pathogenesis and clinical features. Neurology, 43, 957–62. Fisher, M. & Garcia, J.H. (1996). Evolving stroke and the ischemic penumbra. Neurology, 47, 884–8. Gautier, J.C. (1985). Stroke-in-progression. Stroke, 16, 729–33. Heinsius, T., Bogousslavsky, J., & van Melle, G. (1998). Large infarcts in the middle cerebral artery territory. Etiology and outcome patterns. Neurology, 50, 341–50. Irino, T., Watanabe, M., Nishide, M., Gotoh, M., & Tsuchiya, T. (1983). Angiographical analysis of acute cerebral infarction followed by ‘cascade’-like deterioration of minor neurological deficits: what is progressing stroke? Stroke, 14, 363–8. Jones, H.R. & Millikan, C.H. (1976). Temporal profile of acute cerebral infarction in the distribution of the internal carotid artery. Stroke, 7, 64–71. Jones, H.R., Millikan, C.H., & Sandok, B.A. (1980). Temporal profile (clinical course) of acute vertebrobasilar system cerebral infarction. Stroke, 11, 173–7. Kazui, S., Sawada, T., Naritomi, H., Kuriyama, Y., & Yamaguchi, T. (1993). Angiographic evaluation of brain infarction limited to the anterior cerebral artery territory. Stroke, 24, 549–53. Kazui, S., Naritomi, H., Yamamoto, H., Sawada, T., & Yamaguchi, T. (1996). Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke, 27, 1783–7.

Millikan, C.H., & Siekert, R.G. (1955a). Studies in cerebrovascular disease, I: the syndrome of intermittent insufficiency of the basilar arterial system. Proceedings of Staff Meetings Mayo Clinic, 30, 61–8. Millikan, C.H. & Siekert, R.G. (1955b). Studies in cerebrovascular disease, IV: the syndrome of intermittent insufficiency of the carotid arterial system. Proceedings of Staff Meetings Mayo Clinic, 30, 186–91. Minematsu, K., Yamaguchi, T., & Omae, T. (1992). ‘Spectacular shrinking deficit’: rapid recovery from a major hemispheric syndrome by migration of an embolus. Neurology, 42, 157–62. Mohr, J.P. & Barnett, H.J.M. (1986). Classification of ischemic strokes. In Stroke: Pathophysiology, Diagnosis, and Management, ed. H.J.M. Barnett, B. M.Stein, J.P. Mohr, & F.M.Yatsu, vol 1, pp. 281–91. New York: Churchill Livingston. Mohr, J.P., Caplan, L.R., Melski, J.W. et al. (1978). The Harvard Cooperative Stroke Registry: a prospective registry. Neurology, 28, 754–62. Nakamura, K., Saku, Y., Ibayashi, S., & Fujishima, M. (1999). Progressive motor deficits in lacunar infarction. Neurology, 52, 29–33. Neau, J-P. & Bogousslavsky, J. (1996). The syndrome of posterior choroidal artery territory infarction. Annals in Neurology, 39, 779–88. Patrick, B.K., Ramirez-Lassepas, M., & Snyder, B.D. (1980). Temporal profile of vertebrobasilar territory infarction. Prognostic implications. Stroke, 11, 643–8. Rothrock, J.F., Lyden, P.D., Yee, J., & Wiederholt, W.C. (1988). ‘Crescendo’ transient ischemic attacks: clinical and angiographic correlations. Neurology, 38, 198–201. Schwarz, S., Egelhof, T., Schwab, S., & Hacke, W. (1997). Basilar artery embolism. Clinical syndrome and neuroradiologic patterns in patients without permanent occlusion of the basilar artery. Neurology, 49, 1346–52. Toni, D., Fiorelli, M., Gentile, M. et al. (1995). Progressing neurological deficit secondary to acute ischemic stroke: a study on predictability, pathogenesis and prognosis. Archives of Neurology, 52, 670–5. Toni, D., Fiorelli, M., Zanette, E.M. et al. (1998). Early spontaneous improvement and deterioration of ischemic stroke patients. A serial study with transcranial Doppler ultrasonography. Stroke, 29, 1144–8. Vuilleumier, P., Bogousslavsky, J., & Regli, F. (1995). Infarction of the lower brainstem. Clinical, aetiological and MRI-topographical correlations. Brain, 118, 1013–25. Yamamoto, H., Bogousslavsky, J., & van Melle, G. (1998). Different predictors of neurological worsening in different causes of stroke. Archives of Neurology, 55, 481–6. Yamawaki, T., Yanagimoto, S., Kinugawa H., & Naritomi, H. (1998). Subtype and location in progressing stroke. Cerebrovascular Disease, 8(4), 40 (Abstract).

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Clinical types of transient ischemic attacks Graeme J. Hankey Department of Neurology, Royal Perth Hospital and University of Western Australia

Definition of transient ischemic attacks (TIAs) A transient ischemic attack of the brain or eye (TIA) is a clinical syndrome characterized by an acute loss of focal brain or monocular function with symptoms lasting less than 24 hours and which is thought to be due to inadequate cerebral or ocular blood supply as a result of low blood flow (hypotension), arterial thrombosis or embolism associated with disease of the arteries, heart or blood (Hankey & Warlow, 1994). Focal symptoms are those which allow clinicoanatomical correlation (Table 2.1), whereas non-focal symptoms are not anatomically localizing and are therefore not usually TIAs (Table 2.2). The distinction between focal and non-focal neurological symptoms has a grey area, however; sensory and motor disturbances in a pseudo-radicular pattern (such as a wrist drop or tingling in two or three fingers) probably reflect focal neurological dysfunction (Youl et al., 1991; Bassetti et al., 1993; Kim, 1996); so may cognitive changes but these can be difficult to characterize and quantify and are usually not considered as focal neurological symptoms. The symptoms of TIAs are usually ‘negative’ in quality, representing a loss of function (e.g. loss of sensation, power, vision, etc.). If different parts of the body (e.g. face, upper limb and lower limb) are affected, the symptoms usually start at the same time and do not intensify, spread or ‘march’; i.e. they are maximal at onset. The symptoms usually resolve slowly, but completely, within about 15 to 60 minutes (Pessin et al., 1977; Bogousslavsky et al., 1986; Levy, 1988; Werdelin & Juhler, 1988; Dennis, 1988). Sometimes, however, they last longer – by definition not more than 24 hours. Episodes of transient monocular blindness (amaurosis fugax (AFx)) tend to be briefer, lasting less than 5 minutes in most cases, than

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transient ischemic attacks of the brain (Hankey & Warlow, 1994). The difference in duration of attacks may have several explanations, all of which are speculative. Following symptomatic recovery, a few physical signs such as reflex asymmetry or an extensor plantar response, which are not important functionally and are therefore not noticed by the patient, may be elicited in about 5% of patients (Hankey et al., 1991), depending on when the patient is examined after the resolution of symptoms, on the thoroughness of the examination, and on the competence of the examiner. Cranial computerized tomography (CT) or magnetic resonance imaging (MRI) may also reveal evidence of infarction in an area of the brain relevant to the transient symptoms (Dennis et al., 1990; Hankey & Warlow, 1994); the proportion of TIA/ischemic stroke patients with an appropriate infarct on CT scanning gradually rises with the duration of symptoms, from 10% with attacks under 30 minutes, to 40% with symptoms lasting 1–6 weeks (Koudstaal et al., 1992). The only factor which distinguishes a TIA from a mild ischemic stroke is the duration of the symptoms of focal neurological dysfunction (i.e. less or more than 24 hours). Otherwise, patients with TIA and mild ischemic stroke are qualitatively the same; they are of similar age and sex, have a similar prevalence of coexistent vascular risk factors (and probably therefore pathogenesis), share the same longterm prognosis for serious vascular events, and describe qualitatively similar clinical symptoms (Koudstaal et al., 1992).

Clinical symptoms and types of TIAs The symptoms of loss of function of a particular part of the brain or eye due to regional ischemia are determined by the site of ischemia (and therefore the site of the arterial

Clinical types of transient ischemic attacks

Table 2.1. Focal neurological and ocular symptoms

Table 2.2. Non-focal neurological symptoms

Motor symptoms Weakness or clumsiness of one side of the body, in whole or in part Simultaneous bilateral weaknessa Difficulty swallowinga

Generalized weakness and/or sensory disturbance Faintness and/or imbalance Altered consciousness or fainting, in isolation or with impaired vision in both eyes Incontinence of urine or feces Confusion or memory disturbance A spinning sensationa Difficulty swallowinga Slurred speecha Double visiona Loss of balancea

Speech/language disturbances Difficulty understanding or expressing spoken language Difficulty reading or writing Slurred speecha Difficulty calculating Sensory symptoms Somatosensory Altered feeling on one side of the body, in whole or in part Visual Loss of vision in one eye, in whole or in part Loss of vision in the left or the right half of the visual field Bilateral blindness Double visiona Vestibular A spinning sensationa Note: a In isolation these symptoms do not necessarily indicate transient focal cerebral ischemia.

occlusion), the degree of ischemia, the duration of ischemia (which depends on the capacity of the collateral blood supply to perfuse the ischemic area and the rate at which the occluded vessel is recanalized), the activities in which the patient is engaged at the time of the ischemic event, the patient’s recall of the event and ability to communicate it, and the quality of interrogation by the clinician. Therefore, the clinical manifestations of focal brain or eye ischemia, or clinical ‘types’ of TIA, are variable (Table 2.3). As many hours of wakefulness are spent in an alert state with eyes open, a keen sensorium, an upright posture, and often speaking or reading, it is not surprising that most of the symptoms that TIA patients experience are a loss of motor, somatosensory, visual or speech function. Other, more transient activities, such as swallowing and calculation, are less frequently reported as being affected. Presumably TIAs, like strokes, occur during sleep and the patient is unaware of them and there are no sequelae other than perhaps CT scan evidence of infarction if a scan is done for some other reason months or years later. Although TIAs often occur only once, they may recur, and recur frequently up to several times a day (Dennis,

Note: a If these symptoms occur in combination, or with focal neurological symptoms, they may indicate a transient focal cerebral ischemia.

1988; Hankey et al., 1991, 1992). Recurrent TIAs may sometimes be remarkably stereotyped or they may be quite different in terms of the ‘type’ of attack (i.e. the nature of the symptoms). As the Oxfordshire Community Stroke Project (OCSP) is one of the few large community-based prospective studies of TIA and the clinical types of TIA, I will describe the data from the OCSP in some detail, and supplement it with data from other well-studied hospital-referred cohorts (Pessin et al., 1977; Bogousslavsky et al., 1986). In the OCSP, 184 TIA patients reported 201 clinical ‘types’ of attacks; 168 patients (91%) presented with one clinical ‘type’ of attack, 15 patients (8%) experienced more than one ‘type’ of attack and one patient described three separate ‘types’ of attack, although sometimes these appeared to involve the same arterial territory (Table 2.3) (Dennis, 1988).

Motor symptoms Motor symptoms are the most common symptoms described by TIA patients; in the OCSP they were experienced in 101 of the 184 patients (54%), and were a feature in 109 of the 201 (54%) clinical ‘types’ of attack (Dennis, 1988). ‘Weakness’ was by far the most common motor symptom, followed by ‘heaviness’ and ‘clumsiness’. In most series, motor symptoms are reported to be associated with sensory symptoms of some sort; pure motor symptoms are present in only about 15–25% of patients (Pessin et al., 1977; Bogousslavsky et al., 1986; Dennis, 1988). However, it is unwise to be dogmatic about the presence or absence of sensory symptoms because often a weak limb is described by the patient as ‘numb’ or ‘dead’

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and this is often interpreted by the doctor as a combination of motor and sensory symptoms.

focal neurological (usually cranial nerve) dysfunction may represent a TIA; this was the case for eight TIA patients (4%) in the OCSP (Table 2.3) (Dennis, 1988).

Weakness on one side of the body In the OCSP, motor symptoms (i.e. weakness) involved the left side of the body in 51 patients (28%), the right side in 42 patients (23%) and were both sides in eight patients (4%) (Dennis, 1988). Among the 93 patients with unilateral motor symptoms, weakness involved the face and upper and lower limb in 8%, the face and upper limb in 36%, the upper and lower limb (hemiparesis) in 26%, and either the face, upper limb or lower limb only (monoparesis) in 30%. Similar findings were reported by Bogousslavsky et al. (1986). Unilateral facial weakness is probably under-reported in TIAs because many patients do not realize they have had facial weakness unless they have seen themselves in the mirror, or unless the attack has been witnessed by an observer. If there is a clear history of dysarthria, in the absence of symptoms of cerebellar or bulbar dysfunction, it is reasonable to suspect facial weakness because facial weakness may cause dysarthria (if the patient attempts to speak). Having established that facial weakness was present, it can be even more difficult to determine which side of the face was weak. This is because the interpretation and recall of the patient and any witnesses may have been affected by anxiety and panic during the attack. Alternatively, the patient and witnesses may have suffered from left–right confusion or misinterpreted which side of the ‘twisted’ face was weak and which side was contracting. So, the side of the face which is reported to have been weak is very unreliable and cannot be assumed to have been ipsilateral to the limb weakness, unless there was also sensory loss (as well as motor loss) on one side of the face. Transient weakness of only one lower limb usually indicates a disturbance in the parasagittal region of the contralateral cerebral cortex due to ischemia in the anterior cerebral artery territory or the boundary zone between the anterior and middle cerebral artery territories. The latter is more likely if the upper extremity is also somewhat weak and if the symptoms have been precipitated or aggravated by standing or walking. These patients usually have underlying carotid occlusive disease (Yanagihara et al., 1988).

Weakness on both sides of the body Although generalized weakness is a non-focal neurological symptom, the sudden onset of clearcut bilateral weakness (quadriparesis, paraparesis, bilateral facial, and face and contralateral hand weakness) together with symptoms of

Unsteadiness Unsteadiness is a fairly common symptom in TIA patients (12% of the OCSP cohort) but, unless associated with clearly focal symptoms, it can be difficult to decide whether the patient simply means weakness, incoordination or both.

Difficulty swallowing Although dysphagia is a common feature of acute stroke, it is uncommonly reported by TIA patients. In the OCSP only one patient described dysphagia during a TIA, the attack occurring during a meal. The rarity of this symptom in a TIA is not surprising; although we are continually swallowing saliva, it is usually performed subconsciously and any transient deficit is likely to pass unnoticed. Difficulty in swallowing food is far more likely to be noticed but as we do not spend much of the day eating, a TIA is unlikely to coincide with such activity.

Movement disorders Episodic movement disorders are rare manifestations of transient cerebral ischemia and include paroxysmal dyskinesia (Margolin & Marsden, 1982; Stark, 1985; Hess et al., 1991) and orthostatic ‘limb-shaking’ spells (see below) (Yanagihara et al., 1985; Baquis et al., 1985).

Speech disturbances Patients with TIA may complain of transient speech disturbances due to an articulatory and/or a language disturbance. If the patient describes slurred speech, as if drunk, and if the ability to understand and express spoken and written language was preserved, the diagnosis is dysarthria, which is usually due to facial weakness or incoordination of the respiratory, bulbar or facial muscles. If the main difficulty was that of understanding or producing sentences, with words in their proper place, the diagnosis is dysphasia, which is usually due to dominant frontotemporo-parietal ischemia. If speech production was so severely affected that the patient was mute, it may be extremely difficult to ascertain retrospectively whether a language deficit was present, unless there was an associated disturbance of comprehension, reading or writing (not due to weakness) or the examiner has tested language function during the attack. The type of speech disturbance during the phase of recovery may be a helpful clue. Dysphasia and dysarthria may coexist. In the OCSP, dysarthria was the most common form of

Clinical types of transient ischemic attacks

speech disorder, occurring simultaneously with other focal neurological symptoms in 43 patients (23%) (Dennis, 1988). Dysarthria occurring in isolation, without any other symptoms, is not considered to be a TIA. Dysphasia was present in 34 patients (18%), a few of whom also described slurred speech. No patient described transient problems with reading, writing or calculation as part of the TIA; these deficits possibly occurred but were not recognized as the patient needs to be engaged in the relevant activities at the time of the TIA to notice any deficit and be asked about them later by a more than usually inquisitive clinician!

Sensory symptoms Somatosensory symptoms Somatosensory symptoms, when present, are usually described by the patient as a numbness, tingling or dead sensation and very rarely as pain. The anatomical distribution of somatosensory symptoms is usually unilateral affecting the face, arm and/or leg, as it is for motor symptoms (Table 2.3). In the OCSP, 64 patients (35%) described somatosensory symptoms, usually in the form of ‘numbness’. Associated motor symptoms were present in 53 patients. Only 11 patients (6%) had purely somatosensory symptoms. Bogousslavsky et al. (1986) reported pure somatosensory TIAs as the most common single type of carotid TIA (27%), at least in patients who underwent angiography, with another 45% having sensory symptoms combined with motor, visual or speech disturbances. Pessin et al. (1977) found pure sensory symptoms in 15% and combined motor and sensory symptoms in another 58% of patients with carotid TIAs. However, it can be very difficult to interpret transient isolated sensory symptoms involving a part of one extremity or only one side of the face during a single attack because they may be a manifestation of other disorders such as an entrapment mononeuropathy (e.g. median neuropathy at the wrist), multiple sclerosis, hyperventilation and even hysteria. This difficulty probably accounts for some of the variation in both the diagnosis of TIA among different observers and the prevalence of sensory symptoms among different TIA cohorts.

‘Neglect’ Visual–spatial–perceptual dysfunction, sometimes manifesting as ‘neglect’ of one side of the body or extrapersonal space, can occur in patients with ischemia of the contralateral non-dominant cerebral hemisphere. It is probably the corollary to dysphasia, which may occur during ischemia in the dominant cerebral hemisphere subserving language function. Unlike dysphasia, however, visual–spatial–per-

ceptual dysfunction is a difficult symptom to recognize, particularly when it is transient and associated with other more striking neurological deficits, such as hemiparesis. In the OCSP, only two patients had symptoms other than weakness or numbness that indicated ischemia of the nondominant hemisphere (Dennis, 1988). For example, one man complained that, during the TIA, his left arm was twisted up in the sheets and this was his explanation of why he was unable to use it. His wife and the attending general practitioner were certain that he had quite severe weakness of the left side of which he was unaware. This lack of awareness may have been due to ‘neglect’ of his left side. It is possible that some of the patients who are described as being confused during the attack actually have nondominant hemisphere ischemia (causing dressing apraxia, etc.) or alternatively, dominant hemisphere ischemia (causing dysphasia) and that other coexisting focal neurological symptoms are not recalled or reported; although these can be found in most stroke patients with confusional states.

Visual symptoms Visual symptoms associated with transient cerebral and retinal ischemia are generally of three types: obscuration or loss of vision in one eye, in both eyes, or double vision. Positive visual effects such as shimmering and visual hallucinations are usually binocular and associated with migraine. In the OCSP (Dennis, 1988), 60 patients (33%) experienced visual symptoms during their TIA, most commonly monocular blindness (AFx).

Loss of vision in one eye: transient monocular blindness (amaurosis fugax) Amaurosis fugax (meaning literally ‘fleeting blindness’) is a term used to describe the abrupt onset, over seconds, of loss of vision (greyish haze or black) in one eye due to transient ischemia in the territory of supply of the ophthalmic or central retinal artery. Typically, the symptoms arise spontaneously, without provocation, and recover rapidly after several seconds to a few (usually less than 5) minutes. Uncommonly the visual loss lasts for several hours before full recovery occurs. The visual deficit is usually complete immediately but it may appear as if a curtain or shade has progressively obscured vision over a few seconds. The ‘curtain’ usually comes down from above but sometimes it comes up from below. The loss of vision may be complete or partial and usually involves the entire visual field. Occasionally, however, it is restricted to either the upper or lower half of the visual field and, even less frequently, to the peripheral nasal and/or

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Table 2.3. Clinical features in a cohort of 184 community TIA patients % of 184

95% confidence interval

Type of attack ‘Single ‘type’ of attack’ ‘More than one ‘type’ of attack’

91 9

87 to 95 5 to 13

Vascular territory Carotid TIA eye (amaurosis fugax) TIA brain TIA brain and eye Vertebrobasilar Uncertain (hemiphenomena) More than one vascular territory

80 17 62 1 13 7 1

74 to 86 12 to 22 55 to 69 0 to 3 8 to 18 3 to 11 0 to 3

Motor symptoms Weakness/heaviness/clumsiness unilateral left side of body right side of body bilateral quadriparesis paraparesis facea and contralateral arm ‘Unsteadiness’ Dysphagia Limb shaking

54 51 28 23 4 1 2 1 12 1 1

47 to 61 43 to 57 22 to 34 17 to 29 1 to 7 0 to 3 0 to 4 0 to 3 7 to 1 0 to 3 0 to 3

Speech disturbances Dysarthria (with other focal symptoms) Dysphasia ‘Dyslexia, Dysgraphia, Dyscalculia’

40 23 18 0

33 to 47 17 to 29 12 to 24 0 to 3

Somatosensory symptoms isolated associated with motor symptoms ‘Neglect’

35 6 29 1

28 to 42 3 to 9 22 to 36 0 to 3

Visual symptoms Monocular blindness Hemianopia (isolated) Bilateral blindness (with other focal symptoms) Double vision (with other focal symptoms) Blurred vision in both eyes (with other focal symptoms)

33 18 5 1 5 4

26 to 40 12 to 24 2 to 8 0 to 3 2 to 8 1 to 7

Vestibular symptoms Vertigo (with other focal symptoms)

5

2 to 8

Loss of consciousness

1

0 to 3

Note: a Patients have difficulty detecting facial weakness; they usually only note dysarthria and a witness is usually required to describe facial weakness. Source: From Dennis (1988).

Clinical types of transient ischemic attacks

temporal field. Patchy and sectorial loss may also occur but presumably is less likely to be noticed by the patient (Bogousslavsky et al., 1986). Occasionally, young patients describe a series of ‘blobs’ or lacunae throughout the field of vision which may gradually coalesce into a complete loss of visual field; it has been suggested that this pattern of visual loss may correspond to the lobular arrangement of the blood supply in the choriocapillaris and indicate ischemia in the choroid circulation rather than the retinal circulation (O’Sullivan et al., 1992). Flashing lights, shooting stars, scintillations or other positive phenomena in the area of impaired vision can occasionally arise during retinal or optic nerve ischemia (Goodwin et al., 1987), but they are far more commonly encountered during migraine, involving the retina or occipital lobe. Amaurosis fugax (AFx) may not be the only symptom; other symptoms may coexist such as transient sensory symptoms (paraesthesias) over the same side of the face (Ropper, 1985) and contralateral hemiparesis and hemisensory deficit. Amaurosis fugax may recur, usually in a stereotyped fashion, but the area of visual impairment may vary from one episode to the next, depending on which part of the retina is ischemic.

Lone bilateral blindness Sudden, spontaneous and simultaneous blindness in both eyes indicates retinal, chiasmal or occipital lobe dysfunction bilaterally. In the OCSP register of patients with suspected TIA (and without prior stroke), 14 patients had lone bilateral blindness, defined as rapid onset of dimming or loss of vision over all of both visual fields simultaneously, lasting less than 24 hours, without associated symptoms of focal cerebral ischemia, seizures or reduction in consciousness. The age of these patients was close to that of the 184 patients who presented with TIAs, and they had an equally high prevalence of vascular risk factors. During a mean follow-up period of 2.4 years, five of the 14 had a first-ever stroke (only 0.31 expected). In view of their 16 times excess risk of stroke, such patients are now considered, for practical purposes, as TIAs (Dennis et al., 1989b). The differential diagnosis of patients who describe the simultaneous occurrence of binocular blurring, dimming or complete loss of vision depends on the associated symptoms. If the symptoms arise when the patient is feeling faint and experiencing other pre-syncopal symptoms, the likely cause is global cerebral hypoperfusion. If bilateral blindness occurs in isolation, it is probably caused by bilateral posterior cerebral artery ischemia, unless it has been provoked by a photostress such as bright or white light, in which case it is probably bilateral retinal ischemia (see below).

Loss of vision in the left or right half of the visual field Isolated homonymous hemianopia is rare in comparison to other varieties of TIA, although asymptomatic visual field defects, chiefly located in the upper part of the visual field, have been reported in 29% of 17 patients with TIA and 57% of 14 patients with minor stroke (Falke et al., 1991). In the OCSP, nine patients (5%) had isolated sudden onset of hemianopia with no positive visual symptoms (or brainstem symptoms) (Dennis, 1988). Part of the reason for the relatively low frequency of this symptom may be that patients have difficulty recognising and also describing it, particularly if there are other symptoms (such as hemiparesis) which are more readily appreciated and described. Also, it can be difficult to distinguish binocular loss of vision (such as a homonymous hemianopia) from monocular loss of vision; the patient needs to have covered each eye in turn during the symptoms and noted the effect (of objects that were previously seen in the centre of the visual field now appearing to be split in half). Even if the patient has covered each eye in turn during the attack, it may not be possible to be really confident of the distinction because an incongruous homonymous hemianopia does not necessarily split macular vision and may be interpreted by the patient as a loss of vision in one eye only. Similarly, if patients have only one functioning eye, it is almost impossible to distinguish a homonymous hemianopia from visual loss caused by ischemia in the good eye unless symptoms of posterior (or middle) cerebral artery ischemia coexist. It is therefore important to recognize that neurological conditions, such as migraine, that affect postchiasmal pathways and cause homonymous visual field defects are not infrequently described (erroneously) by the patient as monocular.

Visual loss in bright or white light In 1979, Furlan et al. reported the phenomenon of unilateral loss of vision (causing things to appear bleached like a photographic negative) in five patients when exposed to bright sunlight. All patients had decreased retinal artery pressure on the symptomatic side and high-grade stenosis or occlusion of the ipsilateral internal carotid artery (ICA). Attenuation of the visual evoked response immediately after exposure to bright light was subsequently demonstrated in four such patients but not in controls (Donnan et al., 1982). A similar phenomenon of unilateral loss of vision induced by white light is also recognized in patients with ipsilateral carotid occlusive disease (Sempere et al., 1992). Light exposure may also induce episodic bilateral visual impairment in patients with high-grade stenosis or occlusion of both internal carotid arteries (Wiebers et al., 1989). The visual symptoms consist of blurring, dimming or scotomata in both eyes (and never a shade or blind effect). The

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symptoms persist for as long as the patient is exposed to bright light and for seconds to hours after the exposure. Other clues to the presence of anterior circulation disease may be the presence of venous-stasis retinopathy. Sunglasses may be an effective treatment. The diagnosis of episodic bilateral visual impairment associated with light exposure in patients with bilateral carotid occlusive disease needs to be differentiated from that caused by bilateral occipital lobe ischemia in vertebrobasilar system disease; bilateral blindness from occipital lobe ischemia is usually more rapid in onset and not related to light exposure (see above) (Dennis et al., 1989b). Visual loss in bright or white light is considered to represent macular dysfunction as a result of retinal ischemia from reduced choroidal (choriocapillaris) blood flow causing a delay in the regeneration of visual pigments in the retinal pigment epithelial layer. Other possible causes of loss of vision by photostress include macular disease due to chorioretinitis or retinal pigmentary degeneration (Glaser et al., 1977).

Diplopia Transient diplopia alone is a relatively non-specific symptom that may or may not be an indication of a brainstem ischemic event. However, the occurrence of transient diplopia in association with other symptoms of brainstem or cerebellar dysfunction, such as unilateral or bilateral motor or sensory disturbances, vertigo, ataxia or dysarthria, usually signifies a vertebrobasilar circulation TIA. In the OCSP, nine TIA patients (5%) suffered double vision with other brainstem symptoms (Dennis, 1988).

Vestibular symptoms Vertigo Episodic vertigo is a well-recognized symptom of vertebrobasilar ischemia when it occurs together with other symptoms of ischemic brainstem dysfunction, such as diplopia or bilateral sensorimotor symptoms. In the OCSP, ten patients (5%) gave a convincing history of vertigo (a sensation of rotational movement or spinning) associated with other symptoms of focal neurological (brainstem) dysfunction (Dennis, 1988). Vertigo in isolation is generally not considered a focal neurological symptom and therefore is not classified as a TIA. Although it may be due to selective ischemia of the vestibular nerve or the superior vestibular labyrinth in the inner ear (Grad & Baloh, 1989; Baloh, 1992; Oas & Baloh, 1992, Gomez et al., 1996), this is all but impossible to tell in practice. If such attacks do exist, they are vastly outnumbered by disorders of the peripheral vestibular apparatus

(e.g. benign positional vertigo) and even more by episodes of non-rotatory dizziness such as orthostatic hypotension or hyperventilation. So, unless associated with other concurrent brainstem symptoms, vertigo should not be classified as a TIA, and this applies even more strongly to non-rotatory dizziness.

Associated symptoms Headache Headache at the onset of a TIA is not uncommon but is generally not severe. The site of the headache associated with TIA is usually ipsilateral to the site of cerebral or ocular ischemia, at least in carotid territory TIAs, and is often above the eye in patients with AFx who experience headache. A prospective study of 3126 patients with acute cerebral or retinal ischemia revealed that headache occurred in 16% of all patients with TIA of the brain, 16% of those with TIA of the eye (AFx), 18% of those with reversible ischemic neurological deficits and in 19% of patients with minor stroke (Koudstaal et al., 1991). The headache was mostly continuous and not throbbing. The occurrence of headache was not related to the mode of onset, mode of disappearance, or duration of the attack. However, patients with evidence of cortical ischemia or vertebrobasilar circulation ischemia had headache more often than patients with lacunar syndromes. These findings concur with the lower frequency of headache reported in series of patients with only carotid territory TIAs, e.g. 4% (Bogousslavksy et al., 1986). Some other studies have noted a higher frequency of headache in TIA patients, e.g. 36% (Portenoy et al., 1984), 30% (Loeb et al., 1985), but have not mentioned the possibility that some of these patients may have been migraine sufferers (and misdiagnosed as TIA) and have not stated the distinguishing diagnostic criteria. The cause of the headache associated with TIA is unknown. Edmeads (1979, 1983) has suggested that the headache in cerebral ischemia may be due to the release of vasoactive substances, such as serotonin and prostaglandins, from platelets activated by cortical cerebral ischemia. Castillo et al. (1995) propose that the ischemic penumbra may cause a state of cortical hyperexcitability that is responsible for the cortical release of amino acid neurotransmitters and the induction of headache by altering pain perception mechanisms. Another possibility is dilatation of collateral arterial pathways causing headache. Some of the headaches are probably due to muscle tension.

Symptoms of panic and anxiety The sudden loss of limb, speech or eye function is a frightening experience which often evokes considerable anxiety

Clinical types of transient ischemic attacks

Table 2.4. Where is the TIA? Arterial Territory Symptom

Carotid

Dysphasia Monocular visual loss Unilateral weaknessa Unilateral sensory disturbancea Dysarthriab Homonymous hemianopia Unsteadiness/Ataxiab Dysphagiab Diplopiab Vertigob Bilateral simultaneous visual loss Bilateral simultaneous weakness Bilateral simultaneous sensory disturbance Crossed sensory/motor loss

⫹ ⫹

Either

Vertebrobasilar

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

Notes: a Usually regarded as carotid distribution. b Not necessarily if isolated symptom, only if associated with ⱖ 1 other on list.

and panic in patients and carers, particularly in the first, if not later attacks. Patients may consequently hyperventilate and in turn develop sensory symptoms, such as peripheral paraesthesias and pre-syncopal symptoms. It is important to meticulously distinguish the primary (TIA) and secondary (panic/anxiety) symptoms under these circumstances.

Brief loss of consciousness Loss of consciousness is seldom recognised as a symptom of focal brain ischemia and therefore does not usually indicate a TIA unless accompanied before or after by clearcut focal neurological symptoms. When loss of consciousness does occur, it seems to be associated with ischemia of the deep diencephalic and mesencephalic structures superimposed on widespread bihemispheric ischemia as a result of either bilateral carotid (Yanagihara et al., 1989) or vertebrobasilar occlusive disease.

Neurovascular relevance of clinical types of TIAs The clinical symptoms of TIAs (i.e. the ‘types’ of attacks) not only help to establish the diagnosis of a TIA but also to identify the neuroanatomical and neurovascular site of the ischemia.

Carotid and vertebrobasilar territory TIAs were originally described as distinct clinical syndromes by Millikan and Siekert (1955a,b). It has since been established from community studies that about 80% of TIAs involve the carotid artery territory (63% cerebral, 17% ocular), and the remainder are either vertebrobasilar or the vascular distribution is uncertain (Table 2.3) (Dennis et al., 1989a).

Carotid territory TIAs (Table 2.4) Carotid distribution TIAs can be subclassified as either monocular or hemispheric; rarely the eye and ipsilateral hemisphere are affected simultaneously (Pessin et al., 1977). The only symptoms that almost definitely indicate carotid territory ischemia are TMB (AFx) and dysphasia.

Transient monocular blindness Unless a patient with transient visual disturbance alternately covers and uncovers each eye during the event, it can be difficult to ascertain afterwards whether vision was obscured or lost in one eye only, or in one half of the visual field. The distinction is important because monocular ischemic events are generally due to ischemia of the retina and/or optic nerve (as a result of carotid, central retinal artery or posterior ciliary artery ischemia) whereas homonymous hemianopic events usually indicate dysfunction of the contralateral optic tracts, optic radiations or calcarine

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cortex which are supplied by the middle (carotid territory) and posterior (vertebrobasilar territory) cerebral arteries; predominantly the latter, at least in most patients.

Dysphasia Similarly, it is necessary to make a clear distinction between dysarthria (a pure speech disorder due to difficulty with articulation) and dysphasia (a language disorder). The former is a relatively non-localizing symptom and may be seen with ischemia in the anterior or posterior circulation. Dysphasia indicates a disturbance of the dominant cerebral hemisphere (almost invariably the left hemisphere in right-handed individuals and the right hemisphere in more than 50% of left-handed individuals), as a rule from anterior circulation (carotid) ischemia. However, it is identifiable only if the patient actually tried to speak during the TIA.

Hemiphenomena The most common symptoms in patients presenting with what have been considered as carotid TIAs are contralateral limb weakness and/or sensory disturbance. Symptoms of unilateral motor and/or sensory dysfunction (involving some or all parts of the face, upper and lower limbs), homonymous hemianopia or dysarthria occurring in isolation may indicate ischemia anywhere along the pathways of the contralateral corticospinal and/or ascending sensory tracts, optic radiation or corticobulbar tracts, respectively. As these pathways share both carotid and vertebrobasilar arterial supply at different sites along their course, it is not possible to tell whether the ischemia was in the carotid or vertebrobasilar arterial territory unless other unequivocally localising symptoms were also present, e.g dysphasia (carotid) or diplopia (vertebrobasilar). These episodes of isolated unilateral motor and/or sensory dysfunction may be classified as ‘hemiphenomena’ due to contralateral brain ischemia. Although these symptoms, particularly unilateral weakness and/or sensory loss, are probably due to carotid territory ischemia most of the time (because carotid ischemic events are more common than vertebrobasilar events), it is impossible to be sure.

Vertebrobasilar TIAs Vertebrobasilar territory ischemia may cause any of a whole constellation of symptoms as outlined in Table 2.4 (Caplan, 1985). These occur simultaneously, in combination with one another. The most common symptoms are vertigo, visual disturbance (reduced vision bilaterally or double vision) and unilateral, crossed or bilateral weak-

ness and/or sensory loss involving any combination of the limbs and face. If some of these symptoms occur in isolation, such as diplopia or vertigo then the attack may have been a TIA but other causes must be considered, e.g. vestibular disease. For example, if the patient describes true vertigo, the presence of associated auditory symptoms, e.g. tinnitus, hearing loss, usually indicates peripheral labyrinthine dysfunction whereas the simultaneous presence of symptoms of brainstem dysfunction, e.g. diplopia, usually indicates a central brainstem disturbance. Impairment or loss of consciousness is very unusual in TIA and usually suggests a non-focal neurological disorder such as a generalized seizure or systemic or metabolic disturbance (see above). In adolescence, transient bilateral loss of vision is usually benign and does not share the same prognosis as other forms of TIA. Prosopagnosia (inability to recognize familar faces or their photographs despite being able to identify the persons by their voice or clothing) has been reported as a TIA on one occasion, due to presumed ischemia of the inferomedial occipitotemporal cortex bilaterally (Marti-Vilalta et al., 1981). Symptoms compatible with vertebrobasilar ischemia (such as transient bilateral motor, sensory or visual impairment) have been reported in patients with unilateral or bilateral carotid occlusive disease (Bogousslavsky & Regli, 1985; Yanagihara et al., 1989; Sloan & Haley, 1990). Subtle alterations in perfusion pressure in patients with severe hemodynamic lesions of both internal carotid arteries may provoke simultaneous bilateral border zone ischemia and a syndrome of bilateral motor and/or sensory symptoms with facial sparing, gait disturbances, or bilateral visual phenomena, but no intrinsic brainstem symptoms. In rare cases, the occurrence of diplopia might reflect parietooccipital dysfunction due to posterior border zone (middle cerebral artery/posterior cerebral artery) ischemia as opposed to intrinsic brainstem ischemia (Bogousslavsky & Regli, 1985).

Etiological relevance of clinical types of TIAs A TIA is a symptom of one or more of any number of underlying pathological processes. Not only is it important to accurately elicit and interpret the patient’s symptoms, so that the diagnosis of TIA and its likely vascular territory can be established, but it is also important to know which symptoms or types of TIAs, if any, help predict the underlying cause of the TIA. After all, it is not the symptoms which usually need to be treated (as they are transient anyway), but the cause of the TIA, to reduce the risk of stroke and other serious vascular events.

Clinical types of transient ischemic attacks

Clinical history Very few studies of TIA patients have correlated TIA symptoms (e.g. nature of symptoms, duration and number of attacks, etc.) with underlying pathology. Bogousslavsky et al. (1986) attempted to identify clinical predictors of cardiac and arterial lesions in 205 patients with carotid TIA but the number of patients in each subgroup analysis was really too small to reach any definitive conclusions other than the negative observation that very few clinical characteristics of TIAs give a clue to the underlying cause. Nevertheless, there are a few distinct TIA syndromes which probably do have some pathogenic significance, such as ‘lacunar’ TIAs, ‘cortical’ TIAs, and ‘low flow’ TIAs.

‘Lacunar’ and ‘cortical’ TIAs A theoretical analogy with lacunar and cortical stroke syndromes Several stroke syndromes are recognized, which carry pathogenic, prognostic and potential therapeutic implications. Ischemic lacunar stroke syndromes, which account for about 25% of all ischemic strokes are usually caused by thrombosis complicating microatheroma or lipohyalinosis of a single small perforating artery (Fisher, 1969; Bamford et al., 1987; Bamford & Warlow, 1988; Boiten et al., 1996; Gan et al., 1997). Ischemic cortical stroke syndromes in the carotid artery distribution are usually caused by occlusion of the main stem or branches of the anterior (ACA) or, much more often, the middle cerebral artery (MCA) in patients who either have a cardiac source of embolus or atherothrombosis of the ipsilateral extracranial carotid artery giving rise to artery-to-artery embolism and/or hemodynamic compromise (Kase, 1988; World Health Organization Task Force, 1989; Lodder et al., 1990; Bamford et al., 1991). Whilst a qualitative difference (in arterial pathology) seems to exist between ischemic ‘lacunar’ strokes (small vessel disease) and ischemic ‘cortical’ strokes (large vessel or cardiac disease), the difference between ischemic stroke and transient ischemic attack (TIA) is only quantitative being based arbitrarily on the duration of the patient’s symptoms up to or beyond 24 hours; there appears to be no major difference in the age, sex, prevalence of coexistent vascular diseases and risk factors, nor prognosis of patients with TIA and mild ischemic stroke (Dennis et al., 1989c). It is therefore plausible that qualitative differences in arterial disease and pathophysiology are shared by TIAs as well as ischemic strokes, and that these may be more relevant for management and prognosis than the quantitative differences by which TIAs and strokes are conventionally separated.

How can ‘lacunar’ TIAs be recognized? In patients with radiological or pathological evidence of lacunar infarction, the clinical history and physical signs at the time of maximal neurological deficit are usually one of four distinct clinical syndromes: (a) a pure motor syndrome: unilateral weakness of the face and upper limb, upper and lower limbs, or face and upper and lower limbs; (b) a pure sensory syndrome: a unilateral sensory disturbance in distributions similar to those of the pure motor syndrome; (c) a sensorimotor syndrome: a unilateral motor and sensory disturbance again in distributions similar to those of the pure motor syndrome; and (d) an ataxic hemiparesis; all occurring without cortical involvement (e.g. dysphasia, visual spatial perceptual disturbance) (Bamford et al., 1987). Although clinical–radiological–pathological correlation is rarely possible for TIA patients, it may often be possible to distinguish ‘lacunar’ and ‘cortical’ TIAs by means of the same clinical criteria as used for lacunar infarction (obtained from the clinical history); i.e. if a fully conscious right-handed patient experiences transient right-sided facial and limb symptoms and also attempts to speak during the TIA, it should be possible to infer whether the TIA involved the cortical branches of the MCA (‘cortical’ TIA) or the penetrating lenticulostriate branches (‘lacunar’ TIA) because in the former the speech may be dysphasic and in the latter it may be normal or dysarthric (Hankey & Warlow, 1991). Even if the patient does not attempt to speak, or if speech is normal, or if the patient has left sided weakness, it may still be possible to diagnose ‘cortical’ dysfunction if the motor and/or sensory disturbance involved only one body area (face or upper limb or lower limb) or two body areas incompletely, since permanent deficits of these types are usually due to ‘cortical’ rather than ‘lacunar’ strokes (Kase, 1988; Boiten & Lodder, 1991). However, if the patient does not attempt to speak and the weakness involves all of the face and upper limb, upper and lower limb, or face and upper limb and lower limb, it is impossible to tell whether the ischemic event was lacunar or cortical (Hankey & Warlow, 1991). The interobserver agreement for the diagnosis of a ‘lacunar’ TIA can be very good; in one study four neurologists interviewed 36 patients (referred for TIA) in alternating pairs and the chance-corrected agreement rate (kappa statistic) was 0.88 (Landi et al., 1992).

Are ‘lacunar’ TIAs of clinical relevance? Several studies have shown that the vast majority of ‘lacunar’ TIAs (and lacunar ischemic strokes), when they can be recognized as such, occur in patients with little ICA disease in the neck (Harrison et al., 1986; Rothrock et al.,

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1988; Hankey & Warlow, 1991; Kappelle et al., 1991). In contrast, most ‘cortical’ TIAs (and ischemic strokes) in the carotid territory arise in patients with significant stenosis of the origin of the symptomatic ICA or an embolic source in the heart. If these results can be interpreted in pathogenic terms, it would seem reasonable to postulate that, in patients without an obvious cardiac embolic source, the majority of ‘lacunar’ TIAs arise from small vessel disease (lipohyalinosis or microatheroma) and that most ‘cortical’ TIAs are due to significant disease (usually atheroma) at the origin of the ICA. However, this clinical distinction is not always possible (it requires right-handed patients with left carotid TIAs who attempt to speak), nor is it robust, because (a) cardiac, large vessel and small vessel disease may coexist in the same patient (Bogousslavsky et al., 1986), (b) cardiac sources of emboli may be missed by clinical evaluation and echocardiography, particularly in the older age groups, (c) ‘lacunar’ syndromes may also occur with (i) brainstem ischemia outside the carotid artery territory (Stiller et al., 1982), (ii) intracerebral hemorrhage (Bamford et al., 1987; Mori et al., 1985), (iii) cortical ischemia due to occlusion of the extracranial ICA (as in one of our cases) (Aleksic & George, 1973) or the MCA (Adams et al., 1983) or (iv) subcortical ischemia due to cardiac emboli (Santamaria et al., 1983), and (d) some small deep infarcts, like those seen in the majority of lacunar syndromes, may give rise to restricted neurological deficits suggestive of cortical involvement (Huang & Broe, 1984).

‘Low flow’ TIAs It is often difficult to be certain about the exact pathophysiological mechanism of a TIA but most TIAs are probably caused by artery-to-artery or cardiogenic embolism and, less often, by acute arterial thrombosis or low flow. Attacks that are due to low flow almost always occur in the setting of a severely stenosed or occluded artery in the neck which makes the patient susceptible to a small drop in blood pressure, perhaps because autoregulation is impaired or cerebral perfusion is exhausted; a sudden fall in systemic blood pressure in people with a normal arterial tree causes non-focal neurological symptoms such as faintness, imbalance, bilateral visual blurring and loss of consciousness (Russell, 1988). The evidence favouring low flow is sometimes circumstantial, usually when a precipitating event is recognized, such as a clinically or electrophysiologically obvious cardiac arrhythmia, exercising, chewing (increasing blood flow from the common carotid artery up the external carotid, thereby reducing the fraction going up the ICA), extending the neck, eating a heavy meal, having a

hot bath (Raymond et al., 1980), sitting or standing up quickly; and medications that lower blood pressure (Purvin & Dunn, 1981). The nature of ‘low flow’ TIAs may be atypical. They may not arise abruptly but instead over several seconds to minutes. Also, they may consist of monocular or binocular visual blurring, dimming, fragmentation or bleaching, often only in bright or white light (Furlan et al., 1979; Wiebers et al., 1989; Sempere et al., 1992). Other types of ‘low flow’ TIAs include lower limb weakness (Yanagihara et al., 1988), and irregular shaking of the arm or leg contralateral to cerebral ischemia (Yanagihara et al., 1985; Baquis et al., 1985; Tatemichi et al., 1990). Patients with severe carotid occlusive disease have been observed to experience brief, repetitive, involuntary, coarse, irregular, wavering, trembling or jerking movements of the contralateral arm and/or leg, resembling simple partial motor seizures. They are usually provoked by postural change (from lying to sitting or standing up) or by hyperextension of the neck. They may be alleviated promptly by sitting or lying down. Electroencephalography reveals no epileptiform activity at rest, during sleep or during the involuntary movements. Perfusion insufficiency has been demonstrated by xenon133 inhalation (Tatemichi et al., 1990) and, in some cases, the attacks have ceased following carotid endarterectomy (Baquis et al., 1985; Stark, 1985).

Cardioembolic TIAs With the aid of a stethoscope and modern non-invasive imaging, it is becoming easier to identify, in the individual patient, one or more of the large variety of heart diseases that may be a potential source of cardiogenic embolism. The real difficulty, however, is not in identifying a potential source of cardiogenic embolism but in deciding whether an identified potential embolic source is actually the source. The rather imprecise mainstay of the diagnosis of cardioembolic TIA continues to be the presence of a potential cardioembolic source in the absence of cerebrovascular or hematological disease in a patient with non-lacunar TIAs (Hart, 1992). The following features favour embolism from the heart as a cause of the TIA: (a) Cortical TIAs (lacunar TIAs and infarcts are uncommonly embolic in origin) (b) TIAs in more than one arterial territory (c) Ischemic episodes in organs other than the brain (d) Calcific emboli visible in the retina (from calcified mitral or aortic valves) (e) A probable source of embolism in the heart is present. (f) No other likely cause of TIA identified, e.g. absence of other manifestations of atherosclerosis (such as angina,

Clinical types of transient ischemic attacks

peripheral vascular disease, cervical bruit or duplex carotid ultrasound evidence of carotid stenosis) and risk factors (such as hypertension). (g) Patient younger than 50 years of age.

Conclusions The clinical types of TIA of the brain are generally the same as the clinical types of ischemic stroke. There is no qualitative difference between a mild ischemic stroke and a TIA in its clinical manifestations, etiology or prognosis. The only difference between TIA and ischemic stroke is quantitative and even this is arbitrary, enshrined in the temporal distinction of symptoms lasting more or less than 24 hours. So, anything which causes an ischemic stroke may, if less severe or less prolonged, cause a TIA while anything which causes a TIA may, if more severe or more prolonged, cause an ischemic stroke. It is not so certain, however, whether the clinical types of TIA of the eye are the same as the clinical types of ischemic stroke of the eye (retinal infarction). It has never been answered whether there is a similar small vessel disease which affects the blood supply to the retina and optic nerve, causing ‘lacunar’ syndromes of the eye equivalent to lacunar syndromes of the brain. It is clear that a high proportion of patients with ischemic amaurosis fugax, retinal infarction, and acute ischemic optic neuropathy do not have any detectable and likely proximal source of embolism (or low flow) in the heart or in the arterial blood supply to the eye, and perhaps it is these patients who have symptomatic small vessel disease like patients with lacunar infarcts in the brain.

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Furlan, A.J., Whisnant, J.P., & Kearns, T.P. (1979). Unilateral visual loss in bright light: an unusual symptom of carotid artery occlusive disease. Archives of Neurology, 36, 675–6. Gan, R., Sacco, R.L., Kargman, D.E., Roberts, J.K., Boden-Albala, B., & Gu, Q. (1997).Testing the validity of the lacunar hypothesis: The Northern Manhattan Stroke Study experience. Neurology, 48, 1204–11. Glaser, J.S., Savino, P.J., Sumers, K.D., McDonald, S.A., & Knighton, R.W. (1977). The photostress recovery test in the clinical assessment of visual function. American Journal of Ophthalmology, 83, 255–60. Gomez, C.R., Cruz-Flores, S., Malkoff, M.D., Sauer, C.M., & Burch, C.M. (1996). Isolated vertigo as a manifestation of vertebrobasilar ischemia. Neurology, 47, 94–7. Goodwin, J.A., Gorelick, P.B., & Helgason, C.M. (1987). Symptoms of amaurosis fugax in atherosclerotic carotid artery disease. Neurology, 37, 829–32. Grad, A. & Baloh, R.W. (1989). Vertigo of vascular origin. Clinical and electronystagmographic features in 84 cases. Archives of Neurology, 46, 281–4. Hankey, G.J. & Warlow, C.P. (1991). Lacunar transient ischemic attacks: a clinically useful concept? Lancet, 337, 335–8. Hankey, G.J. & Warlow, C.P. (1994). Transient Ischaemic Attacks of the Brain and Eye. London: W.B. Saunders/Balliere Tindall. Hankey, G.J., Slattery, J.M., & Warlow, C.P. (1991). The prognosis of hospital-referred transient ischemic attacks. Journal of Neurology, Neurosurgery and Psychiatry, 54, 793–802. Hankey, G.J., Slattery, J.M., & Warlow, C.P. (1992). Transient ischemic attacks: which patients are at high (and low) risk of serious vascular events? Journal of Neurology, Neurosurgery and Psychiatry, 55, 640–52. Harrison, M.J.G., Iansek, R., & Marshall, J. (1986). Clinical identification of TIAs due to carotid stenosis. Stroke, 17, 391–2. Hart, R.G. (1992). Cardiogenic embolism to the brain. Lancet, 339, 589–94. Hess, D.C., Nichols, F.T., Sethi, K.D., & Adams, R.J. (1991). Transient cerebral ischemia masquerading as paroxysmal dyskinesia. Cerebrovascular Diseases, 1, 54–7. Huang, C.Y. & Broe, G. (1984). Isolated facial palsy: a new lacunar syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 47, 84–6. Kappelle, L.J., van Latum, J.C., Koudstaal, P.J., & van Gijn, J. for the Dutch TIA study group (1991). Transient ischemic attacks and small vessel disease. Lancet, 337, 339–41. Kase, C.S. (1988). Middle cerebral artery syndromes. In Handbook of Clinical Neurology, ed. P.J. Vinken, G.W. Bruyn, H.L. Klawans & J.F. Toole, pp. 353–70. Amsterdam: Elsevier. Kim, J.S. (1996). Restricted nonacral sensory syndrome. Stroke, 27, 988–90. Koudstaal, P.J., van Gijn, J., & Kappelle, L.J. for the Dutch TIA Study Group (1991). Headache in transient or permanent cerebral ischemia. Stroke, 22, 754–9. Koudstaal, P.J., van Gijn, J., Frenken, C.W.G.M. et al. for the Dutch Transient Ischaemic Attack Group. (1992). TIA, RIND, minor

stroke: a continuum, or different subgroups? Journal of Neurology, Neurosurgery and Psychiatry, 55, 95–7. Landi, G., Candelise, L., Cella, E., & Pinardi, G. (1992). Interobserver reliability of the diagnosis of lacunar transient ischemic attack. Cerebrovascular Diseases, 2, 297–300. Levy, D.E. (1988). How transient are transient ischemic attacks? Neurology, 38, 674–7. Lodder, J., Bamford, J.M., Sandercock, P.A.G., Jones, L.N., & Warlow, C.P. (1990). Risk factors amongst subgroups of cerebral infarction in the Oxfordshire Community Stroke Project: are hypertension or cardiac embolism likely causes of lacunar infarction? Stroke, 21, 375–81. Loeb, C., Gandolfo, C., & Dall’Agata, D. (1985). Headache in transient ischemic attacks (TIA). Cephalalgia, Suppl 2, 17–19. Margolin, D.I. & Marsden, C.D. (1982). Episodic dyskinesias and transient cerebral ischemia. Neurology, 32, 1379–80. Marti-Vilalta, J.L., Dalmau, J. & Santalo, M. (1981). Prosopagnosia, a transient ischemic attack. Stroke, 12, 702. Millikan, C.H. & Siekert, R.G. (1955a). Studies in cerebrovascular disease. I. The syndrome of intermittent insufficiency of the basilar arterial system. Proceedings of Staff Meetings Mayo Clinic, 30, 61–8. Millikan, C.H. & Siekert, R.G. (1955b). Studies in cerebrovascular disease. IV. The syndrome of intermittent insufficiency of the carotid arterial system. Proceedings of Staff Meetings Mayo Clinic, 30, 186–91. Mori, E., Tabuchi, M., & Yamadori, A. (1985). Lacunar syndrome due to intracerebral haemorrhage. Stroke, 16, 454–9. Oas, J.G. & Baloh, R.W. (1992). Vertigo and the anterior inferior cerebellar artery syndrome. Neurology, 42, 2274–9. O’Sullivan, F., Rossor, M., & Elston, J.S. (1992). Amaurosis fugax in young people. British Journal of Ophthalmology, 76, 660–2. Pessin, M.S., Duncan, G.W., Mohr, J.P., & Poskanzer, D.C. (1977). Clinical and angiographic features of carotid transient ischemic attacks. New England Journal of Medicine, 296, 358–62. Portenoy, R.K., Abissi, C.J., Lipton, R.B. et al. (1984). Headache in cerebrovascular disease. Stroke, 15, 1009–12. Purvin, V.A. & Dunn, D.W. (1981). Nitrate-induced transient ischemic attacks. Southern Medical Journal, 74, 1130–1. Raymond, L.A., Sacks, J.G., Choromokos, E., & Khodadad, G. (1980). Short posterior ciliary artery insufficiency with hyperthermia (Uhthoff’s symptom). American Journal of Ophthalmology, 90, 619–23. Ropper, A.H. (1985). Transient ipsilateral paraesthesias (TIPS) with transient monocular blindness. Archives of Neurology, 42, 295–6. Rothrock, J.F., Lyden, P.D., Yee, J., & Wiederholt, W.C. (1988). ‘Crescendo’ transient ischemic attacks: clinical and angiographic correlation. Neurology, 38, 198–201. Russell, R.W.R. (1988). Cause and treatment of insufficiency in the cerebral circulation. Clinical Neurology and Neurosurgery, 90, 19–24. Santamaria, J., Graus, F., Rubio, F., Arbizu, T., & Peres, J. (1983). Cerebral infarction of the basal ganglia due to embolism from the heart. Stroke, 14, 911–14.

Clinical types of transient ischemic attacks

Sempere, A.P., Duarte, J., Coria, F., & Claveria, L.E. (1992). Loss of vision by the colour white: a sign of carotid occlusive disease. Stroke, 23, 1179. Sloan, M.A. & Haley, E.C. (1990). The syndrome of bilateral hemispheric border zone ischemia. Stroke, 21, 1668–73. Stark, S.R. (1985). Transient dyskinesia and cerebral ischemia (letter). Neurology, 35, 445. Stiller, J., Shanzer, S., & Yang, W. (1982). Brainstem lesions with pure motor hemiparesis. Computed tomographic demonstration. Archives of Neurology, 39, 660–1. Tatemichi, T.K., Young, W.L., Prohovnik, I., Gitelman, D.R., Correll, J.W., & Mohr, J.P. (1990). Perfusion insufficiency in limb-shaking transient ischemic attacks. Stroke, 21, 341–7. Werdelin, L. & Juhler, M. (1988). The course of transient ischemic attacks. Neurology, 38, 677–80. Wiebers, D.O., Swanson, J.W., Cascino, T.L., & Whisnant, J.P. (1989). Bilateral loss of vision in bright light. Stroke, 20, 554–8.

World Health Organization Task Force on Stroke and Other Cerebrovascular Disorders: Stroke (1989). Recommendations on stroke prevention, diagnosis and therapy. Stroke, 20, 1407–31. Yanagihara, T., Piepgras, D.G., & Klass, D.W. (1985). Repetitive involuntary movements associated with episodic cerebral ischemia. Annals of Neurology, 18, 244–50. Yanagihara, T., Sundt, T.M., & Piepgras, D.G. (1988). Weakness of the lower extremity in carotid occlusive disease. Archives in Neurology, 45, 297–301. Yanagihara, T., Klass, D.W., Piepgras, D.G., & Houser, O.W. (1989). Brief loss of consciousness in bilateral carotid occlusive disease. Archives in Neurology, 46, 858–61. Youl, B.D., Adams, R.W. & Lance, J.W. (1991).Parietal sensory loss simulating a peripheral lesion, documented by somatosensory evoked potentials. Neurology, 41, 152–4.

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3

Hemiparesis and other types of motor weakness Teresa Pinho e Melo1 and Julien Bogousslavsky2 Department of Neurology, University of Lisbon, Portugal and 2Department of Neurology, University of Lausanne, Switzerland

1

Introduction Motor weakness, isolated or in association with other symptoms or signs, is the commonest problem of stroke patients. In epidemiological stroke studies, motor deficit (paresis/paralysis) is found in 80–90% of all patients (Herman et al., 1982; Bogousslavsky et al., 1988; Libman et al., 1992). There have been attempts to explain this fact using a variety of distinct arguments: (i) motor weakness is easily recorded by the patient, family, or physician; (ii) it can be caused by a stroke anywhere along the corticospinal pathways, from the cerebral cortex to the spinal cord; (iii) the most frequent types of stroke (lacunar, cardioembolic) have a ‘predilection’ for anatomic motor centres or tracts. Motor-weakness profiles and associated abnormalities can be helpful in predicting stroke subtypes (localization, cause) in the acute phase, which is essential for etiologic diagnostic strategies, for treatment, and for prognosis in individual patients. Motor weakness is also a major element in the rating scales for clinical stroke, because it is important for daily living activities, it is not difficult to evaluate, and its assessment has shown a good interobserver reliability.

Anatomic considerations The motor cortex is not confined to the large motor cells of Betz in the fifth layer of the precentral gyrus (primary motor cortex), as formulated at the turn of the century. Experimental studies in monkeys have indicated that only 60% of the corticospinal fibres arise from the primary motor cortex and the premotor and supplementary motor areas. The remaining fibres arise mainly from the postcentral gyrus and parietal cortex. The consensus is that in

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humans, approximately 60% of the corticospinal axons arise from the primary motor cortex, and the remainder from the premotor area, supplementary area, and the parietal lobe. According to the classic view, the primary motor cortex contains a somatotopic representation of body parts (homunculus) (Schott, 1993), the face being in the most inferior part of the precentral gyrus on the lateral surface of the hemisphere, and the leg in the paracentral lobule on the medial surface of the cerebral hemisphere. The particular parts of the body capable of the most delicate movements have the largest cortical representations. However, recent investigations support the notion of multiple representations of different body parts within the primary motor cortex (Strick & Preston, 1978). The corticospinal fibres converge within the corona radiata and pass downward through the internal capsule, crus cerebri, pons, and medulla. At the junction of the medulla and spinal cord, some 75–90% of the fibres cross the midline, and three separate corticospinal tracts are formed (crossed lateral or pyramidal, anterior or ventral, and uncrossed lateral). The positioning of the corticospinal tract in the internal capsule has evoked conflicting opinions. The largely accepted conclusions reached by Charcot (1883) and Dejérine (1901) that fibres occupy the anterior half of the posterior limb of the internal capsule are in apparent contradiction to the observations of fibres’ degeneration in patients with amyotrophic lateral sclerosis (Hirayama et al., 1962) as well as the findings from stereotaxic stimulation studies (Guiot et al., 1959) and from case reports of patients with isolated internal-capsule infarct (Englander et al., 1975). Such data indicate that in the internal capsule the corticospinal tract lies within a compact bundle in the third quarter of the posterior limb. This controversy probably arose because the corticospinal tract does not maintain a fixed position in the internal capsule. In 1980, Elliott

Hemiparesis and other types of motor weakness

Ross concluded that the pyramidal tract enters the rostral capsule in the anterior half of the posterior limb and progressively shifts into the posterior half of the posterior limb in the more caudal horizontal section. In progressively caudal horizontal sections, the anterior limb attenuates, and at the lower thalamic level the internal capsule has only a posterior limb. In the traditional view, the somatotopic motor representation is as a homunculus, with the head and eye in its anterior limb, the mouth and larynx/pharynx in the genu, the upper extremities in the anterior part of the posterior limb, and the lower extremities in the posterior part of the posterior limb (Dejérine, 1901). Although this somatotopic organization is suggested by clinicotopographic correlations in many cases, in others (Mohr et al., 1982) the pattern of hemiparesis is not exactly like a homunculus. Magnetic-resonance imaging (MRI) and use of the concept that the corticospinal tract assumes an oblique direction within the posterior limb of the internal capsule will help to solve this problem in the future. Although lesion sites other than the corticospinal tract have been reported to produce motor weakness (Critchley, 1930; Fisher, 1979; Donnan et al., 1982; Caplan et al., 1990; Boiten & Lodder, 1991a), the main cause is damage to the primary crossed corticospinal tract. Other lesions probably result in motor deficit by affecting indirect pathways that do not run in the pyramidal tract.

Hemiparesis When one is assessing a stroke patient with motor weakness, one of the first questions to be asked is whether or not the weakness is isolated. When analysed independently of other symptoms or signs, motor weakness is found in some 80–90% of all patients with stroke (Herman et al., 1982; Bogousslavsky et al., 1988; Libman et al., 1992). Hemiparesis with uniform weakness of the hand, foot, shoulder, and hip is the most frequent (at least two-thirds of cases) motor-deficit profile (Herman et al., 1982; Mohr et al., 1984). Monoplegia is found in about 19% of all stroke patients, and paraplegia in 1%, and in 2% of stroke patients three or four limbs are involved (Herman et al., 1982). It must be emphasized that inability to perform movements correctly can result not only from hemiparesis but also from neuropsychological dysfunction. Patients with motor neglect have a lack of initiative in moving the contralateral limbs, despite preserved muscular strength, and patients with motor impersistence are unable to maintain a voluntary action such as keeping arms or legs outstretched. Apraxia is another cause of inability to perform

correctly learned skilled movements in the absence of weakness. An abnormality in reaching a goal under visual control (visuomotor ataxia) may more rarely be confounded with hemiparesis. On the other hand some patients with acute hemiplegia are unaware of their weakness (anosognosia). To avoid erroneous diagnosis, highlevel cortical functions must be carefully tested. Hemiparesis with uniform weakness of the arm and leg does not predict the severity of the stroke, but when that is accompanied by trunk weakness or hemisensory deficit, it usually indicates a large lesion. Faciobrachial paresis is, in the majority of the patients, due to middle cerebral artery superficial infarcts (Freitas et al., 2000). Monoplegia is usually associated with small infarcts of the cortex or centrum ovale (Bogousslavsky & Regli, 1992). Distal predominance of the hemiparesis is usually related to cortical involvement, and only rarely (1 of 52 patients from the NINDS) to stroke confined to the putamen or internal capsule (Mohr et al., 1984).This has been thought to reflect the density of the body-parts representation over the hemispheral surface. Schneider and Gautier (1994) studied the infarct topography that caused leg-predominant weakness in 63 patients with acute stroke. Lesions restricted to the rear portion of the medial part of the precentral gyrus caused a contralateral, predominantly distal, severe leg weakness, with little improvement. Lesions involving the medial part of the premotor cortex, the supplementary motor area and the rear portion of the medial part of the precentral gyrus caused a contralateral distally predominant hemiparesis with leg plegia, and recovery was much better for the arm than for the leg. Lesions affecting the medial part of the premotor cortex, the supplementary motor area but sparing the precentral gyrus caused a contralateral proximal hemiparesis predominating on the leg, with good recovery for leg and arm. Some authors tried to find differences, in terms of frequency, severity, or profile of the hemiparesis, between right- and left-sided lesions, but in the majority of such studies no significant differences have been found (Herman et al., 1982; Mohr et al., 1984, 1993). Recently Freitas et al. (2000) found a higher frequency of left hemispheric infarcts in patients with motor deficit sparing the leg. In patients with acute spinal vascular lesions, the paralysis of voluntary movements typically is associated with flaccidity and abolishment of spinal reflexes (spinal shock) that after a few days will give way to a state of spasticity (hypertonus and heightened stretch reflexes). However, in patients with brain lesions, that sequence of changes is not a rule: Limb spasticity may develop in the acute phase, and

23

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T. Pinho e Melo and J. Bogousslavsky

limb flaccidity may be associated with retained reflexes; not rarely, tonus and/or reflexes will remain normal or will even be increased. Patients with massive brain hemorrhages and infarcts may present at onset with spastic limbs (bilateral or contralateral to the hemispheric lesion). This spasticity is not persistent and usually implies abnormal extensor responses of the arm and leg, termed decerebrate rigidity. Mohr et al. (1993) studied the infarct topography and hemiparesis profiles in 183 patients with infarction at the middle cerebral artery convexity. In this stroke subtype, they found a good correlation between infarct size and the severity of weakness, whether estimated by overall motor function on one side or by arm or hand function alone, but their attempts to correlate a specific syndrome with a specific brain location were frustrating. However, Foix and Lévy (1927), using autopsy findings in individual cases, described the characteristics of hemiplegia from different infarct topographies of the middle cerebral arteries. Infarction involving the whole territory of the middle cerebral artery produced a severe controlateral hemiplegia. But two patterns of hemiplegia in relation to the infarct extension were possible when only the deep territory was concerned: (i) a ‘massive hemiplegia’, similar to that found when the infarct involved both the superficial and deep territories, affecting the leg and the arm rendering the patient unable to walk, and usually lacking secondary spasticity (flask hemiplegia), and (ii) a ‘moderate hemiplegia’ involving the leg and the arm proportionally, although in some cases the arm seemed more affected than the leg and developed marked contracture. The syndrome of hemiplegia caused by an infarct of the entire surface territory of the middle cerebral artery was characterized by brachial predominance of hemiplegia, not rarely involving mainly distal movements. Some authors have found a possible correlation between specific movements and cerebral–lesion localization. Freund and Hummelsheim (1985) studied 11 patients, each with hemiparesis of proximal muscles and a lesion involving the premotor cortex but not the primary motor cortex. They found a stereotyped syndrome, with the paresis affecting mainly those shoulder muscles that abduct and elevate the arm, and affecting all hip muscles to similar extents, the arm being functionally more affected than the leg. The associated lesions, diagnosed by computed tomography (CT), were border-zone infarcts between the anterior and the middle cerebral arteries. Those authors suggested that the different pattern of involvement of shoulder and hip muscles might be related to a particular role of the human premotor cortex in the act of reaching. Yasuo et al. (1993) reported a 78-year-old man

with a small cortical infarct over the left central sulcus presenting at the time of hospital discharge with isolated mild weakness of his contralateral thumb. Thumb flexion was affected to a greater degree than other thumb movements, suggesting that an arrangement of intracortical efferent zones similar to that found in monkeys (Asanuma & Rosén, 1972) also exists in humans. Motor weakness was present in all but 1 of the 27 patients, each with an infarct in the anterior cerebral artery territory, studied by Bogousslavsky and Regli (1990a). In the majority of those patients the hemiparesis predominated in the lower limb, including three patients with crural monoparesis. Only two patients had isolated motor deficit, involving the arm and leg in one patient and only the leg in the other. Kubis et al. (1999) reported a higher percentage of patients with isolated motor deficit (10 from the 16 patients studied), that involved the arm and leg (with leg predominance) in six patients, the arm and face in one patient and only the leg in three patients. Hemiparesis predominating in the lower limb is seen mainly in large infarcts in the anterior cerebral artery territory, being associated with involvement of the parasagittal precentral area. When the infarct spares the precentral region and involves the more anterior premotor region or extends deeply towards the internal capsule, the motor deficit may involve either face/arm/leg or face/arm, usually predominating in the upper limb. Recently, Chamorro et al. (1997) suggested that the faciobrachial paresis is not caused by corticospinal tract weakness, but by motor neglect caused by damage of medial premotor areas or its connections. Infarcts of the posterior cerebral artery cause a spectrum of manifestations (hemianopia, abnormal visual perception, neuropsychological signs and symptoms), but usually without weakness. However, hemiparesis can sometimes occur, resulting from infarction of the cerebral peduncle (peduncular perforators and anterior circumflex arteries) (Hommel et al., 1990). In cerebellar infarcts a motor deficit suggests brainstem lesion or compression of motor fibres by a mass effect due to edema (Kanis et al., 1994). In pontine infarcts motor weakness depends on the topography of the lesion. Ventromedial pontine infarcts, usually large infarcts, cause severe faciobrachiocrural hemiparesis with ataxia and dysarthria, while ventrolateral pontine infarcts, usually small infarcts, cause mild motor dysfunction corresponding to lacunar syndromes (Bassetti et al., 1996). Kim et al. (1995a) compared rostral, middle and caudal pontine ventromedial infarcts and found that large lesions involving the caudal or middle pons correlated with severe hemiparesis, whereas lesions of similar size located

Hemiparesis and other types of motor weakness

in the rostral pons tended to have minimal or no limb weakness. Pontine hemiparesis is usually more marked in the upper than lower limb and in distal than proximal parts of the limbs. A mild facial palsy, much more commonly homolateral to the motor deficit, is often present, and can be attributed to the damage of supranuclear fibers at the ventrotegmental junction of the upper middle pons. Hemiparesis is the hallmark of medial medullary infarct, a rare localization for posterior circulation strokes. The motor deficit is usually contralateral, more pronounced in the upper extremity and in the distal portion of the limbs. Hemiparesis can occasionally be isolated (pure motor stroke). Other patterns of motor deficit can be observed: tetraparesis caused by bilateral pyramid infarct, ipsilateral hemiparesis caused by infarct below the pyramidal decussation, crural predominance in more ventral infarcts and rarely weakness can be minimal or absent. In about one half of patients ipsilateral lingual palsy is associated with the contralateral hemiparesis. In the absence of lingual palsy signs of involvement of structures close to the pyramids such as lemniscal hyposthesia, mild decrease in pain sensation, nystagmus and mental changes are helpful for the clinical diagnosis of medial medullary infarct (Bassetti et al., 1997; Kim et al., 1995b).

Faciobrachial paresis A considerable number of patients develop stroke without involvement of the lower limb. This pattern of paresis is highly suggestive of damage to the motor cortex, due to involvement of the superficial branches of the middle cerebral artery, but it is often seen in lesions involving the complete territory of the middle cerebral artery, the complete territory of the lenticulostriate arteries or the territory of the lateral lenticulostriate arteries. More rarely it was reported after anterior cerebral artery or brainstem infarcts. Even if we considered only ‘pure faciobrachial paresis’ it is frequently caused by a cortical infarct. The majority of the 895 patients with paresis sparing the leg (73% faciobrachial, 21% brachial and 6% facial) studied by Freitas et al. (2000) had a superficial infarct, restricted to the superficial branches of the middle cerebral artery in half of the patients. Even when only patients with pure motor weakness were considered, the most common site of the lesions was still the superficial middle cerebral artery territory. Studies performed in patients with middle cerebral artery infarcts showed that faciobrachial paresis accounts for about three-quarters of all types of motor deficit after anterior middle cerebral artery infarcts, and for about two-

thirds after posterior middle cerebral artery infarcts (Bogousslavsky et al., 1989). Large-artery disease and cardioembolism are the main causes of strokes sparing the lower limb, while the frequency of strokes due to small-artery disease is low (Freitas et al., 2000).

Pure motor hemiparesis Pure motor hemiparesis (PMH) was reported by Fisher and Curry (1965) as an acute pure motor stroke involving face, arm, and leg on one side, in the absence of sensory deficit, homonymous hemianopia, aphasia, agnosia, or apraxia. They found that it resulted from a small infarct in the internal capsule or in the basis pontis, most often due to occlusion of one of the small penetrating vessels (i.e. a ‘lacune’). However, at the beginning of this century, Pierre Marie (1901) and J. Ferrand (1902) had first stressed the link between isolated sudden hemiparesis and lacunes. In his essay on hemiplegia in old age, Ferrand reported on 88 patients with lacunes in whom the typical picture was a ‘sudden, partial incomplete and often transient hemiparesis not rarely accompanied by dysarthria’. Nowadays, PMH is considered the most common lacunar syndrome (Mohr et al., 1978; Nelson et al., 1980; Donnan et al., 1982; Bamford et al., 1987; Arboix et al., 1990; Sohn et al., 1990; Norrving & Staaf, 1991; Gan et al., 1997), but the original restrictive definition has been broadened by some authors to include cases with little or no facial involvement and other types of nonproportional hemiparesis (Rascol et al., 1982; Bamford et al., 1987; Kappelle et al., 1988; Orgogozo & Bogousslavsky, 1989; Arboix et al., 1990). Dysarthia may be present (Fisher, 1979) and it is probably due in the majority of patients to facio-oral weakness. The presence of dysarthria in patients with isolated hemiparesis does not influence the determination of stroke type and localization (Melo et al., 1992a). As the majority of the studies on isolated hemiparesis were performed in selected populations with so-called lacunar stroke, the incidence of this syndrome among stroke patients in general is not well defined. In the Lausanne Stroke Registry (Melo et al., 1992a) and in the Norrving & Staaf (1991) series, all patients with unilateral motor weakness, partial or complete, were included. About 14% of all patients who had suffered a first stroke had isolated unilateral hemiparesis or hemiplegia, with face/arm/leg involvement in half of them. In the Oxfordshire Community Stroke Project (Bamford et al., 1987) and in the Harvard Cooperative Stroke Registry (Mohr et al., 1978), the incidence of isolated hemiparesis

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T. Pinho e Melo and J. Bogousslavsky

Table 3.1. PMH stroke series Strokea

Reference Fisher & Curry

Weakness

Percentage

Imaging/

No lesion

Deep

Superficial

Number of

distribution

of all

autopsy

visible

infarct

infarct

Hemorrhage

Brain-stem

cases

(%)

strokes

(no. of cases)

(%)

(%)

(%)

(%)

infarct (%)

50

FULb

—

AUc (9)

—

67

—

—

33

14

?

—

Brain scan (11)

82

—

18

—

—

25

FUL

3

Brain scan (18)

67

—

33

—

—

?

—

CT (29)

31

34

24

10

(1965) Chokroverty & Rubino (1975) Richter et al. (1977) Weisberg (1979) Pullicino

29 18

d

d

d

—

?

—

CT (18)

—

61

39

—

—

26

FUL

8e

CT (26)

38

42

19

—

—

30

FUL (53);

—

CT (30)

3

83

—

7

7

14

CT (123)

43

41

13

2

—

14

CT (255)

20

47

25

4

4

(1994) Nelson et al. (1980) Rascol et al. (1982)

FU (43); L (3)

Norrving &

199

Staaf (1991)

FUL (67); FU (8); UL (21); F, U, L (4)

Melo et al.

255

(1992a)

FUL (50); FU (29); UL (9); U (10); F, L (2)

Notes: a

Patients with imaging autopsy.

b

F, face; U, Upper limb; L, lower limb.

c

AU, autopsy

d

Only patients with infarct on CT.

e

312 patients with stroke and CT.

f

Only patients with presumed lacunar stroke (n ⫽ 180).

was lower, around 9%, probably because patients with monoparesis were excluded. Some studies have attempted to clarify how the distribution of weakness in PMH correlates with stroke type, topography, and potential cause (Norrving & Staaf, 1991; Chamorro et al.,1991; Melo et al., 1992a; Gan et al., 1997). When face, arm, and leg weakness are considered in any possible combination, a significant number of patients will be found to have a cortical or brainstem infarction or a hemorrhage, whereas less than half of patients will be found to have a deep infarct (Table 3.1 and 3.2). Rarely non-

vascular occasional causes of PMH have been reported: nocardial abscess (Weintraub & Glaser, 1970), cerebral metastases (Chokroverty & Rubino, 1975; Weisberg, 1979), subdural hematoma, and demyelinating disease (Weisberg, 1979). These rare cases may now be easily detected by imaging techniques. In all PMH series studied, face/arm/leg involvement was the most common type of weakness distribution (50–70%), and isolated leg or face weakness was rare. The percentages of face/arm, arm/leg, and isolated arm weakness varied with inclusion criteria. When all stroke patients were

Hemiparesis and other types of motor weakness

Table 3.2. Distribution of weakness related to stroke type and localization Stroke type

Distribution of weaknessa FUL (%) FU (%) UL (%) U (%) L (%) F (%)

No lesion visible (n⫽51)

Deep infarct (n⫽121)

Superficial infarct (n⫽65)

(18b (35.3) (15 (29.4) ( 7 (14) (10b (20) (1 (2) (0

(89c (73.6) (19c (15.7) (9 (7.4) (2c (1.7) (1 (0.8) (1 (0.8)

( 6 (9.2) (39 (60) (5 (7.7) (12 (18.5) ( 2 (3.1) (1 (1.5)

Hemorrhage (n⫽9) (7 (77.8) (0 (1 (11.1) (1 (11.1) (0 (0

Brainstem infarct (n⫽9) (8 (88.9) (1 (11.1) (0 (0 (0 (0 (0

Total (n⫽255) 128 (50.2) 74 (29) 22 (8.6) 25 (9.8) 4 (1.6) 2 (0.8)

Notes: a F, face; U, upper limb; L, lower limb. b The percentage among patients without visible lesions differed significantly (P⬍0.05) from that among patients with ischemic infarcts seen on CT c The percentage among patients with deep infarcts differed significantly (P⬍0.05) from that among other patients with other lesions seen on CT. Source: Lausanne Stroke Registry.

included, face/arm was the second more frequent type of distribution (29–43%) (Rascol et al., 1982; Melo et al., 1992a), but when only patients with a presumed lacunar stroke were studied, a higher percentage of arm/leg distribution was found (Donnan et al., 1982; Arboix et al., 1990; Norrving & Staaf, 1991), because patients with face/arm motor-weakness distributions more frequently have cortical infarct. Traditionally, brachiocrural hemiparesis, with facial sparing, was suggestive of a medullary lacune involving the corticospinal tract within the pyramid (Fisher & Curry, 1965; Ropper et al., 1979; Bogousslavsky et al., 1986). Melo et al. (1992a) suggest that an arm/leg weakness distribution in hypertensive patients is highly suggestive of a deep infarct. This fact may be explained by the rostro-caudal displacement of the pyramidal tract in the internal capsule. In rostral sections, face and limb fibers are less close to each other. A cortical infarct may produce an isolated (usually nonproportional) hemiparesis. However, this is not common, because of the proximity of the motor and sensory cortices. Table 3.3 correlates weakness distribution profiles with superficial infarct localization in Lausanne Stroke Registry patients with isolated motor deficit (Melo et al., 1992a).

About half of the patients with face/arm or isolated arm weakness had a superficial infarct, which was in the anterior superficial middle cerebral artery territory in the majority of cases. Isolated motor deficits in any possible combination were the clinical manifestation in about half of the patients having infarcts of the middle cerebral artery pial territory, affecting the anterior superior division in the majority of cases (69%) (Bogousslavsky et al., 1989). Moreover, when PMH involving face, arm, and leg is considered, infarcts in the posterior inferior division of the middle cerebral artery are never responsible. We studied which variables would give good predictions of the presence of a deep infarct in patients with PMH (Melo et al., 1992a). We concluded that patients with proportional face/arm/leg involvement and hypertension had a 90% probability of deep infarct, whereas patients either with a face/arm/leg distribution but no hypertension or with an arm/leg distribution and hypertension had each a 70% probability of deep infarct; when weakness distribution other than face/arm/leg or arm/leg was present, such probability fell to 38% for patients with hypertension, and to 18% for patients without hypertension. Recently, Gan et al. (1997) determined for the PMH syndrome a positive predictive value of 79% for detecting radiological lacunes.

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Table 3.3. Superficial infarct topography correlated with distribution of weakness Topography of superficial infarcts

Distribution of weaknessa

Anterior superficial MCAb (n⫽53)

Posterior superficial MCA (n⫽2)

ACAc (n⫽5)

Watershed (n⫽5)

FUL FU UL U L F

5 36 1 10 0 1

0 2 0 0 0 0

0 0 4 0 1 0

1 1 0 2 1 0

Notes: a F, face; U, upper limb; L, lower limb. b MCA, middle cerebral artery. c ACA, anterior cerebral artery.

However they did not find change in this value when only the proportional face/arm/leg involvement was considered. Toni et al. (1994) aver that PMH are poorly predictive of lacunar stroke when patients are evaluated within 12 hours of the event. Some of their patients, during hospitalization, present further clinical changes, developing cortical signs and symptoms. When the potential mechanism of infarct is considered and not only the infarct size and location, a non-lacunar mechanism is found in about onethird of the patients with PMH (Melo et al., 1992a; Gan et al., 1997). In our study the remaining deep infarcts were mainly large deep infarcts (striatocapsular, anterior choroidal artery territory, thalamic, junctional) most frequently due to embolism (heart-to-heart or artery-to-artery) or hypoperfusion. In those large deep infarcts, despite maximal ischemia in the depth of the hemisphere, there was also compromise of the cortical blood supply, resulting in clinical ‘cortical’ features. Thus, the frequency of patients presenting with isolated motor deficit as manifestations of large deep infarct is rather low, varying between zero and 17% (Ghika et al., 1989; Bogousslavsky & Regli, 1992). Kittner et al. (1992) studied the features of the neurological examinations as they related to a cardiac embolic stroke mechanism and concluded that ‘hemiparesis’ that included both arm and leg without sensory or ‘cortical’ deficits had a strong inverse association with a cardiac source of embolism. For a significant number of patients with isolated motor deficits, CT will reveal no appropriate lesions (Weisberg,

1979; Melo et al., 1992a). A very small deep infarct may be the cause in such cases, but some studies suggest that patients in whom CT shows no lesions and patients with deep infarcts revealed by CT have different characteristics (Melo et al., 1992a). Patients in whom CT does not reveal appropriate lesion less often have a proportional distribution of weakness, whereas brachial monoparesis may be more frequent. Also, hypertension and diabetes, which are the most important vascular risk factors for lacunar infarcts, are less frequent in patients in whom CT shows no appropriate lesions. Nighoghossian et al. (1993) studied with MRI a small series of patients with PMH and repeatedly negative CT and found a pontine paramedian infarct in all these patients. They suggest that the combination of dysarthria and a history of previous transient gait abnormality or vertigo may favour a pontine location. Transient episodes of PMH have been said to constitute a capsular warning syndrome by Donnan et al. (1993). This form of transient ischemic attack (TIA) may be due to a hemodynamic phenomenon, with diseased single small penetrating vessels, that subsequently leads to early capsular infarction in a high proportion of cases (42%). In conclusion, isolated hemiparesis or hemiplegia is a common manifestation of stroke and can be due to lesions at various locations, with different mechanisms. The pattern of distribution of motor weaknesses seems to be best predictor of stroke type, topography, and cause.

Isolated monoparesis Isolated monoparesis following cerebral infarction is rare. It was found in only 1.7% of patients in the Lausanne Stroke Registry (Melo et al., 1992a) and in 1.2% of patients in the series reported by Norrving and Staaf (1991). The majority of such patients have brachial monoparesis; crural monoparesis is almost never present (0.2% of all strokes). Fisher (1982) stated that ‘monoplegia is never due to occlusion of a penetrating branch’. However, Bennett and Campbell (1885) had reported an isolated paresis of the upper limb in an 80-year-old man who at autopsy was found to have had a small infarct immediately posterior to the genu of the internal capsule; however, transient facial involvement had been present initially. Subsequently, others have found small deep infarcts revealed by CT to be the causes of isolated brachial weakness and crural weakness in single patients. Recent representative studies have shown that isolated monoparesis can be the clinical presentation in up to 4% of patients with lacunar infarcts (Arboix et al., 1990; Norrving & Staaf, 1991). This does not

Hemiparesis and other types of motor weakness

contradict the fact that the lesion underlying isolated monoparesis is usually localized in the cortex or centrum semiovale. In the study by Arboix et al. (1990), none of the eight patients with isolated monoparesis had positive CT findings (each patient had at least two CT scans), and only 1 of those patients studied with MRI had a lacune in the internal capsule. Such findings are in accord with those from the Lausanne Stroke Registry (Melo et al., 1992a), in which CT revealed no lesions in 40% of patients with isolated brachial monoparesis. That finding may have been due to the fact that some small cortical infarcts will not be revealed by CT. Melo et al. (1992a) and Boiten and Lodder (1991b) support the rule that a brachial monoparesis is usually due to a small infarct involving the cortex and adjacent subcortex in the territory of the middle cerebral artery. Moreover, among 380 (selected from 1303 patients in the Lausanne Stroke Registry) in whom CT revealed infarcts in the middle cerebral artery pial territory, 13% had a brachial monoparesis. Schneider and Gautier (1994) studied nine patients with crural monoparesis. Three patients had a cortical infarct, one a lacune of the posterior limb of the internal capsule, one a brainstem infarct and two a thalamic hematoma.

Isolated facial paresis Isolated facial paresis of the upper motor neuron type without involvement of the extremities is a rare manifestation of stroke. It has no strong localizing value (Melo et al., 1992a). In a series of 227 patients with lacunar infarcts, there were six patients with motor deficits involving only the face (Arboix et al., 1990). In four of those patients, CT revealed appropriate infarcts, involving the genu of the internal capsule in three patients and the pons in one patient. Donnan et al. (1982) emphasized a capsular-corona radiata localization. Several patients with supranuclear facial palsy and pontine vascular lesion confirmed by CT or MRI have been reported (Hopf et al., 1990). One of the two patients with isolated facial paresis included in the Lausanne Stroke Registry (Table 3.3) had an infarct in the anterior superior middle cerebral artery territory. Figure 3.1 shows a CT scan from a 60-year-old man who developed an acute isolated supranuclear facial palsy caused by an infarct in the genu and anterior limb of the internal capsule. Bogousslavsky and Regli (1990b) reported a ‘capsular genu syndrome’ characterized by contralateral facial and lingual weakness, with dysarthria and mild limb involvement limited to hand weakness.

Fig. 3.1. Infarction localized to the genu and anterior limb of internal capsule in a 60-year-old man with actue isolated supranuclear facial palsy.

Patients described as having isolated facial paresis generally shared dysarthria. The existence of pure supranuclear facial paresis without dysarthria or pure dysarthria remains unconvincing. Kim (1994) suggests that pure dysarthria or isolated facial paresis syndrome be considered as an extreme continuum of dysarthria–facial paresis syndrome, usually associated with small strokes in the corona radiata, basal ganglia/internal capsule or pons.

Hemiparesis and other associated signs Hemiparesis and lacunar syndromes Though not specific, a few neurological syndromes are associated with small infarcts in the territory of the deep perforating branches. PMH is most commonly the result of infarction in the internal capsule. When hemiparesis is associated with homolateral ataxia (i.e. ataxic hemiparesis) the infarct, in the majority of patients, will be located in the pons, corona radiata, or internal capsule (Fisher, 1978). If sensory loss (proprioception, pain) is found with the same distribution as motor weakness (sensorimotor stroke) (Mohr et al., 1977) the infarct usually will be in the internal capsule. Some cases of sensorimotor stroke may represent infarcts in the anterior choroidal artery territory, although

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additional deficits are usually present. Hemiparesis with homolateral hemiataxia and sensory abnormalities (hypesthetic ataxic hemiparesis) is usually caused by a small thalamic infarct, a capsulothalamic infarct, or, more rarely, an infarct in the anterior choroidal artery territory (Helgason & Wilbur,1990; Melo et al., 1992b).

hemiparesis (Weber syndrome). A lower-pontine infarct may produce a unilateral abducens or facial palsy combined with a contralateral hemiparesis (Millard–Gubler syndrome). Hemiparesis due to pontine infarct can also be associated with a ‘one-and-a-half syndrome’, a lateral-gaze palsy associated with internuclear ophthalmoplegia (see Chapter 5).

Hemiparesis with neuropsychological dysfunction In the Tilburg population-based stroke registry (Herman et al., 1982), 62% of 474 patients had combined motor and speech deficit (dysphasia or dysarthria). Such patients had more severe weaknesses than did those with isolated hemiparesis. Speech disturbances have been traditionally linked to hemiparesis caused by a cortical lesion in the dominant hemisphere. But hemiparesis and dysphasia can also occur in patients with deep infarcts in the dominant hemisphere. Lenticulostriate and anterior choroidal artery territories are usually involved. In its typical form, the anterior choroidal artery syndrome features the triad of hemiplegia, hemianesthesia, and homonymous hemianopia, but incomplete forms of the syndrome are more frequent, and PMH may be present in a considerable number of cases (Mohr et al., 1991). In the presence of thalamic infarct (tuberothalamic territory), hemiparesis is rarely associated with a specific speech disturbance. In these patients, hemiparesis is usually mild. Caudate infarct or hemorrhages can cause all types of weakness distribution and severity. Motor signs are usually temporary, being associated with cognitive and behavioural abnormalities (abulia, agitation, hyperactivity, neglect, language abnormalities). The exact mechanism of this motor deficit is unknown, although disruption of frontopontine fibres or corticospinal projections have been suggested (Caplan et al., 1990).

Hemiparesis with eye-movement disorders Conjugate-gaze palsy is one of the most common eyemovement abnormalities in patients with acute stroke. The eyes may be deviated to one side, either to the side of a hemispheral lesion or to the opposite side of a pons lesion, with gaze paresis towards the opposite side. This gaze palsy is almost invariably accompanied by hemiparesis. Abnormal ocular movements in association with motor hemiparesis may be caused by a brainstem vascular lesion involving specific oculomotor centers located near the corticospinal tract. An infarct in the cerebral peduncle usually produces an ipsilateral ophthalmoplegia due to involvement of the third-nerve intraaxial fibres and a contralateral

Bilateral weakness Weakness affecting both sides of the body is not common following a stroke (Herman et al., 1982). It may be caused by spinal-cord, bilateral hemispheric, or brainstem infarcts. A spinal-cord infarct may produce a paraparesis or a quadriparesis, depending on the level of infarct (see Chapter 34). Paralysis of extremities and the lower cranial musculature, with sparing of consciousness (the locked-in syndrome), results from bilateral corticobulbar and cortico-spinal-tract lesions, usually caused by basilar artery occlusion. Simultaneous bilateral infarctions in the anterior cerebral artery territory can occur in relation to the anatomic variants of the junction between the anterior cerebral artery and the anterior communicating artery. Paraplegia combined with akinetic mutism, incontinence, and bilateral grasp is the classic picture produced by this type of infarct. The acute onset of bilateral motor signs, especially with sparing of facial function, can be caused by bilateral border-zone infarctions. Bilateral anterior watershed infarcts (between the anterior cerebral artery and middle cerebral artery territories) limited to the cortex may produce a picture of bibrachial paralysis (man-in-thebarrel), because the junction of the anterior cerebral artery and middle cerebral artery territories is at the level of the arm-shoulder representation on the motor strip. A variant with triplegia has been reported (Fisher & McQuillen, 1981), but the face is usually spared, because the border zone rarely extends laterally over the convexity. Headache, seizures, and bilateral weakness predominating in the legs are suggestive of sagittal sinus thrombosis.

Pseudo-bulbar features Lower cranial nerve palsy induced by supranuclear lesions (corticobulbar and corticopontine pathway) in relation to multiple recurrent strokes was named by Lépine (1877) as ‘pseudo-bulbar palsy’. These patients present a striking incongruity between the loss of voluntary movements of

Hemiparesis and other types of motor weakness

Fig. 3.2. CT scan showing bilateral opercular lesions in a 46-yearold man presenting with Foix–Chavany–Marie syndrome.

muscles innervated by the motor nuclei of the lower pons and medulla (inability to swallow, phonate, articulate, move the tongue, forcefully close the eyes, etc.) and the preservation of reflexive pontomedullary activities (yawning, coughing, throat clearing, spasmodic laughing or crying). Thurel (1929) divided pseudo-bulbar palsy into three forms: the cortical form, characterized by a faciopharyngoglossomasticatory diplegia with automatic voluntary dissociation; the striatal form, having the same features, but also with pyramidal signs, emotional lability, and intellectual impairment; and the pontine form, with faciopharyngoglossomasticatory diplegia associated with emotional lability, pyramidal signs and sometimes cerebellar signs, but a lack of dementia. Some of these features can appear in isolation, without any other manifestation of pseudobulbar palsy. One of the most commonly reported isolated features is spasmodic laughing and crying: inappropriate laughing and crying unrelated to surrounding circumstances or stimulation, with no corresponding emotional feeling.

Although in many patients pseudobulbar palsy results from bilateral and multiple recurrent strokes, acute pseudobulbar palsy has been reported. Besson et al. (1991) studied 13 patients with pseudobulbar palsy of acute onset either with or without prior stroke. They concluded that it may be associated with infarcts or hemorrhages involving the frontal opercular region or the corticonuclear pathways in both cerebral hemispheres, but sparing the corticospinal pathways. The acute onset may be due to acute damage to corticonuclear fibres on one side when contralateral corticonuclear fibres have previously interrupted, with little or no symptom. Helgason et al. (1988) reported eight patients with acute pseudobulbar palsy caused by consecutive bilateral anterior choroidal artery territory. Acute pseudobulbar palsy has also been reported in patients with pontine infarction (Bassetti et al., 1996; Kim et al., 1995a). Foix–Chavany–Marie syndrome is a rare type of pseudobulbar palsy usually associated with cerebrovascular disease (Foix et al., 1926). This syndrome is characterized by anarthria and bilateral central voluntary paresis of lower cranial nerves, with preserved involuntary and emotional innervation. In the majority of patients this syndrome is caused by bilateral opercular lesions (Fig. 3.2), being considered as the cortical or opercular type of pseudobulbar palsy. In contrast to the non-cortical suprabulbar palsy, in the cortical type, the onset is most often acute. Paralysed muscles remain hypotonic, patients are completely unable to talk and swallow, and pathological laughter or crying and emotional lability are less common.

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Kim, J.S. (1994). Pure dysarthria, isolated facial paresis, or dysarthria-facial paresis syndrome. Stroke, 25,1994–8. Kim, J.S., Lee, J.H., Im, J.H., & Lee, M.C. (1995a). Syndromes of pontine base information. A clinical-radiological correlation study. Stroke, 26, 950–5. Kim, J.S., Kim, H.G., & Chung, C.S. (1995b). Medial medullary syndrome. Report of 18 new patients and a review of the literature. Stroke, 26, 1548–52. Kittner, S.J., Sharkness, C.M., Sloan, M.A. et al. (1992). Infarcts with a cardiac source embolism in the NINDS Stroke Data Bank: neurologic examination. Neurology, 42, 299–302. Kubis, N., Guichard, J.-P. & Woimant, F. (1999). Isolated anterior cerebral artery infarcts: a series of 16 patients. Cerebrovascular Diseases, 9, 185–7. Lépine, R. (1877). Note sur la paralysie glosso-labièe cérébrale à forme pseudo-bulbaire. Revue Mens Medicin Chirurgie, 1, 909–22. Libman, R.B., Sacco, R.L., Shi, T., Tatemichi, T.K., & Mohr, J.P. (1992). Neurologic improvement in pure motor hemiparesis: implications for clinical trials. Neurology, 42, 1713–16. Marie, P. (1901). Des foyers lacunaires de désintégration et de différents autres états cavitaires du cerveau. Revue De Medicine (Paris), 21, 281–98. Melo, T.P., Bogousslavsky, J., van Melle, G., & Regli, F. (1992a). Pure motor stroke: a reappraisal. Neurology, 42, 789–98. Melo, T.P., Bogousslavsky, J., Moulin, T., Nader, J., & Regli, F. (1992b). Thalamic ataxia. Journal of Neurology, 239, 331–7. Mohr, J.P, Kase, C.S., Meckler, R.J., & Fisher, C.M. (1977). Sensorimotor stroke due to thalamocapsular ischemia. Archives of Neurology, 34, 739–41. Mohr, J.P, Caplan, L.R., Melski, J.W. et al. (1978). The Harvard Cooperative Stroke Registry: a prospective registry. Neurology, 28, 754–62. Mohr, J.P, Kase, C.S., Wolf, P.A. et al. (1982). Lacunes in the NINCDS Pilot Stroke Data Bank. Annals of Neurology, 1, 84. Mohr, J.P., Rubinstein, L.V., Edelstein, S.Z. et al. (1984). Hemiparesis profiles in acute stroke: the NINCDS Stroke Data Bank. Annals of Neurology, 1, 156. Mohr, J.P, Steinke, W., Timsit, S.G., Sacco, R.L., & Tatemichi, T.K. (1991). The anterior choroidal artery does not supply the corona radiata and lateral ventricular wall. Stroke, 22, 1502–7. Mohr, J.P, Foulkes, M.A., Polis, A.T. et al. (1993). Infarct topography and hemiparesis profiles with cerebral convexity infarction: the Stroke Data Bank. Journal of Neurology, Neurosurgery and Psychiatry, 56, 344–51. Nelson, R.F., Pullicino, P., Kendall, B.E., & Marshall, J. (1980).

Computed tomography in patients presenting lacunar syndromes. Stroke, 11, 256–61. Nighoghossian, N., Ryvlin, P., Trouillas, P., Laharottte, J.C., & Froment, J.C. (1993). Pontine versus capsular pure motor hemiparesis. Neurology, 43, 2197–201. Norrving, B. & Staaf, G. (1991). Pure motor stroke from presumed lacunar infarct. Incidence, risk factors and initial clinical course. Cerebrovascular Disease, 1, 203–9. Orgogozo, J. M. & Bogousslavsky, J. (1989). Lacunar syndromes. In the Handbook of Clinical Neurology, vol. 54, ed. P.J. Vinken, G.W. Bruyn & H.L. Klawans, pp. 235–69. Amsterdam: Elsevier. Pullicino, P. (1994). Bilateral distal upper limb amyotrophy and watershed infarcts from vertebral dissection. Stroke, 25, 1870–2. Rascol, A., Clanet, M., Manelfe, C., Guiraud, B., & Bonafe, A. (1982). Pure motor hemiplegia: CT study of 30 cases. Stroke, 13, 11–17. Richter, R.W., Brust, J.C.M., Bruun, B., & Shafer, S.Q. (1977). Frequency and course of pure motor hemiparesis: a clinical study. Stroke, 18, 58–60. Ropper, A.L., Fisher, C.M., & Kleinman, G.M. (1979). Pyramidal infarction in the medulla: a cause of pure motor hemiplegia sparing the face. Neurology, 29, 91–5. Ross, E.D. (1980). Localization of the pyramidal tract in the internal capsule by whole brain dissection. Neurology, 30, 59–64. Schneider, R. & Gautier J-C. (1994). Leg weakness due to stroke. Site of lesions, weakness patterns and causes. Brain, 117, 347–54. Schott, G.D. (1993). Penfield’s homunculus: a note on cerebral cartography. Journal of Neurology, Neurosurgery and Psychiatry, 56, 329–33. Sohn, Y.H., Lee, B.J., Sunwoo, I.N., Kim, K.W., & Suh, J.H. (1990). Effect of capsular infarct size on clinical presentation of stroke. Stroke, 21, 1258–61. Strick, P.L. & Preston, J.B. (1978). Multiple representation in the primate motor coetex. Brain Research, 154, 366–70. Thurel, R. (1929). Les pseudobulbaires: etude clinique et anatomopathologique. Paris Thesis. Toni, D., Del Luca, R., Fiorelli, M. et al. (1994). Pure motor hemiparesis and sensorimotor stroke. Accuracy of very early clinical diagnosis of lacunar strokes. Stroke, 25, 92–6. Weintraub, M.E. & Glaser, G.H. (1970). Nocardial brain abcess and pure motor hemiplegia. New York State Journal of Medicine, 70, 2717–21. Weisberg, L.A. (1979). Computed tomography and pure motor hemiparesis. Neurology, 29, 490–5. Yasuo, T., Terao, Y., Hayashi, H., Kanda, T., & Tanabe, H. (1993). Discrete cortical infarction with prominent impairment of thumb flexion. Stroke, 24, 2118–20.

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Sensory abnormality Jong Sung Kim Asan Medical Center, Seoul, South Korea

Functional anatomy of somatosensory system Functional anatomy of the sensory system is briefly discussed here. For further details, readers are referred to previous literature (Woolsey, 1958; Martin & Jessell, 1991; Parent, 1996; Kim, 1998a). There are two functionally and anatomically distinct sensory pathways, the medial lemniscal system and the spinothalamic system (Fig. 4.1). The medial lemniscal system subserves proprioception, vibration, tactile discrimination, and some touch sensations. These fibres ascend at the posterior column of the spinal cord up to the caudal medulla where they synapse on the dorsal column nuclei neurons (nuclei of Goll and Burdach). They then decussate as the internal arcuate fibres and ascend through the opposite medial lemniscus, which is located at the medial portion of the medulla oblongata. The spinothalamic system fibres are responsible for pain and temperature sensations. The peripheral fibres, after entering the dorsal root entry zone, ascend a few segments at Lissauer’s tract and then synapse at the dorsal horn. From there, some fibres ascend ipsilaterally, but the majority of the fibres cross the midline in the white commissure and ascend toward the medulla. In the brainstem, the spinothalamic tract is located at the dorso-lateral tegmentum. Some of the spinothalamic fibres are also projected to reticular formations. The facial (trigeminal) sensations are conveyed to the brainstem through the trigeminal nerves which enter the lateral pons. The fibres carrying touch and tactile discrimination synapse at the principal trigeminal nucleus located in the lateral pons. The secondary fibres (quintothalamic fibres) cross the midline and ascend to the thalamus. The fibres subserving pain and thermal sensations do not synapse at the principal sensory nucleus. Instead, just after entering the pons, they run down as descending trigeminal

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tracts and synapse at the trigeminal nuclei that form a long vertical structure extending far down to the second cervical cord. After the synapse, the fibres decussate and then ascend as the secondary ascending trigeminal tract toward the thalamus. Sensory tracts of both systems as well as fibres carrying trigeminal sensations are converged into the thalamus, the principal sensory relay station of the brain. The sensory relay nucleus ventralis posterolateralis (VPL) receives somatic sensation from the limbs and the trunk, and the ventralis posteromedialis (VPM) receives sensory inputs from the face and oral area. In these nuclei, the sensory homunculi for the acral body parts (lip, fingers and toes) are disproportionately large (Fig. 4.2). While the medial lemniscal tracts terminate mainly in the VP nuclei, spinothalamic fibres synapse in more diffuse areas including the posterior nuclei and the intralaminar nuclei as well. From the thalamus, the impulses involved in sensation reach localized areas of the cortex through the thalamocortical projection in the posterior limb of the internal capsule/corona radiata. The primary function of the sensory cortex is to discriminate sensation: appreciation and recognition of spatial relations, appreciation of similarity and differences of external objects, precise localization of the point touched, and identification of objects (stereognosis). The cortical area subserving general somatic sensation (superficial and deep) is located in the postcentral gyrus, Broadman’s area 3,1, and 2 (somatosensory area I, SI) where the various regions of the body are represented somatotopically. Again, the cortical areas representing the mouth, face, hands (especially the thumb and index finger), and toes are disproportionately large (Fig. 4.1). There are observations that the somesthetic cortical area is not limited to the postcentral gyrus (Nii et al., 1996). Electrical stimulation or the occurrence of small

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pathologic lesions in the precentral gyrus or posterior parietal area often produces sensory symptoms (Penfield & Boldrey, 1937). Nevertheless, the sensory threshold is lower in the post-central gyrus compared to other regions (Corkin & Milner, 1970). The somatosensory area II (SII) has been shown to be located in the parietal opercular region, and seems to be unrelated to discriminative sensory function (Roland, 1987). According to animal experiments, sensory cortices have reciprocal connections through the corpus callosum such that SI neurons send fibres to both the contralateral SI and SII while SII area restricts most of its projections to the opposite SII. The post-central gyrus representing the symmetrical axis of the body has ample interhemispheric connections while distal limb-representing regions lack the connections (Jones, 1967; Whitsel et al., 1969).

Sensory dysfunction after stroke Sensory dysfunction tends to be less carefully examined than motor or speech abnormalities in the evaluation of stroke patients (Bowsher, 1993; Carey, 1995). Yet, it must be realized that somatosensory abnormality is present in at least half of the patients suffering from strokes (Carey, 1995). Moreover, if meticulously tested, sensory abnormalities are actually much more frequent. Examinations with the use of tools for quantitative thermal detection (Samuelsson et al., 1994) or discriminative sensations (Kim & Choi-Kwon, 1996) have shown that most of the patients with a clinically defined ‘pure motor stroke’ have concomitant sensory abnormalities. In addition to the high frequency of abnormalities, there are other reasons why a proper understanding of the sensory system dysfunction is important. First, because each pattern of sensory abnormalities differs according to the location of a stroke, a careful sensory examination helps us localize the lesion in stroke patients. In turn, this attempt of clinical–anatomical correlation would allow us to understand the functional neuroanatomy, which frequently has been studied only through animal experiments. Secondly, sensory abnormalities after a stroke often lead the patients to suffer central post-stroke pain (CPSP), involuntary movements (Sharp et al., 1994; Hallett, 1995; Ghika & Bogousslavksy, 1997) including alien hand syndrome (Ay et al., 1998), and abnormal motor execution (Ghika et al., 1998) associated with poor rehabilitation outcome (Stern et al., 1971; Reding & Potes, 1988; Chester & McLaren, 1989; Zeman & Yiannikas, 1989). Therefore, a better understanding of sensory system dysfunction may

Fig. 4.1. A schematic diagram of sensory tracts and sensory homunculus in the parietal cortex. Solid lines represent spinothalamic tract and dotted lines represent medial lemniscal fibers. 1: Lissauer’s tract, 2: fasciculus cuneatus, 3: fasciculus gracilis, 4: posterior column, 5: spinothalamic tract, 6: spinal nucleus of trigeminal nerve, 7: nucleus gracilis, 8: spinal tract of trigeminal nerve, 9: principal trigeminal nucleus, 10: medial lemniscus, 11: thalamus, 12: thalamo-parietal projection, 13: sensory cortex (From Kim, 1998, with permission.)

Dorsal

Medial

VPM

VPL

Fig. 4.2. Schematic somatotopic body representation in the ventral posterior nucleus of thalamus in primates. (Modified from Kim, 1998, with permission.)

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allow us to develop ways to prevent or alleviate pain or other disabling sequelae in stroke victims in the future.

Medial lemniscus leg trunk

arm Corticospinal tract Ascending trigeminal thalamic tract

Medullary stroke In the medulla oblongata, the fibres of the two different sensory systems are widely separated: the medial lemniscus is located medially and the spinothalamic tract, laterally. These tracts are separately involved by medial medullary infarction (MMI) and lateral medullary infarction (LMI), respectively. The descending trigeminal fibres/nuclei are located in the dorsal area while ascending secondary trigeminal tracts are situated ventro-medially (Fig. 4.3). In patients with LMI, sensory abnormalities are fairly common and remain as the most important sequela (Peterman & Siekert, 1960). In the acute stage, they occur in the contralateral body/limbs in approximately 85% and in the face in 58–68% (Sacco et al., 1993; Kim et al., 1997). It has been traditionally taught that sensations in the ipsilateral trigeminal and contralateral body/limbs are typically affected in these patients. However, a recent study (Kim et al., 1997) showed that this ‘classical’ sensory pattern occurred only in one fourth of the LMI patients, who had lesions located dorso-laterally. Other sensory patterns occurring in a similar frequency include the contralateral– trigeminal pattern, the bilateral trigeminal pattern and the sensory pattern limited to body/limbs sparing the face, each of them correlating with a ventrally located lesion, a large lesion encompassing both the posterolateral and ventromedial area, and a small lateral-superficial lesion, respectively (Figs. 4.3, 4.4). In addition, a small portion of the patients with posteriorly located lesions have sensory symptoms limited to the ipsilateral face sparing the body and limbs (Nakamura et al., 1996), while some do not have sensory symptoms/signs at all (Kim et al., 1997). However, because trigeminal sensory symptoms on the side contralateral to the lesion tend to improve rapidly, the classical, ipsilateral trigeminal–contralateral body/limb pattern is the one most commonly found in patients with chronic LMI. In the body/limbs, approximately 30% of LMI patients exhibit sensory gradient or sensory level (pseudospinal type) (Kim et al., 1997). This probably is related to an anatomical arrangement of spinothalamic sensory fibres where fibres from the sacral, leg, trunk, and arm areas are located from the most outer to inner areas (Matsumoto et al., 1988) (Fig. 4.3). Thus, small lesions preferentially involving the superficial area may show a sensory level or have sensory symptoms greater in the leg than in the arm

D

sacral leg trunk arm

Spinothalamic tract

B C Descending trigeminal tract

A

A+B

B+C

A+B+C

B

A

D

Fig. 4.3. Upper: Anatomical structures of medulla. Lower: Various patterns of sensory dysfunction caused by medullary infarction. Lightly dotted area ⫽ decreased spinothalamic sensation, heavily dotted area ⫽ decreased lemniscal sensation.

(Fig. 4.4(c)). The trigeminal sensory abnormalities are also diverse in their manifestation, presenting with onion skin pattern (Kim et al., 1997), divisional pattern (Currier et al., 1961) or a complex mixture of the two. It seems that the perioral area tends to be spared or less severely involved in patients with contralateral–trigeminal pattern (Kim et al., 1997). Although a selective loss of the spinothalamic sensation is a rule, vibration sensation is occasionally involved as well in the hypalgic body/limbs, due probably to the fact that some of vibratory sensations are carried through the lateral column (Calne & Pallis, 1966). On rare occasions, patients with the most caudal lesion have lemniscal sensory deficits on the side ipsilateral to the lesion (Kim et al., 1995a; Brochier et al., 1999). Involvement of the ascending or decussating dorsal column sensory tracts by the lower-most lesion may explain this phenomenon. Finally, some patients with LMI show dissociated spinothalamic sensory dysfunction, i.e. severe deficit of pinprick sensation with mild impairment of temperature sensation or vice versa (Head & Holmes, 1911; Dejerine, 1914). A recent report (Kim, 1998b) showed that small, ventrally located lesions tend to produce a greater deficit of the pinprick than temperature sensations. This observation

Sensory abnormality

(a )

(b)

(c )

Fig. 4.4. T2-weighted magnetic resonance imaging shows infarcts involving (a) dorso-lateral, (b) ventromedial ⫹ dorso-lateral, and (c) lateral–superficial areas of the lateral medulla, producing sensory impairment in the ipsilateral trigeminal–contralateral body/limbs, bilateral trigeminal–contralateral body/limbs, and in the area of contralateral body/limbs below T10 level, respectively.

agrees with an alleged topography of the spinothalamic tract in the spinal cord: fibres carrying the pain sensation are located more ventrally than those subserving temperature sensations (Friehs et al., 1995). A dissociation of warm and cold sensory impairment was also described (Kutner & Kramer, 1907), but awaits further pathological or radiological examination. In patients with MMI, sensory abnormality is the second most frequent symptom followed by muscle weakness, which is characterized by the presence of paresthesias and a selective loss of the lemniscal sensation (Fig. 4.3). However, the degree of impairment between vibration and joint position senses may differ among individual patients (Kim et al., 1995b) reflecting the previous notion that the anatomical pathways for the two sensory modalities are not strictly bound (Ross, 1991). In addition, spinothalamic sensations are occasionally impaired in these patients, which could result from an involvement of either the adjacent spinothalamic tract or the medullary reticular formation (Kim et al., 1995b; Bassetti et al., 1997). Although sensory symptoms most often occur on the side contralateral to the lesion, infarcts occurring in the lower-most area below the crossing lemniscal (internal arcuate) fibres may produce ipsilateral sensory deficits (Vuilleumier et al., 1995; Kim et al., 1995b). In patients with MMI, the face is usually, but not always spared, due probably to an involvement of the adjacent ascending trigeminal tract (Kim et al., 1995b; Kinoshita et al., 1998). The trigeminal sensory symptoms are usually transient and mild as compared to those in the body/limbs. Some MMI patients present with restricted sensory symptoms in the legs or show pseudospinal sensory changes (Kim et al., 1998a). This pattern is explained by an anatomical arrangement that sensory fibres from the leg, trunk and arm are arranged from a ventral to dorsal direction in the medullary medial lemnis-

cal tracts (Brodal, 1981) (Fig. 4.3). Thus, a small ventrally located infarct may produce sensory symptoms restricted to the leg.

Pontine stroke Pontine tegmental strokes affecting the sensory tracts frequently produce sensory symptoms. Lesions concomitantly involving the pyramidal tract in the ventral area would produce sensori-motor deficit while those extending far-dorsally may produce ocular motor dysfunction due to an involvement of the abducens nerve nucleus and related structures. In the pontine tegmentum, the ascending trigeminal tract, the medial lemniscus and the spinothalamic tract are located adjacently in a medial to lateral direction (Fig. 4.5(a)). Small dorsal pontine infarcts (Hommel et al., 1989; Iwasaki et al., 1989; Helgason & Wilbur, 1991; Shintani et al., 1994; Kim & Bae, 1997) or hemorrhages (Araga et al., 1987; Deleu et al., 1992; Kim & Jo, 1992; Kim & Bae, 1997) selectively involving the sensory tract produce a pure or predominant hemisensory deficit without other neurological dysfunctions (Fig. 4.5(b)). Although both the spinothalamic and lemniscal sensations may be simultaneously involved, lemniscal sensations are usually more severely affected in these patients (Kim & Bae, 1997; Shintani, 1998) probably because small infarcts or hemorrhages tend to occur in the paramedian area (Kim et al., 1994a) where the medial lemniscus is located. Occasionally, the patients exhibit hemi-paresthesias without objectively detectable sensory deficits. In the pontine medial lemniscal tract, the sensory projections from the arm, trunk and leg are arranged from a medial to lateral direction. Therefore, a medially located lesion may produce preferential involvement of the face

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(a )

corticospinal tract

ascending trigeminal tract arm medial lemniscus

trunk abducens nucleus

leg spinothalamic tract

aqueduct

(b)

Fig. 4.5. (a) Anatomical structures of pons. (b) T1-weighted MRI shows a pontine hemorrhage selectively involving the medial lemniscus that produces pure sensory stroke.

and arm, thus causing cheiro-oral syndrome whereas laterally located lesions produce leg-dominant sensory symptoms (Kim & Bae, 1997). The most medially located lesions sometimes produce bilateral facial or perioral sensory symptoms due probably to concomitant involvement of the trigemino-thalamic fibres bilaterally (Matsumoto et al., 1989; Kim & Bae 1997). Bilateral cheirooral syndrome also occurs most often, though not exclusively, in paramedian pontine strokes (Chen et al., 1997). In addition, sensory symptoms of cheiro-oral-pedal (Yasuda et al., 1992; Kim 1994), oro-crural (Combarros et al., 1996) or cheiro-retroauricular distribution (Ferro & Pierre, 1998) have been reported to be caused by small pontine strokes. As compared to the patients with thalamic lesions, those with a pontine pure sensory stroke more often exhibit dizziness/gait ataxia, predominant lemniscal sensory involvement, and bilateral perioral involvement (Kim & Bae, 1997). Impairment of the smooth pursuit system eval-

uated by electro-oculography may additionally differentiate pontine from thalamic pure sensory strokes (Johkura et al., 1998). Trigeminal sensory deficit is often observed in patients with infarcts affecting the lateral pons or the middle cerebellar peduncle (anterior inferior cerebellar artery territory) usually accompanied by other symptoms such as hearing difficulty, ataxia and vertigo. Isolated trigeminal sensory symptoms without other neurological deficits may occur in patients with small strokes affecting the trigeminal fascicles or nucleus at the lateral pons (Holzman et al., 1987; Berlit, 1989; Kim et al., 1994b). In some patients, trigeminal sensory symptoms are restricted to the intraoral area. This may be explained by an alleged functional anatomy in which at the most rostral part of the trigeminal tract/nucleus represents sensory fibres from the intraoral area (Graham et al., 1988). Isolated involvement of the taste sensation (Sunada et al., 1995) or facial pains indistin-

Sensory abnormality

(a )

crus cerebri substantia nigra ascending trigeminal tract medial lemniscus red nucleus spinothalamic tract oculomotor nucleus aqueduct

(b)

Fig. 4.6. (a) Anatomical structures of midbrain. (b) T2-weighted MRI shows an infarct in the dorso-lateral area producing pure sensory stroke. The infarct was probably caused by an artery-to-artery embolism from a tightly stenosed basilar artery.

guishable from idiopathic trigeminal neuralgia (Balestrino & Leandri, 1997; Kim et al., 1998b) has also been reported to be caused by small pontine strokes.

Mesencephalic stroke In the midbrain, sensory tracts are located dorso-laterally in which the medial lemniscal fibres are situated medioventrally, and the spinothalamic tracts, dorso-laterally (Fig. 4.6(a)). A pure mesencephalic stroke most commonly presents with the third nerve palsy associated with hemiparesis and/or hemiataxia (Kim et al., 1993; Bogousslavsky et al., 1994). Hemisensory symptoms, if present, are usually not prominent. Mesencephalic pure hemisensory syndrome is extremely rare, and caused by small infarcts or hemorrhages affecting the dorso-lateral area (Tuttle & Reinmuth, 1984; Azouvi et al., 1989; Alvarezc-Sabin et al., 1991; Sabin et al., 1991; Kim & Bae, 1997) (Fig. 4.6(b)). The

patients may present with paresthesias only (Tuttle & Reinmuth, 1984) or selective spinothalamic sensory dysfunction (Azouvi et al., 1989). Symptoms restricted to cheiro-oral (Ono & Inoue, 1985; Kim, 1994) or trigeminal areas (Kim & Kang, 1992; Kim, 1993) were also described, which usually were accompanied by the third or fourth nerve palsy.

Thalamic stroke Strokes involving the VP nucleus of the thalamus produce hemisensory symptoms. Concomitant involvement of the adjacent pyramidal tract would induce a sensory-motor stroke, and additional involvement of the cerebellar– thalamic fibres at the ventral–lateral nucleus may produce the so-called 'hypesthetic ataxic hemiparesis’ syndrome. A small lateral thalamic stroke selectively involving the VP nucleus is the most common etiology of pure sensory

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stroke (Fisher, 1982; Kim, 1992). Although both the spinothalamic and lemniscal sensations are usually impaired simultaneously (Kim, 1992; Shintani, 1998), small lesions may produce paresthesias only or a selective impairment of lemniscal (Sacco et al., 1987; Kim, 1992) or spinothalamic sensations (Landi et al., 1984; Kim, 1992; Paciaroni & Bogousslavsky, 1998). The sensory topography includes half of the face, arm, trunk and leg in more than 50% of the cases (Paciaroni & Bogousslavksy, 1998). In some patients, however, initial hemisensory disturbances are gradually restricted to the most vulnerable areas: the perioral area, the hand, and less frequently, the foot. Occasionally, sensory symptoms are restricted to these acral body parts from the onset (Kim, 1994), the most frequent form being cheiro-oral syndrome (Valzelli, 1987; Ten Holter & Tijssen, 1988; Awada 1989; Kawadami et al., 1989; Combarros et al., 1991, Kim & Lee, 1994; Kim, 1994). (Fig. 4.7) Cheiro-oral-pedal or cheiropedal syndrome has also been observed, but much less frequently (Yasuda et al., 1993; Kim, 1994). Occasionally, the thumb and index finger are preferentially or selectively involved (Combarros et al., 1991; Kim, 1994). This restricted acral sensory syndrome is best explained by the anatomical proximity of sensory fibres from acral body parts (Fig. 4.2). For example, the thumb and index fingerrepresentation areas are located in the most medial portion of the VPL and are adjacent to the lip area of VPM in the thalamus of primates (Kaas et al., 1984). In addition, at least two other hypotheses explain the increased vulnerability of the acral body parts. First, distal body parts have disproportionately large representation areas in the human sensory system. Secondly, unlike the sensory fibres subserving the trunk and proximal limbs, neurons representing distal body parts lack interhemispheric connections (Whitsel et al., 1969). In patients with a hemisensory deficit, intraoral regions (gum, hard palate, tongue) are occasionally involved. A loss of taste sensation is uncommon. The author has found that six of 35 patients with thalamic cheiro-oral syndrome had definite hemiageusia. Interestingly, one of them experienced frequent episodes of vivid recollections of the past (Kim, 1997). On rare occasions, sensory symptoms restricted to the proximal limbs and trunk, with the sparing of the face and distal limbs are observed (Kim, 1996a), which may be attributed to selective involvement of the dorsal part of the VPL to which sensations from the proximal body parts are projected (Kaas et al., 1984). Thalamic pure sensory syndrome usually indicates a lacunar syndrome (Fisher, 1978; Gan et al., 1997) caused by an occlusion of a small penetrating branch. However, other etiologies such as atherothrombosis of the proximal poste-

Fig. 4.7. T2-weighted MRI shows a left thalamic infarct producing paresthesias at the contralateral perioral area and the hand (cheiro-oral syndrome).

rior cerebral artery, cardiogenic embolism, or a hypertensive intracerebral hemorrhage may also produce pure sensory syndrome (Paciaroni & Bogousslavsky, 1998) or even restricted acral sensory syndromes (Kim, 1994).

Subcortical stroke Although motor symptoms are usually dominant in patients with subcortical strokes, small (Kim, 1991, 1992, 1994) or even relatively large lesions (Kim, 1999a) primarily affecting the thalamocortical sensory radiation can produce pure or predominant sensory symptoms (Fig. 4.8). The latter lesions appear to produce sensory changes greater in the leg than in the arm. Although subcortical strokes may cause sensory deficits of both modalities (Shintani, 1998), predominant spinothalamic (Kim, 1992) or lemniscal sensory impairment (Groothuis et al., 1977) has been observed. Some patients with very small lesions present with sensory symptoms restricted to cheiro-oral

Sensory abnormality

(Omae et al., 1992; Isono et al., 1993; Kim 1994), cheirooral-pedal (Yasuda et al., 1994; Kim, 1994) or cheiro-pedal (Derouesné et al., 1984; Kim, 1994) distribution suggesting that an identical pattern of sensory topography as in the VP nucleus of the thalamus exists in the thalamic-cortical sensory radiation.

Cortical stroke In the cerebral cortex, lemniscal sensory fibres are abundantly terminated in the parietal cortex (SI), whereas a significant portion of the ascending spinothalamic fibres terminate in the reticular activating system without reaching the cortex. Strokes involving the cerebral cortex characteristically produce an impairment of discriminative sensations that require cortical participation, including loss of position sense, elevation of two-point discrimination threshold, difficulties in localizing touch and pain stimuli (topagnosia), failure to recognize letters or numbers drawn on the skin (graphesthesia), and failure to appreciate texture, size or shape of objects by palpation (astereognosis) despite relatively preserved protopathic (pain, thermal, vibration) sensations. This ‘parietal cortical sensory syndrome’ was described long ago (Verger, 1900; Dejerine & Mouzon, 1914), and is usually accompanied by other neurological deficits such as hemiparesis, hemianopia, aphasia or hemineglect. In clinical practice, however, decreased protopathic sensation is usually present to some extent. Although discriminitive sensory dysfunction is generally detected in the body/limbs contralateral to the lesion, sensory modalities such as point localization, stereognosis (Corkin & Milner, 1970; Kim & Choi-Kwon, 1996), or texture discrimination (Carmon & Benton, 1969) are occasionally impaired on the ipsilateral side as well. In some patients, however, protopathic sensations are heavily affected, just as in cases of thalamic strokes (pseudothalamic syndrome) (Roussy & Foix, 1910). Unlike the patients with thalamic stroke, however, concomitant cortical symptoms such as aphasia, anosognosia, or acalculia are usually present (Fig. 4.9). The protopathic sensory impairment may be related to an involvement of the secondary somatosensory area (SII) (see functional anatomy) or thalamic-SII sensory connection. A patient with an infarct located at the inner bank of the parietal operculum was reported to produce a pure spinothalamic sensory deficit without involvement of proprioceptive and other discriminative sensations (Horiuchi et al., 1996). Occasionally, patients who apparently have preserved primitive sensations do not adequately respond to noxious stimuli (Berthier et al., 1988). This so called ‘asymbolia for

Fig. 4.8. T2-weighted MRI shows a right putaminal hemorrhage producing pure sensory stroke due probably to selective involvement of the thalamic–cortical sensory radiation.

pain’ may be a disconnection syndrome secondary to an interruption between the SII area and the limbic system. The cortical hemisensory symptoms are observed not only after strokes occurring in the SI or SII area, but also after frontal or posterior parietal lesions, confirming that the sensory cortex is not necessarily limited to the post-central gyrus (see functional anatomy). Since the somatotopic representation of body parts is widely spread in the sensory cortex, small cortical lesions occasionally produce sensory symptoms restricted to a distal arm, leg or even to a few finger tips, which may lead inexperienced physicians to make a wrong diagnosis of a root or peripheral nerve disease (Youl et al., 1991; Bassetti et al., 1993; Kim 1994). Sensory abnormalities restricted to the cheiro-oral area (Bogousslavsky et al., 1991) or to proximal body parts with sparing of the distal limbs (Kim, 1999b) are also observed.

Bilateral sensory abnormalities Sensory symptoms almost always occur on the side contralateral to a unilateral stroke. However, they may occur bilaterally under the following conditions. ii(i) Bilateral trigeminal sensory involvement is observed in patients with a large lateral medullary infarct (Fig. 4.3). An infarct situated at the most caudal lateral medulla may produce ipsilateral lemniscal sensory symptoms in addition to contralateral hemihypalgia (see medullary stroke). i(ii) Bilateral perioral or facial sensory symptoms, reported in the pre-MRI era (Caplan & Gorelick, 1983), are now found to occur most often after paramedian pontine strokes (see pontine stroke). Less frequently, however, this phenomenon is also seen in patients

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presents with repeated attacks of tingling sensation (Fisher, 1965, 1982). Pure cortical sensory transient attacks followed by a cortical stroke were reported (Kim, 1992). I have observed patients with hemisensory symptoms lasting less than 24 hours, most of whom were found to have small thalamic infarcts on MRI. One of them had negative MRI findings but had a high-grade stenosis at the proximal part of the posterior cerebral artery. This seems to be ‘sensory transient ischemic attack’ homologous to the so-called ‘capsular warning syndrome’ associated with middle cerebral artery stenosis (Donnan, 1993). Repeated attacks of bilateral perioral or tongue paresthesias with or without involvement of the body/limbs suggest the presence of basilar artery stenosis.

Post-stroke sensory sequelae Out of diverse post-stroke sensory squelae, the following two deserve special attention.

Central post-stroke pain (CPSP)

Fig. 4.9. CT scan shows a left parietal hemorrhage producing conduction aphasia and hemisensory deficits of all modalities.

with supratentorial lesions (Kim, 1996b). This observation agrees with the previous reports that electrical stimulations on the cortical or thalamic areas produced sensory symptoms in the perioral/tongue area bilaterally in about 6–8% of the responses (Tasker et al., 1976; Picard & Olivier, 1983). An anatomical explanation for this phenomenon could be a relatively dominant uncrossed dorsal trigeminothalamic tract in these patients (Nieuwenhuys et al., 1988). (iii) Some modalities of discriminative sensation are impaired bilaterally (see cortical stroke). (iv) As discussed below, some patients with CPSP have delayed-onset sensory symptoms on the side ipsilateral to the lesion (Kim, 1998c).

Sensory transient ischemic attack Sensory symptoms often accompany motor deficits in patients with transient ischemic attack. A pure sensory transient ischemic attack is uncommon and usually

One of the most troublesome sequelae of patients with sensory deficit is a gradual development of uncomfortable, distressful, sometimes painful paresthesias (Dejerine & Roussy, 1906). Once thought as a typical sequela of thalamic strokes (thalamic syndrome of Dejerine & Roussy), it is now recognized that strokes occurring anywhere in the sensory tract can produce similar symptoms (Schmahmann & Leifer, 1992; Leijon et al., 1989; MacGowan et al., 1997; Bowsher et al., 1998). The incidence of CPSP has been reported to be 2–8% (Bowsher, 1993; Andersen et al., 1995). The symptoms are variably described as burning, aching, squeezing, pricking, cold, lacerating, etc. (Leijon et al., 1989; Bowsher, 1993), and are frequently aggravated by a cold environment, psychological stress, heat or fatigue (Bowsher, 1996). They often have a delayed onset and always develop within the area of initial sensory impairment (Bowsher, 1996). The symptoms may be restricted to certain body parts such as distal limbs, and prominent involvement of the anterior chest region may mimic the symptoms of myocardial ischemia (Gorson et al., 1996). Spinothalamic, particularly temperature sensory abnormalities are frequently associated with CPSP (Tasker et al., 1991; Vestergaard et al., 1995; Bowsher 1996), but patients with medial leminiscal sensory deficit (Shintani, 1998) or without objective sensory deficit may also suffer severe CPSP (Tasker et al., 1991). Dysesthesia and allodynia are commonly present (Leijon et al., 1989; Jensen & Lenz, 1995). The pathogenesis of CPSP remains unknown, but a development of hyper-excitation in damaged sensory

Sensory abnormality

pathways, damage to central inhibitory pathways or a combination of the two has been suggested as plausible mechanisms (Schott, 1995). Tasker (1982) proposed that deafferentiation of the spinothalamic system renders a normally non-excitable spinoreticulothalamic system responsive to stimulation, which in turn induces denervation hypersensitivity. When the sensory sequelae of LMI and MMI patients were compared, it was found that CPSP due to LMI more often had a delayed onset, was more often described as 'burning or cold’, and aggravated more often by a cold environment as compared to that caused by MMI (Kim & Choi-Kwon, 1999). These observations suggest the CPSP may occur from both the spinothalamic and medial lemniscal tract injuries, but with different pathogenic mechanisms. The CPSP may be aggravated by another stroke occurring on the opposite side (Kim, 1999c) or alleviated at least temporarily by an ipsilateral subcortical stroke (Soria & Fine, 1991), suggesting that CPSP may be functionally modified by other structures including those at the opposite hemisphere. Finally, some patients with CPSP may develop delayed-onset sensory symptoms on the side ipsilateral to the lesion (Kim, 1998c). This phenomenon may be explained by a development of hyperexcitation of the clinically insignificant ipsilateral sensory pathway in patients developing CPSP. Canavero (1996) also described a patient with bilateral CPSP caused by a unilateral subparietal cavernous angioma. The CPSP is most often treated by adrenergically active antidepressants (amitriptyline) or certain antiepileptics, but the effect is frequently insufficient (Bowsher, 1995). Recently, Canavero and Bonicalzi (1998) postulated that CPSP is caused by unbalanced glutamate/GABA neurotransmission in the central nervous system with a relative hypofunction of the GABAergic inhibitory system. A combination of drugs modulating this derangement may be of benefit for these patients. Subthreshold electrical stimulation of the motor cortex (Tsubokawa et al., 1993) or destructive surgery on the thalamo-cortical radiation (Talairach et al., 1960) has so far shown limited success.

Sensory deficit-related motor dysfunction Patients with a loss of somatosensory function often have considerable difficulties in executing manual tasks especially complex movements requiring coordination among several joints. This 'pseudoparesis’ phenomenon, observed long ago by Mott and Sherrington (1895) in their monkey experiments, has been recently analysed in human patients (Rothwell et al., 1982; Jeannerod et al., 1984; Pause et al., 1989; Ghika et al., 1998), and is considered to be a consequence of the loss of sensory feedback in the sensory–motor circuitry of the central nervous system.

Post-stroke discriminative sensory disturbances, which were found to be very common if meticulously tested (Kim & Choi-Kwon, 1996), seem at least in part to be responsible for the clumsiness of the patients. Several studies have provided evidence that sensory training is of help in the improvement of motor execution in these patients (Carey et al., 1993; Yekutiel & Guttmann, 1993). In addition, severe sensory loss may result in patients’ motor incoordination (sensory ataxia) (Critchley, 1953) or various involuntary movements. While stretching the arms devoid of position sense, the patient’s fingers and hands may wander or drift especially when the eyes are closed. Sometimes, almost continuous purposeless movements are seen in the fingers (pseudoathetosis) (Sharp et al., 1994; Ghika & Bogousslavsky, 1997). There also has been accumulating evidence that dystonic posture is related to sensory input failure (Hallett, 1995; Ghika et al., 1998). A recent study (Bara-Jimenez et al., 1998) showed that in the primary somatosensory cortex, the area representing D1 in relation to D5 was reorganized in patients with hand dystonia, suggesting that abnormal plasticity in the sensory cortex is involved in the pathogenesis of involuntary movements. According to the author’s observation, post-stroke (mostly thalamic) delayed-onset involuntary movements (chorea, dystonia, ataxic tremor) are closely related to successful recovery of paralysed limbs along with persistently impaired proprioceptive sensory and cerebellar functions. Thus, these mysterious movement disorders may at least in part be related to abnormally organized motor circuitry due to unbalanced recoveries among the motor, cerebellar and sensory systems.

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Cerebellar ataxia Dagmar Timmann and Hans Christoph Diener Department of Neurology, University of Essen, Germany

Introduction Definitions The term ‘ataxia’ (Greek, a- (⫽negative article)⫹taxi (⫽order), ‘lack of order’) is commonly used synonymously with incoordination (Dow & Moruzzi, 1958; Gilman et al., 1981; Timmann & Diener, 1998). Ataxia is the most important sign of cerebellar disease. Cerebellar ataxia is defined as lack of accuracy or coordination of movement which is not due to paresis, alteration in tone, loss of postural sense or the presence of involuntary movements (DeJong, 1979). Cerebellar ataxia relates to motor dysfunctions of the limbs, trunk, eyes, and bulbar musculature. Ataxia of gait refers to incoordination of walking, which might be so severe that the patient cannot walk (abasia). Postural ataxia refers to ataxia of stance and sitting and includes truncal ataxia. The patient may be unable to sit or stand without support (astasia). Limb ataxia refers to incoordination of limb movements and ataxia of speech to cerebellar dysarthia. Cerebellar disease results in postural and limb tremor. There may be a rhythmic tremor of the body that can evolve into a severe titubation. Limb tremor occurs as a kinetic and to a lesser extent static tremor. Kinetic tremor occurs as an oscillatory movement when the subject initiates a movement of the limb or during the course of moving the limb. The tremor becomes more prominent as the moving limb approaches a target (intention tremor). Powerful, but brief involuntary movements at the beginning of the movement are due to intention myoclonus, not tremor, and occur in diseases involving the dentate nucleus or the superior cerebellar peduncle.

Neurological findings in cerebellar disease Patients with cerebellar disorders walk with a wide-based, staggering gait, making it seem as if they were intoxicated

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by alcohol. A tendency to fall or deviate to one side suggests a unilateral cerebellar lesion on the same side. The stance is usually on a broad base with the feet several inches apart. In the mildest form patients have difficulty standing with their feet together, in tandem position or on one foot. The Romberg sign might be present or absent in cerebellar disorders depending on the lesion site (Gilman et al., 1981; Dichgans & Diener, 1985; Timmann & Diener, 1998). Several aspects of limb ataxia might be observed using the finger-to-nose and the heel-to-shin-test. Initiation of movement is delayed. Movement may be decomposed in time into its constituent parts (decomposition of movement). The movement path of the limb is erratic and jerky and the nose is rarely touched at once (dysmetria). Subjects more frequently overshoot the target (hypermetria) and rarely stop the movement too soon (hypometria). In cerebellar subjects rapid alternating movements are irregular (dysdiadochokinesis) and slow (bradydiadochokinesis). Kinetic tremor occurs as an oscillatory movement that becomes more prominent as the moving limb approaches a target (intention tremor). Signs of cerebellar dysarthria include a slurred, monotonous and irregular speech with increased variability of pitch and loudness and articulatory impreciseness. The speech tempo is slow. A variety of eye movement abnormalities are seen in cerebellar disease. Gaze-evoked nystagmus is a common finding. Downbeat nystagmus, upbeat nystagmus, and sustained horizontal nystagmus may also be present. Other frequent abnormalities are impairment of smooth pursuit and saccadic (ocular dysmetria) eye movements, inability to suppress the vestibular ocular reflex by fixation and abnormalities of optokinetic nystagmus. Hypotonia, hyporeflexia and asthenia were described as typical symptoms of acute, traumatic cerebellar lesion by Holmes (1939).

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Vermis Intermediate zone Hemisphere

Associated neurological findings The presence of characteristic accompanying neurological symptoms may help to localize the lesion within the territory of one of the cerebellar arteries or the cerebellar pathways. Diplopia, facial numbness, facial droop, vertigo or hearing loss resulting from associated cranial neuropathies (III, IV, V, VI, VII, VIII), Horner’s syndrome and dysautonomia associated with ataxia suggest a disorder in the brainstem. A slight loss of muscular power and increased fatigability of muscles may occur with acute cerebellar disorders. However, paresis associated with increased muscular tone, hyperreflexia and extensor plantar reflexes (Babinski sign) suggest an additional involvement of upper motor neurons (corticospinal or pyramidal syndrome). Pure cerebellar lesions do not cause disturbances in sensation. Hemianesthesia involving one side of the face, arm, and leg suggests an additional lesion of the sensory tracts (i.e. spinothalamic and medial lemniscal tracts) or contralateral parietal lobe. On the contrary, frontal lobe disorders might cause cerebellar-like symptoms with walking difficulties and clumsiness. However, frontal lobe lesions are commonly associated with impairment of cognitive function and changes in personality. Patients have urinary incontinence.

Anatomy of the cerebellar system

Anterior lobe

Primary fissure

Corpus cerebelli

Flocculonodular Flocculus lobe

Nodulus

Anterior lobe (vermis) Primary fissure Posterior lobe (vermis) Nodulus ‘Vestibulocerebellum’ ‘Spinocerebellum’ ‘Cerebrocerebellum’ Fig. 5.1. Main cerebellar subdivisions. Top, a schematic drawing of the partly unfolded cerebellum. Bottom, drawing shows how the unfolding was performed. The dots indicate roughly the cerebellar terminal regions of the main afferent contingents from the spinal cord, from the vestibular apparatus, and from the cerebral cortex via the pontine nuclei. (With permission from Brodal, P. (1998). Fig. 14.2, p. 395.)

Cerebellar subdivisions The cerebellum is located behind and below the cerebral hemispheres, overlying the brainstem. Several classifications have been used to subdivide the cerebellum based on anatomic, phylogenetic, and functional findings (Brodal, 1998). Anatomically, the cerebellum is subdivided into three major components: the flocculonodular, anterior and posterior lobes, the latter two forming the corpus cerebelli (Fig. 5.1; top, left side). The three lobes are subdivided into several lobules. In the past the lobules carried individual names which have been replaced by Larsell’s numbering system, which consists of Roman numerals in the vermis and the prefix H in the hemispheres. The terms archicerebellum, paleocerebellum and neocerebellum originate from phylogenetic and embryological studies. The terms vestibulo-, spino-, cerebrocerebellum originate from termination sides of cerebellar afferent projections. These subdivisions match well with the subdivisions based on phylogenetic studies. The flocculonodular

lobe (⬵archicerebellum) has been named vestibulocerebellum because of heavily projecting vestibular afferents; the vermis and paravermal parts of the cerebellar hemispheres (⬵paleocerebellum) were called spinocerebellum because of their spinal afferents and the cerebellar hemispheres (⬵neocerebellum) cerebrocerebellum (syn. pontocerebellum) based on their corticopontine input (Fig. 5.1; top, right side). On the basis of the efferent projections from the cerebellar cortex to the cerebellar nuclei, Jansen & Brodal (1940) and later Chambers & Sprague (1955a,b) suggested a subdivision into three longitudinal (⫽sagittal) zones: a medial zone (⫽vermis) projecting to the fastigial nucleus, an

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intermediate (⫽paravermal part of cerebellar hemisphere) zone projecting to the interposed nuclei and a lateral (⫽ lateral part of cerebellar hemisphere) zone projecting to the dentate nucleus (Fig. 5.1; top, right side). Later studies showed that the longitudinal subdivision was more detailed (Voogd, 1969; Hawkes et al., 1992).

Cerebellar pathways The cerebellum is connected with the brainstem by afferent and efferent fibres passing through three pairs of tracts, called the inferior, middle and superior cerebellar peduncle (or restiform body, brachium pontis and brachium conjunctivum). The middle cerebellar peduncle contains only afferent fibres. In the inferior peduncle most fibres are afferent, whereas in the superior cerebellar peduncle most fibres are efferent. The cerebellar cortex receives afferent input from most parts of the peripheral (proprioceptive, cutaneous, vestibular and visual) and central nervous system (Bloedel & Courville, 1982). From the trunk and legs, the dorsal and ventral spinocerebellar tract enter the cerebellum through the ipsilateral inferior and contralateral superior cerebellar peduncle, respectively. From the arms and neck, the cuneo- and rostral spinocerebellar tracts enter the cerebellum through the inferior and superior cerebellar peduncles. Many afferent pathways have additional relay stations (pontine nuclei, inferior olives) before they enter the cerebellum. From the inferior olive, climbing fibres enter the cerebellum through the contralateral inferior cerebellar peduncle. The pontine nuclei represent the most important relay for corticocerebellar pathways. Corticopontine projections enter the cerebellum mainly through the contralateral middle cerebellar peduncle. The cerebellar nuclei are the principal source of cerebellar efferent fibres. Efferent cerebellar pathways descend to the brainstem and spinal cord and ascend to the cerebral cortex. Efferents from the flocculonodular lobe project mainly to the vestibular nuclei in the brainstem directly and indirectly via the fastigial nuclei. Efferents from the globose and emboliform nuclei (i.e. from the interposed nucleus) form the major cerebellar projection to the contralateral nucleus ruber (cerebellorubral tract). The main efferent output from the red nucleus projects to the spinal cord on the contralateral side (rubrospinal tract). Most fibres from the dentate nuclei end in the contralateral thalamus. The main projection from the thalamus goes to motor and premotor cortices via the internal capsule (Fig. 5.2). Because the ascending fibres from the cerebellum to the nucleus ruber and the motor cortex and the descending fibres from the nucleus ruber and cerebral cortex to the

Fig. 5.2. The main connections of the dentate and interposed nuclei. Note that the ascending connections to the cerebral cortex from the dentate nucleus are synaptically interrupted in the thalamus (cerebrocerebellum). Both the spinal cord (via the red nucleus) and the cerebral cortex (via the thalamus) can be influenced by the interposed nucleus (intermediate zone). (With permission from Brodal, P. (1998). Based on Fig. 14.7, p. 400 and Fig. 14.9, p. 402.)

spinal cord are crossed, the cerebellar hemisphere exerts its influence on the body half of the same side. Therefore, in unilateral cerebellar lesions symptoms of limb ataxia occur ipsilaterally.

Afferent connections from the cerebral cortex The vast majority of the afferents to the pontine nuclei arise in the cerebral cortex and form the corticopontine tract. The corticopontine tract is uncrossed whereas most of the pontocerebellar fibres cross; thus the cerebral cortex of one side acts mainly on the cerebellar hemisphere of the opposite side. A large portion of the corticopontine fibres arise in the primary motor and sensory cortex (MI and SI). There are, however, substantial contributions also from the SMA and PMA and from areas 5 and 7 of the posterior parietal cortex. The pontine nuclei also receive afferents from the visual cortex and from parts of the hypothalamus and limbic structures (Middleton & Strick, 1994; Brodal, 1998).

Cerebellar ataxia

(a )

(b)

Fig. 5.3. Diagrammatic drawing of a section (a) through the right internal capsule; and (b) through the mesencephalon, indicating the position of the cerebropontine (a, b), pyramidal (a, b) and thalamocortical tracts (b). (Based on (a) Abb. 252, p. 235 from Benninghoff, A. & Goerttler, K. (1979); and (b) Fig. 4.2, p. 186 from Brodal, A. (1981) modified from Foerster (1936), Springer-Verlag Berlin, with permission.)

The corticopontine tract runs in the internal capsule and in the crus cerebri. The frontopontine tract (Arnold’s bundle) is localized in the anterior limb of the internal capsule, the parietopontine tract in the posterior limb, the occipitopontine tract in the retrolenticular portion of the posterior limb, and the temporopontine tract (Türk’s bundle) in the sublenticular portion of the posterior limb of the internal capsule. The frontopontine tract is in close

neighbourhood to the corticobulbar tract located in the genu of the internal capsule and the corticospinal tract located in the anterior part of the posterior limb (Fig. 5.3(a)). The internal capsule turns rostrally into the corona radiata and caudally into the crus cerebri. In the crus cerebri, the frontopontine tract is localized medially and the temporopontine tract laterally of the corticospinal

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Fig. 5.4. Schematic drawing of the afferent and efferent pathways through the brainstem. Note the close vicinity of the corticopontine tracts and the corticospinal tract in the upper base of the pons. (With permission from Benninghoff, A. & Goerttler, K. (1979). Abb. 208, p. 183.)

tract (Fig. 5.3(b)). The smaller parieto- and occipitopontine tracts are found medially of the temporopontine tract. The corticopontine tract remains in close relationship to the corticospinal and corticobulbar tract on their way through the mesencephalon and the base of the pons (Fig. 5.4).

Efferent connections to the cerebral cortex The fibres from the dentate nucleus leave the cerebellum through the superior cerebellar peduncle. They cross the midline in the mesencephalon, and some fibres end in the nucleus ruber of the opposite side. Most fibres continue rostrally, however, to end in the thalamus, primarily in the ventrolateral nucleus (VL). Some also reach the ventroanterior nucleus (VA). Thalamic fibres from the VL and VA nucleus run through the superior thalamic peduncle in the posterior limb of the internal capsule to the precentral region (MI, SMA and PMA). In the internal capsule, the corticospinal tract lies in close vicinity of the thalamic fibres (Figs. 5.2 and 5.3). The sensory tracts do not travel closely to the cerebellar fibres until they reach the thalamus. The spinothalamic tract and the medial lemniscus, however, do travel in close

proximitity to the superior cerebellar peduncle in the superior lateral pons, and, when affected, a crossed hemisensory ataxic syndrome results. The sensory tracts synapse in the ventroposterolateral nucleus (VLP) of the thalamus and run through the superior thalamic peduncle to the postcentral region. Therefore, sensory and cerebellocortical fibres are in close proximity in the thalamus and the posterior limb of the internal capsule (Fig. 5.5).

Vascular supply of the cerebellum The vascular supply of the cerebellum is provided by three arteries, the posterior inferior cerebellar artery (PICA), the anterior inferior cerebellar artery (AICA), and the superior cerebellar artery (SCA). In brief, branches of the PICA supply the inferior aspect of the cerebellar hemispheres extending up to the primary fissure, the cortex of the inferior vermis, the deep cerebellar nuclei as well as the inferior cerebellar peduncle and the lateral medulla oblongata. Branches of the AICA supply the flocculus and adjacent lobules of the inferior and anterior cerebellum, the inferior and middle cerebellar peduncles as well as the nuclei of the

Cerebellar ataxia

Fig. 5.5. Diagram of a three-dimensional reconstruction of the right human thalamus seen from the dorsolateral aspect. Abbreviations for thalamic nuclei: A: anterior; CM: centromedian; Int. Lam.: intralaminar; LD and LP: lateralis dorsalis and posterior; LG: lateral geniculate body; LM: medial geniculate body; MD: dorsomedial; MI: midline; P: pulvinar; R: reticular; VA: ventralis anterior; VL: ventralis lateralis; VPL and VPM: ventralis posterior lateralis and medialis. (With permission from Brodal, A. (1981). Fig. 2.14, p. 95.)

VII–IX and XII cranial nerves in the brainstem and the inner ear (⫽the internal auditory artery and the labyrinthine artery). The superior cerebellar artery (SCA) supplies the superior parts of the cerebellar hemispheres, major parts of the vermis, all deep cerebellar nuclei and all cerebellar peduncles as well as the pons (Barth et al., 1993; Chaves et al., 1994). All cerebellar arteries supply cerebellar as well as brainstem structures. Therefore, vascular disorders frequently damage the cerebellum and brainstem together (for further details and diagrammatic drawings, see Part II Chapter 42 Cerebellar stroke syndromes).

Cerebellar syndromes Cerebellar syndromes are commonly classified based on the three major functional subdivisions of the cerebellum (Dow & Moruzzi, 1958; Dichgans & Diener, 1985). In brief, lesions of the lower vermis (so-called flocculonodular syndrome) cause postural ataxia of head and trunk during sitting, standing, and walking. Patients frequently fall even during sitting. There is no incoordination of the limbs when the patient is lying in bed. Postural sway is omnidirectional and contains frequency components of < 1 Hz. In patients with such lesions, severe postural sway is present with eyes open and is essentially unchanged with eyes closed. Fine coordinated movements of the limbs are relatively preserved. Damage to the anterior lobe (⫽spino- or paleocerebel-

lum) results in ataxia of stance and gait. Patients with this disorder develop a severe disturbance of standing and walking with relatively preserved fine coordinated movements of the upper limbs. Lesions of the spinocerebellar part of the anterior lobe lead to anteroposterior body sway with a frequency of about 3 Hz. Visual stabilization of posture is preserved and the tremor is provoked by eye closure. Diseases of the cerebellar hemisphere (⫽cerebro- or neocerebellum) are correlated with severe disturbances of limb movements including hypotonia in acute lesions, asynergia, dysdiadochokinesis, and, if the dentate nucleus is involved, kinetic tremor. Past pointing and deviation of gait to the affected side are associated symptoms. Symmetrical involvement of both hemispheres and vermis produces bilateral limb ataxia and ataxia of stance and gait. Dysarthria and oculomotor disturbances are also frequently present. The paramedian regions of the superior cerebellar hemispheres are most relevant for the development of cerebellar dysarthria (Ackermann et al., 1992). Left hemispheric cerebellar lesions appear to be more frequently associated with cerebellar dysarthria than right hemispheric lesions (Lechtenberg & Gilman, 1978). Three principal syndromes of specific cerebellar oculomotor disorders have been identified: the syndrome of the dorsal vermis and underlying fastigial vermis, the syndrome of the flocculus and paraflocculus, and the syndrome of the nodulus. Lesions of the dorsal vermis and fastigial nucleus cause saccadic dysmetria and mild deficits of smooth pursuit. Lesions of the nodulus are accompanied by prolongation of vestibular responses and periodic alternating nystagmus, which is a spontaneous horizontal nystagmus that changes direction every few minutes. Lesions of the flocculus and paraflocculus cause impaired smooth pursuit, gaze-evoked, rebound and downbeat nystagmus, impaired optokinetic nystagmus, and disability to adjust the gain of the VOR (Lewis & Zee, 1993).

Vascular syndromes resulting in ataxia Vascular lesions of the cerebellum itself and of the corticoponto-cerebellar and dentato-thalamic pathways might result in ataxia.

Stroke of the cerebellum The vascular supply of the three functional subdivisions of the cerebellum does not match the territory of any of the

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three cerebellar arteries. Therefore, vascular syndromes in the distribution of one of the cerebellar arteries present as combinations of the cerebellar syndromes described above. Infarction in the territory of any of the three cerebellar arteries results in limb and gait ataxia (Toghi et al., 1993; Kase, 1994). Dysarthria is a characteristic finding in SCA distribution infarcts, whereas vertigo is particularly common in infarcts in the PICA and AICA territories (Kase et al., 1993; Kase, 1994; Erdemoglu & Duman, 1998). AICA territory infarcts almost always include the lateropontine area and are frequently predominated by brainstem signs. The dorsal medullary territory of the PICA and the dorsal mesencephalic territory of the SCA are less frequently involved than assumed previously (Barth et al., 1993). Motor weakness in the setting of cerebellar infarction allows one to suspect multiple cerebellar infarctions (Canaple & Bogousslavsky, 1999). During the first stage after a cerebellar stroke goaldirected movements are hypermetric, due to a delayed onset of the antagonist activity. Both the intensities of the agonist and antagonist are depressed. As a result, patients initially complain of weakness. Recovery of dysmetria following a stroke has been demonstrated to take place in four phases, which can be explained in terms of a differential recovery of agonist and antagonist activities (Manto et al., 1995). Abnormal reprogramming of the EMG pattern may result in the shifting from severe hypermetria to severe hypometria (Manto et al., 1998).

Posterior inferior cerebellar artery (PICA) In instances of combined cerebellar and medullary infarction in the PICA territory, the patient has the features of Wallenberg’s lateral medullary syndrome: ipsilateral limb ataxia and gait imbalance is accompanied by vertigo, nystagmus, occipitocervical headache and ipsilateral facial pain, dysphonia and dysphagia, ipsilateral facial loss of pain and temperature sensation, Horner’s syndrome, palatal weakness, and by thermanalgesia of the limbs and trunk. Ipsilateral lateropulsion may be present. All these features can be present in full and can occur in various combinations. Brainstem involvement, however, is rare (Amarenco et al., 1990; Kase et al., 1993; Chaves et al., 1994). Cerebellar infarcts in the PICA territory that spare the dorsolateral medulla present with occipitocervical headache ipsilateral to the infarct, along with acute vertigo, nausea and vomiting, nystagmus, ipsilateral limb ataxia, and gait ataxia (Barth et al., 1993; Kase et al., 1993; Kase, 1994; Chaves et al., 1994). Initial hoarseness has been described, but no dysarthric deficits (Ackermann et al.,

1992). Isolated vertigo and gait imbalance without other manifestations may be present, which resembles the presentation of labyrinthitis (Duncan et al., 1975). In labyrinthitis, however, the direction of nystagmus is independent of the direction of gaze, whereas in PICA infarction gazeevoked nystagmus is primarily direction changing.

Superior cerebellar artery (SCA) A unilateral isolated full SCA infarct, including the pontine territory, is rare. It results in ipsilateral limb ataxia, Horner’s syndrome, choreiform involuntary movements, contralateral thermoanalgesia and fourth nerve palsy (Kase, 1994; Amarenco & Hauw 1990a). The majority of SCA infarcts affect only fractions of the territory. A common presentation is acute onset of gait imbalance and ipsilateral limb ataxia that is sometimes associated with headache, vertigo, nausea and vomiting (Kase et al., 1985; Kase, 1994; Barth et al., 1993; Amarenco et al., 1991; Terao et al., 1996; Erdemoglu & Duman, 1998). Axial lateropulsion occurs. Vertigo, however, is less common than in PICA- and AICA-distribution infarcts. The relatively lower frequency of vertigo in SCA cases has been related to the comparatively less vestibular connections of those portions of the cerebellum supplied by the SCA, in contrast to the rich connections of the flocculonodular lobe supplied by the PICA and AICA (Kase et al., 1993). Horizontal nystagmus is present in at least 50% of patients. Dysarthria is a prominent feature (Ackermann et al., 1992). Limb ataxia appears to be more prominent in SCA cases as compared to PICA distribution infarcts (Chaves et al., 1994; Toghi et al., 1993). SCA infarcts are often accompanied by other infarcts in the territory of branches of the rostral basilar artery. Symptoms of rostral brainstem and occipital involvement may overshadow signs of cerebellar involvement (Amarenco & Hauw, 1990a,b; Canaple & Bogousslavsky, 1999).

Anterior inferior cerebellar artery (AICA) In PICA and SCA territory infarcts, the clinical signs are dominated by cerebellar infarction, while in AICA territory pontocerebellar infarcts, brainstem signs predominate (Amarenco & Hauw, 1990b; Amarenco et al., 1993). An almost complete syndrome is observed in most cases. The classic syndrome of AICA occlusion involves vertigo, tinnitus, ipsilateral hearing loss, dysarthria, peripheral facial palsy, Horner’s syndrome, multimodal facial hypaethesia, and ipsilateral limb ataxia accompanied by contralateral thermanalgesia of the limbs and trunk. Partial AICA can be confused with Wallenberg’s syndrome. The prominence of the auditory involvement and peripheral facial

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palsy point to a clinical diagnosis of AICA. Partial AICA syndromes rarely can present with pure vertigo (mimicking labyrinthitis) or isolated ipsilateral ataxia (Amarenco et al., 1993; Kase, 1994; Roquer et al., 1998).

Stroke of the pons, thalamus and internal capsule: ‘Ataxic hemiparesis’ Vascular lesions in the course of the cortico-ponto-cerebellar and dentato-thalamic pathways may result in ataxia, primarily of the limbs. Because of the close vicinity of the cerebellar pathways and the corticospinal tracts in the base of the pons, crus cerebri and internal capsule, hemiataxia is frequently associated with homolateral pyramidal signs (Figs. 5.3, 5.4). The vascular syndrome of ‘ataxic hemiparesis’ (i.e. hemiparesis or pyramidal signs and ipsilateral incoordination without sensory loss) was first named by Fisher in 1978. Fisher also coined the terms ‘homolateral ataxia and crural paresis’ (i.e. weakness of the lower limb and Babinski sign associated with ipsilateral ataxia) and ‘dysarthria-clumsy hand syndrome’ to identify separate stroke syndromes (Fisher & Cole, 1965; Fisher, 1967). De Smet (1991) proposed that ‘ataxic hemiparesis’ results from a lesion involving, simultaneously, both the cortico-spinal and cortico-ponto-cerebello-dentatorubro-thalamo-cortical tracts, anywhere between the subcortical and inferior pontine level (Fig. 5.2). He regarded ‘dysarthria-clumsy hand syndrome’ and ‘homolateral ataxia and crural paresis’ as two clinical variants of one and the same syndrome: ‘ataxic hemiparesis’. Although Glass et al. (1990) proposed that the lack of dysarthria, prominent hemiparesis and frequent sensory symptoms and signs in ‘ataxic hemiparesis’ serve to distinguish the ‘ataxic hemiparesis’ and ‘dysarthria-clumsy hand syndrome’, to date, most authors agree that the latter is a variant of the ‘ataxic hemiparesis’, at least at the pontine level (Fisher, 1982; De Smet, 1991; Kim et al., 1995; Bassetti et al., 1996; Gorman et al., 1998). Bogousslavsky et al. (1992), however, provided evidence that ‘homolateral ataxia and crural paresis’ is merely found in superficial anterior cerebral artery infarction. The anatomic and pathophysiological specificity of ataxic hemiparesis had been questioned by Landau in 1988. Landau argued that all patients with hemiparesis are clumsy, and that there ‘are no data to support the concept of a special measurable quality of clumsiness that identifies cerebellar anatomic correlation’. However, previous kinematic and electromyographic studies in patients with ataxic hemiparesis following a stroke of the corona radiata or pons showed disorders that are known to be

characteristic of patients with cerebellar lesions (Wild & Dichgans, 1993; Bartholome et al., 1996). Ataxic hemiparesis has been found to be highly predictive of a lacunar lesion (Chamorro et al., 1991; Gan et al., 1997; Gorman et al., 1998). The syndrome, however, does not seem to predict the lesion locus. Rather, in ataxic hemiparesis infarcts are scattered throughout the motor pathway. The most common lesion sites are the posterior limb of the internal capsule (23–39%) and pons (19–31%). Other lesion sites are the thalamus (11–13%), the anterior part of the corona radiata (13–31%) and the basal ganglia (8–14%) (Boiten & Lodder, 1990; Chamorro et al., 1991; Moulin et al., 1995; Gan et al., 1997). Although the most common lesion in all studies was a small deep infarct (ca. 50%), cerebral hemorrhage and superficial infarcts in the cerebellum (SCA territory) and frontal cortex (A. cerebri anterior territory) have also been shown to cause ataxic hemiparesis in a small percentage of cases (Moulin et al., 1995; Gorman et al., 1998). The clinical features of ataxic hemiparesis with different locations are almost identical. Ataxia nearly always involves the arm and leg with equal intensity. Minor associated signs are common, e.g. paraesthesiae with thalamic infarction, and dysarthria, nystagmus and gait ataxia with a pontine infarct (Huang & Lui, 1984; Moulin et al., 1995; Gorman et al., 1998). The origin of limb ataxia in ataxic hemiparesis remains debated. Some investigators believe that the syndrome of ataxic hemiparesis is due to simultaneous involvement of corticospinal and dentato-rubro-thalamocortico-pontocerebellar pathways, whereas blood flow studies suggest an ipsilateral cerebellar diaschisis (Giroud et al., 1994; Bassetti et al., 1996). Crossed cerebellar diaschisis is a condition in which cerebellar hypoperfusion and hypometabolism is ascribed to functional deactivation of the contralateral cerebellar hemisphere from the cerebral cortex (e.g. motor and premotor areas) or from subcortical areas (e.g. thalamus, pons) (Tanaka et al., 1992; Fazekas et al., 1993; Infeld et al., 1995; Lim et al., 1998; Rousseaux & Steinling, 1999; de Reuck et al., 1999). Interruption of the cerebro-ponto-cerebellar (anterograde) and dentato-thalamic pathway (retrograde) is thought to be the most likely mechanism of this remote transneuronal metabolic depression (Fig. 5.2) (Tien & Ashdown, 1992; Fazekas et al., 1993; Ishihara et al., 1999). It is, however, unclear whether crossed cerebellar diaschisis is merely an epiphenomenon, as its clinical significance remains unkown. The majority of PET and SPECT studies found no association of cerebellar hypoperfusion to clinical signs and symptoms. Most patients did

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not present with cerebellar signs (Piero di et al., 1990; Tien & Ashdown, 1992; Fazekas et al., 1993; Tanaka et al., 1992; Infeld et al., 1995; Kim et al., 1997). As remote consequences are not correlated with clinical deficits, ataxia in ataxic hemiparesis appears to be directly related to the local consequences of the lesion (Kim et al., 1997).

Eye movement disorders, sensory disturbances, and cranial nerve dysfunction (V–VII) suggest additional tegmental pontine infarction. Occassionally, bilateral infarcts can be limited to the ventral pons, presenting with ataxic tetraparesis, almost isolated para- and tetraplegia or locked-in syndrome (Withiam-Leitch & Pullicino, 1995; Bassetti et al., 1996).

Internal capsule The posterior limb of the contralateral internal capsule is a common lesion site in ataxic hemiparesis, sometimes extending toward the corona radiata region and lateral thalamus (Moulin et al., 1995; Helgason & Wilbur, 1990). In these cases, the frontopontine and temporoparietopontine bundles are not involved, because they course in the anterior limb and retro- or sublenticular portion of the internal capsule, respectively (Fig. 5.3). It has been suggested that the cerebellar dysfunction is related to destruction of corticopontine fibres from the precentral cortex or connecting fibres between the ventrolateral nucleus of the thalamus and the precentral region (i.e. superior thalamic tract) (Bogousslavsky et al., 1992). Saitoh et al. (1987) studied ataxia and the readiness potential in four cases of ataxic hemiparesis resulting from a small infarct in the posterior limb of the internal capsule. On the basis of normal readiness potentials the dentatothalamo-cortical system, secondary to interruption of the thalamic radiation at the internal capsule, did not appear to be significantly involved. Therefore, Saitoh et al. concluded that the ataxia appeared to be the result of involvement of the corticopontine tract originating from the precentral region (areas 4 and 6) at this level. Ataxic hemiparesis is frequently accompanied by hemisensory signs because the sensory tracts course within the superior thalamic tract in the posterior limb of the internal capsule (Fig. 5.3; Helgason & Wilbur, 1990).

Pons Bassetti et al. (1996) delineated three main syndromes of isolated infarcts of the pons (ventral, tegmental and bilateral). Ventral lesions interrupt the corticospinal, corticobulbar and corticopontine fibres to various extents (Fig. 5.4). In ventral pontine infarcts, pontine hemiparesis is often accompanied by homolateral (to the motor deficit) facial palsy and brachiocrural ataxia as well as dysarthria. Smaller infarctions in the anterolateral territory are associated with a mild motor dysfunction corresponding to the lacunar syndromes ‘ataxic hemiparesis’ and ‘dysarthriaclumsy hand syndrome’ (Bogousslavsky et al., 1986; Glass et al., 1990; Kim et al., 1995), which can be considered variants of one syndrome (Kim et al., 1995; Bassetti et al., 1996).

Thalamus Hemiataxia is a common occurrence in thalamic infarction involving the ventrolateral part of the thalamus usually from involvement of the thalamogeniculate territory (Bogousslavsky et al., 1984, 1988; Melo et al., 1992). Hemiataxia as a manifestation of thalamic infarction rarely occurs in isolation, being associated with ipsilateral hemiparesis (ataxic hemiparesis), pain and hemiparesis (painful ataxic hemiparesis), ipsilateral sensory disturbance (hemiataxia–hypaesthesia) and ipsilateral sensory disturbance and hemiparesis (hypaesthetic ataxic hemiparesis). These four syndromes might be explained by variations in blood supply to the capsulothalamic region (Moulin et al., 1995). Accompanying sensory signs are frequent in thalamic hemiataxia because of the close neighbourhood of the sensory (i.e. VPL) and cerebellar (i.e. VL (and VA)) thalamic nuclei in the ventral thalamic group (Fig. 5.5). The occurrence of pain has localizing value. Pain is not present in pontine, mesencephalic or capsular ataxic hemiparesis (Bogousslavsky et al., 1984). In contrast to the ascending dentato-thalamic and sensory pathways the corticospinal tract is not part of the thalamus. Corticospinal signs in thalamic ataxic hemiparesis are probably due to ischemia or edema compressing the adjacent corticospinal tract or associated infarction of the adjacent internal capsule, as the thalamogeniculate branches sometimes contribute to the innermost part of the posterior limb of the internal capsule (Moulin et al., 1995; Helgason & Wilbur, 1990). It has been proposed that, if hemiparesis is mild and transient in ataxic hemiparesis, it suggests a thalamic lesion site (Solomon et al., 1994). Infarction or hemorrhage in the thalamus can produce striking problems in balance. Stength, sensation and coordination are normal; however, patients cannot stand without falling. It has been called thalamic astasia, but similar pictures are seen after midbrain and putaminal lesions (Masdeu & Gorelick, 1988).

Subcortical white-matter lesions Abnormalities of gait are common in subcortical arteriosclerotic encephalopathy (SAE) (Thompson & Marsden,

Cerebellar ataxia

1987; Elble et al., 1996). The gait pattern in SAE shows similarities to that of some patients with hydrocephalus, frontal lobe lesions, and ‘senile’ disorders of gait (Bronstein et al., 1996). Thompson and Marsden (1987) evaluated the disordered gaits of 12 patients suspected to have SAE because of typical low-density periventricular cerebral white matter changes on CT scans. The gait disorder was termed parkinsonian-ataxia since it had elements of both parkinsonism and cerebellar ataxia. Patients stood on a wide base, were slightly ataxic, and took slow and shuffling ‘parkinsonian’ steps. Patients show relatively preserved function of the upper limb, lively facial expression and less flexed posture, which has led to the use of ‘lower body parkinsonism’ (syn. marche petits pas, arteriosclerotic parkinsonism) (Nutt et al., 1993). Frequently associated signs are cognitive impairment and urinary incontinence. Gait initiation failure may remain the sole symptom for many years (isolated gait initiation failure, syn. Petren’s gait). On the other hand, the clinical picture may be dominated by impairment of balance (e.g. truncal ataxia) severe enough to prevent standing and walking (frontal disequilibrium) (Elble et al., 1996; Yamonouchi & Nagura, 1997; van Zagten et al., 1998). Thompson and Marsden (1987) proposed that periventricular low density on CT might indicate significantly damaged afferent and efferent interconnections of the leg areas of the motor and supplementary motor areas of the cerebral cortex with the cerebellum and basal ganglia.

Cortical stroke Bogousslavsky et al. (1992) reported five patients with superficial anterior cerebral artery infarction in the paracentral area, who developed a hemiparesis which was predominant in the leg and with homolateral ataxia in the arm. This syndrome of ‘homolateral ataxia and crural paresis’ had been ascribed to lacunar infarction (Fisher & Cole, 1965). Involvement of the corticopontine fibres at their origin, together with damage to the lower limb motor strip or underlying white matter, appears to have been the cause of the clinical syndrome. It has been suggested that homolateral ataxia and crural hemiparesis is not a lacunar syndrome, and that it should not be considered to be merely a variant of ataxic hemiparesis (Bogousslavsky et al., 1992; Moulin et al., 1995).

Concluding remarks Limb ataxia and ataxia of gait are common in SCA, PICA and AICA territory infarctions. Dysarthria is a characteristic

symptom of stroke in the SCA distribution. Vertigo as presenting sign is most common in PICA and AICA territory infarcts. Concomitant brainstem infarction is the rule in stroke in the AICA distribution, but not in the SCA or PICA territory. ‘Ataxic hemiparesis’ occurs most commonly in lacunar lesions of the internal capsule and basis of the pons. Accompanying sensory signs and pain suggest a lesion site in the thalamus and dysarthria in the pons. The ‘dysarthria-clumsy hand syndrome’ is a variant of ‘ataxic hemiparesis’, at least at the pontine level. ‘Homolateral ataxia and crural paresis’ is the result of superficial anterior cerebral artery infarction. Gait disorders in subcortical ateriosclerotic encephalopathy show parkinsonian and ataxic features.

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Headache: stroke symptoms and signs Conrado J. Estol Centre for Neurological Treatment and Rehabilitation, Buenos Aires, Argentina

A riddle wrapped in a mystery inside an enigma. Winston Churchill

Introduction The stroke–migraine interaction is one of the most fascinating and intriguing among neurological diseases. It appears obvious; however, it remains unravelled. The coexistence of headache and stroke encompasses a large spectrum of possibilities including stroke caused by migraine headache, migraine developing after a stroke and non-migraine headache occurring in relation to stroke. Headache occurs in approximately 200 000 of the 550 000 patients who have a stroke annually in the US (Vestergaard et al., 1993). Although not frequent, the bidirectional association between migraine and stroke is well known and important to recognize for diagnostic, treatment and prognostic reasons. Despite recent and significant advances in understanding of the pathophysiology linking both processes, the exact mechanisms relating migraine and stroke have not been fully elucidated. When referring to migraine, we should think of a complex syndrome with many characteristics among which headache is the most prominent and is almost invariably – but not always – present. Migraine and stroke can result in focal sequelae and both share headache as a frequent symptom. All the potential scenarios in the headache–stroke relationship include: (i) patients with history of migraine who at one point in their lives develop a stroke (temporally unrelated to migraine); (ii) patients with migraine who develop brain infarction during a typical migraine attack; (iii) patients who develop migraine immediately after a stroke; (iv) patients who develop migraine some time after having a stroke; (v) patients with migraine as a manifestation of vascular disease (thrombosis, vascular malformation) without the occurrence of a stroke; (vi) patients in whom migraine disappears after stroke occurrence; (vii) patients with non-migrainous headache only present at

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the time of a stroke; (viii) patients with non-migrainous headache following a stroke. I will analyse the most frequent and significant of these manifestations.

Definitions The different categories developed by the Classification Committee of the International Headache Society (IHS) cover most combinations of different headaches in relation to cerebrovascular disease (Headache Classification Committee of the International Headache Society, 1988). The classification includes headache type (migraine, cluster, tension), specific cerebrovascular event (thromboembolic, intracranial hematoma, venous thrombosis), and whether headache occurs de novo after cerebrovascular disease or if pre-existing headache worsened as a result of the vascular episode. For example, a patient who develops headache after a vascular event (group 6), proven ischemic (group 6.1), with a thromboembolic mechanism (group 6.1.2) and migraine as the resulting headache syndrome (group 6.1.2.1.) can be specifically classified by each of these parameters. The classification adds a time limit of 2 weeks to accept the headache as a result of the cerebrovascular event. To establish the diagnosis of ‘migrainous stroke’ (i.e. stroke caused by migraine), the IHS criteria requires a prior diagnosis of migraine with aura and excludes patients that have migraine without aura. The higher frequency of stroke in patients with this migraine type, suggests that aura may be secondary to mechanisms that predispose to ischemic cerebrovascular disease. However, ischemia may also occur, although less frequently, in patients with migraine without aura, supporting that underlying mechanisms common to different migraine types, or genetic

Headache: stroke symptoms and signs

Table 6.1. Classification of migraine related Stroke I

Coexisting migraine and stroke

II

Cerebrovascular disease with clinical features of migraine IIa: Established (symptomatic migraine): AVM, old infarct, etc. IIb: New onset (migraine mimic): arterial dissection, thrombosis, embolism, etc.

III

Migraine induced stroke IIIa: Without risk factors IIIb: With risk factors: oral contraceptives, smoking, etc.

IV

Uncertain: mitral valve prolapse, antiphospholipid antibodies, etc.

Source: Modified from Welch (1994).

factors as yet unidentified, may be responsible for stroke predisposition in different migraine patients. This situation probably reflects limitations in the present IHS classification more than constituting a strong argument against causality between migraine without aura and stroke. Thus, according to IHS criteria, if a stroke occurs during an attack of migraine without aura, the etiology of stroke should be considered as ‘uncertain’. The IHS definition of Migrainous Infarction requires that: (i) the present attack is typical of previous attacks, but neurological deficits are not completely reversible within 7 days and/or neuroimaging demonstrates ischemic infarction in a relevant area; (ii) the patient has fulfilled criteria for migraine with aura; (iii) other causes of infarction are ruled out by appropriate investigations. Welch proposed inclusion, in this third point, of the possibility that stroke risk factors could be present, to allow classification of patients with potential contributing factors such as smoking, use of birth control pills, and others, as ‘migrainous stroke’ (Welch,1994). These criteria for migrainous infarction do not accurately define: (i) cerebral infarction of other cause coexisting with migraine, and (ii) brain infarction of other cause presenting with symptoms resembling migraine (Table 6.1). In summary, and according to the IHS criteria, the different possible scenarios in the migraine–stroke interaction are as follows. ii(i) Young patients who have a stroke during a migraine attack. To be ‘accepted’ as a migrainous stroke, the deficit should be identical to the symptoms that occur during previous auras. However, if stroke occurs during an attack of migraine without aura or the deficit is different from the usual aura, according to the IHS classification, the event is not accepted as a ‘migrainous stroke’.

i(ii) Young patients with migraine who develop a stroke remote from a migraine attack. The chances that migraine could play an etiologic role are significant, especially in patients without any other coexisting stroke risk factors. It remains to be clarified if migraine is a contributing risk factor among all others, to precipitate a stroke even in the absence of a migraine attack. (iii) Older patients with migraine who have a stroke during a migraine attack. In these patients, there is probably a contributing role of coexisting vascular risk factors. However, it has not been demonstrated that stroke in these patients is more frequent than in younger migraine patients without the associated vascular risk factors. (iv) Older patients with migraine who have a stroke remote from a migraine attack. It is difficult to prove causality in this subgroup of patients, especially if they have multiple coexisting stroke risk factors.

Pathophysiology of headache in migraine and stroke The mechanisms of migraine can be summarized as hemodynamic changes preceded by causal neuronal alterations (Olesen et al., 1981; Skyhoj-Olsen et al., 1987; Olesen, 1992). A spreading wave of neuronal depression, similar to that described by Leno, correlates with a spreading wave of blood flow depression which may reach ischemic thresholds (Woods et al., 1994). Persistently decreased blood flow beyond a reversible ischemic window, hypercoagulation secondary to altered coagulation factors, increased platelet aggregation, excessive vasoconstriction related to serotonin or other vasoactive substances, are among the mechanisms that participate in the occurrence of an ischemic infarction.

The trigemino-vascular system and serotonin The trigemino-vascular system is a relatively recent model that integrates the different participating pathways in the genesis of headache. (Olesen, 1987; Welch, 1987; Humphrey et al., 1990; Moskowitz, 1984, 1991). There is strong evidence linking serotonin (5-hydroxytryptamine, 5-HT) with the headache process. During a headache attack plasma serotonin decreases and its metabolite, 5hydroxy-indolacetic acid increases in urine. Stimulation of serotonin 1 a–d receptors by triptans and ergotamine mediate headache improvement.

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Integration of cortical and trigeminal phenomena How are all the above phenomena integrated? The trigeminal spinal tract and nucleus receive afferent branches that innervate vessels in the anterior (carotid artery) and posterior (basilar artery) circulations – visceral afferents – and from the skin in the face, head and occipital region – somatic afferents. Dural and pial arteries have a dense innervation in contrast with subcortical vessels which have poor afferent projections. A variety of stimuli which include the spreading cortical depression, altered potassium concentrations and neurochemical changes in the monoamine brainstem systems, trigger the trigeminal tract and nucleus. Once activated, the trigeminal reflex delivers substance P and other substances to the involved vessels initiating an inflammatory response in the area sorrounding the affected vessel (sterile inflammation).

Vascular alterations and ischemia Severe vasospasm has been well documented with TCD studies revealing high velocities and pulsatility indexes during a migraine attack (Thie et al.,1988). Angiography has also shown, or caused, significant vasospasm in migrainous patients. Angiographic evidence of arterial reopening after severe vasospasm and apparent arterial occlusion, support this hypothesis (Caplan, 1991).

Ischemia The trigemino-vascular system explains the vasodilation occurring in headache, the unilaterality of pain, the role of vasoactive peptides and the pattern of referred vascular pain. Pain sensitive vessels include the intracranial internal carotid artery, middle cerebral artery (MCA), and origin of the anterior cerebral artery (ACA) in the anterior circulation and the top of the basilar artery (including superior cerebellar arteries), and the vertebral arteries (including the postero-inferior cerebellar artery) in the posterior circulation. In the case of ischemia, direct stimulation of the vessel’s wall or sorrounding nociceptors by the vascular occluding process (embolus, atherosclerotic plaque) or cortical neuronal depolarization secondary to the ischemia, may initiate activity of the trigemino-vascular system. Serotonin may also play a role in stroke if ischemia alters the synthesis, metabolism, molecule or receptors of this neurotransmitter (Moskowitz et al.,1989).

Hemorrhage In hemorrhages, blood accumulation may cause pain through increased intracranial pressure or by direct or indirect traction of the meninges and its vessels. Clinico-

pathological observations have failed to show that blood in the CSF or surface of the brain relates to pain. A richer innervation by the trigemino-vascular system of vessels in the posterior circulation may explain why posterior fossa hematomas are more frequently associated with headaches.

Migrainous stroke What is the incidence of migraine-related stroke? In different studies, the incidence of stroke in patients younger than 50 years is up to 25 per 100 000 (Leno et al., 1993). Studies from Portugal and the US have reported migraine as the cause of ischemic stroke in approximately 25% of these young patients. This percentage becomes less significant (3% in the Oxfordshire Community Stroke Project) when stroke patients of all ages are considered (Ferro et al.,1995; Broderick & Swanson, 1987). The incidence of stroke attributed to migraine is close to 17 per 100 000. This figure is not limited to migrainous infarction as defined by the IHS but rather includes all scenarios of the migraine-stroke interrelation. In a more strict definition, among the general population, the annual incidence rate of migrainous stroke (i.e. excluding migrainous patients who suffer a stroke unrelated to a migraine attack) was 3 per 100 000 in the Oxfordshire study and 2 per 100 000 in Rochester (Minnesota). Part of the variation in results can be attributed to whether associated stroke risk factors are considered in the population studied or not (Henrich et al., 1986; Broderick & Swanson,1987). If these rates could be extrapolated to all populations, there will be approximately 150 000 migraine-related strokes worldwide annually. To put these numbers in context, other data should be considered. Most epidemiologic studies on headache and stroke have important limitations, the most relevant being lack of controls, no evaluation of associated vascular risk factors in some, no strict definition of migraine related stroke, and most important, incomplete diagnostic evaluations due to technologic limitations inherent to the time of the studies. The latter probably has resulted in attributing to migraine the stroke in patients with cardiogenic or aortic embolic foci, hypercoagulable states, intracranial dissections and other pathologies strongly dependent on recently developed technology for their diagnosis. Also, the percentage of strokes attributed to migraine is strongly dependent on age since older patients have a greater incidence of atherosclerosis and other etiologies than younger patients.

Headache: stroke symptoms and signs

Is migraine a stroke risk factor? Carolei et al. performed a case control study of 308 patients under 44 years of age with history of TIA or stroke with 600 controls matched by age and sex (Carolei et al., 1996). A history of migraine was significantly more common in the TIA/stroke patients. A history of migraine with aura was more frequent in the stroke compared to the TIA patients. Migraine was the most significant risk factor for stroke in women under 35 years of age. In men and patients older than 35, the usual vascular risk factors accounted for most of the risk. The authors concluded that aggressive control of vascular risk factors and smoking cessation are specially important in young women with migraine with aura. Although with some methodologic limitations, this recent study and a few others suggest that migraine is an independent risk factor for stroke in young patients (Collaborative Group for the Study of Stroke in Young Women, 1975; Henrich & Horowitz, 1989; Tzourio et al., 1993, 1995; Merikangas et al., 1997). In different analyses the increased risk ranges from two to fourfold, in most the risk was associated only with migraine with aura, and the age range at greater risk was under 45. The presence of vascular risk factors in migraine patients is not different from the incidence in non-migraineurs suggesting other underlying mechanism to explain their greater stroke risk (Launer et al., 1999). One study among physicians in the US showed a doubled risk of stroke in those with migraine, after adjusting for all confounding variables, compared to those with non-migrainous headaches (Buring et al., 1995). Tzourio et al., to confirm whether or not headache was more common in women under 45 who had ischemic strokes, interviewed regarding headache history 53 women admitted to three neurological centers with neuroimaging confirmed ischemic stroke and a control group (rheumatologic and surgical disease). Results showed that migraine was significantly more common in patients with stroke (67%) than in controls (27%) even after correcting for birth control pill and tobacco use (Tzourio et al., 1994). Other factors that support migraine as a stroke risk factor include a higher stroke recurrence rate in migraine patients with aura and a very unusual occurrence of arterial lesions in migrainous stroke patients compared to patients without migraine (Rothrock et al., 1993; Bogousslavsky et al., 1988). Alterations in platelets, mitral valve prolapse, smoking, birth control pills, age greater than 35, gender (women) and the migraine with aura type, have all been proposed as factors that predict greater risk of a cerebrovascular event in migraine patients. To evaluate the potential causative value of these variables, Rothrock et al. studied 310 consecutive migraine patients and 30 patients with migrainous stroke

(Rothrock et al., 1993).There were no statistically significant differences in mean age at migraine onset, gender (most patients being women), family history of migraine, smoking, use of estrogen-containing medications, mitral valve prolapse, and hypertension between the stroke and non-stroke groups. Migraine with aura was significantly more common in the stroke group although aura type was not different between the groups. A history of stroke was more frequent in the migrainous stroke group. Interestingly, in this group prior strokes were also probably migraine related, whereas in the non-stroke migraine group, previous strokes had non-migrainous identified etiologies (cardiac embolism, arterial dissection, amphetamine use, ICH). The authors emphasized the significant frequency of stroke recurrence detected and the fact that, despite obtaining studies to exclude patent foramen ovale and antiphospholipid antibodies, they could not detect a variable predictive of recurrence. History of stroke is per se a risk factor for a new stroke; thus patients with migraine and a prior stroke do have an added risk for a new ischemic event. Broderick and Swanson in the Rochester study, reported a 1% annual stroke recurrence in patients with a mean follow-up of 7 years (Broderick & Swanson, 1987). This rate is significantly lower than the 9% reported by Rothrock, although the difference could be attributed to the fact that almost a third of the patients in Rothrock’s group had prior cerebrovascular events (Rothrock et al., 1993). To assess the relation of migraine and stroke, one hospitalbased study evaluated 291 women between 20 and 44 years who had recently suffered an ischemic or hemorrhagic stroke (Chang et al., 1999). Each patient had a matched control. Data from a headache questionnaire revealed that a history of migraine was present in 25% of the patients with stroke vs. 13% of the controls. The risk detected was only for ischemic stroke and affected equally patients with migraine with or without aura. Birth control pill use, smoking and history of hypertension all significantly increased the risk for migrainous stroke. Since this was part of a study on contraceptive use and cardiovascular disease, data revealed that, although low dose (10 ml) related more frequently to headache, it was not an independent predictor. Ferro et al. interviewed 90 survivors of ICH and found that 27% never had headaches, 43% had ongoing headaches at the time of ICH, 11% developed headaches after ICH and in 19% headaches dissapeared after ICH (Ferro et al., 1998). In the latter group, improvement was attributed to discontinuation of alcohol intake as a precipitant of previous migraines. New onset headaches were attributed to depression after stroke and manifested as the tension-type group. As is the case in the general epidemiology of migraine, headaches were more frequent in women. Most headaches (pre-existing and new onset) began after a headache free interval of weeks to months and headache frequency and intensity were less severe than non-ICH headaches. It is important to recognize the high frequency and characteristics of headache occurring late after an ICH to avoid the risks and high costs of extensive cerebrovascular eval-

uations. Considering that ICH recurrence approximates 10%, if headaches are sudden, unusually severe or atypical compared to their usual pattern, the suspicion and evaluation to rule out a new event is warranted. The location of pain relates to hemorrhage topography and duration is more prolonged compared to ischemic disease (Arboix et al., 1994). Melo et al. reported that patients with posterior fossa hemorrhages referred their pain to the occipital region. They postulated that irritation of pain sensitive structures such as the tentorium and occipital roots, explain this location of pain. On the other hand, for occipital hematomas, Ropper et al reported pain more commonly localized to the ipsilateral eye (Ropper & Davies, 1980).

Summary of headache characteristics in cerebrovascular disease (Table 6.2) Most studies have not reported a greater frequency of stroke-related headache in women compared to men (Portenoy et al., 1984). Headache is recognized in approximately one-third of patients with stroke and is most frequent in ICH followed by ischemic infarcts, TIA and lacunar infarctions. Headache is most severe in hemorrhagic stroke (Gorelick et al., 1986). There is no significant correlation between infarct size and headache severity (Vestergaard et al., 1993). A severe headache at onset associated with vomiting has been predictive of SAH (Gorelick et al., 1986). Lack of onset headache, sentinel headache or associated vomiting are predictive of ischemic stroke. A history of throbbing headache is predictive of developing headache during a stroke. A headache preceding the cerebrovascular event (sentinel headache) has been a common occurrence in most studies reported in up to 60% of

Headache: stroke symptoms and signs

patients. In some studies, incidence of sentinel headaches has been greater for thromboembolic disease and ICH than for embolic disease and SAH (Mohr et al., 1978; Fisher, 1968). However, others have reported sentinel headache most frequently in SAH (Gorelick, 1986). One study which excluded SAH, showed that 25% of patients had peri-stroke (from 3 days prior to 3 days after) headache (Vestergaard et al., 1993). Duration of headache may range from a few hours to weeks or months after the stroke and some patients develop a chronic headache. In general, headaches are more frequent in posterior circulation than anterior circulation disease. The location of the pain is, in general, a reliable indicator of pathology topography: pain in the forehead or eyes is secondary to internal carotid artery disease, in the temple suggests MCA involvement, the external corner of the eye and eyebrow is related to posterior cerebral artery (PCA) disease, the vertex with the basilar artery and the neck, mastoid and occiput with the vertebral arteries. Because midline structures such as the ACA and superior sagittal sinus receive bilateral trigeminal innervation, their involvement causes diffuse pain. At times, headache does not follow the previous rules and can be contralateral to the arterial pathology or diffuse with focal arterial pathology. Headache is most common with PCA disease, followed by basilar artery, ICA and MCA involvement (Fisher, 1968; Mohr et al., 1978; Edmeads, 1979). Pain is most unusual with ACA disease. The most common headache (IHS criteria) in one study was tensiontype headache although migraine was significantly more common in vertebrobasilar strokes (Vestergaard, 1993).

Special vascular disease scenarios Vertebrobasilar migraine A greater than coincidental relationship between migraine and posterior circulation ischemia should not be unexpected since most aura – visual (occipital lobes), sensory (thalamus), vestibular (brainstem or temporal), and confusional (hippocampic) – reflect transient dysfunction in the vertebrobasilar vascular territory. What leads to a permanent deficit, for example, in a patient who has suffered recurrent episodes of hemianopsia over the years, or to migraine after ischemia occurs, is as yet unknown. The coincidence of migraine and stroke – especially in the posterior circulation – suggests a shared basic mechanism. Bickerstaff coined the term ‘basilar artery migraine’ which he described as a benign condition affecting women more frequently and manifesting with different combinations of transient posterior circulation territory dysfunction.

Caplan reported his findings in nine patients with vertebrobasilar ischemia concluding that: (i) permanent ischemic lesions were not uncommon in the posterior circulation territory of patients with migraine, which questions the ‘benign’ evolution postulated by Bickerstaff, (ii) the spectrum of subjects affected included both sexes and all ages, (iii) migraine may begin after stroke (in two of Caplan’s patients), (iv) ischemia may be transient, permanent, recurrent and affect different territories and (v) arterial occlusions may be temporary (Caplan, 1991). Brainstem symptoms vary from minor, brief episodes, to severe dysfunction. One report described a patient suffering migraine with aura and recurrent episodes of encephalopathy during childhood (Corbin et al., 1991). During at least one of the attacks, the patient was unresponsive to painful stimuli with extensor plantar responses.

Arterial dissections Irrespective of the specific vessel affected or the location (extracranial, intracranial, posterior or anterior circulation), vascular dissections are the classic example of arterial pathology associated with severe headache. In patients with history of migraine with aura, the cerebrovascular episode could be erroneously attributed to a migrainous stroke if the appropriate evaluation (Duplex, Transcranial Doppler, MRA, and catheter angiography) is not completed. The pain in dissections could have a double origin: one secondary to the accumulation of blood in the dissected arterial wall and another from the distention of perivascular structures once the dissecting hematoma expands, deforming the arterial anatomy. Although the pain mechanism is not clear, it may be mediated by the fifth, ninth and tenth cranial nerves. When the affected artery is the internal carotid extracranially, the pain is mostly located in the neck, although it usually radiates to the temple and ipsilateral hemiface. When a dissection affects the vertebral artery, the pain is localized to the ipsilateral mastoid bone and it radiates to the occiput. An intracranial carotid artery dissection – a more unusual occurrence – causes diffuse hemicraneal pain. When branches of the MCA beyond the M1 segment are affected, the occurrence of pain is rare. Pain improves as dissection resolves over a period of 3 to 6 months. Horner’s syndrome is the most frequently associated sign, seen in 50% of cases at onset, and helps diagnose carotid artery dissection. In one study, the next most common symptom of carotid artery dissection was transient monocular blindness (Biousse et al., 1998).

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Since the vertebral artery is the second most common dissection site, patients with a new onset migrainous headache should be tested for equilibrium and face and hemibody sensation to rule out a Wallenberg syndrome. Recently, German investigators have found a relation between infections, abnormal collagen structure and the occurrence of dissections (Grau et al., 1998). Other causes to keep in the differential diagnosis during the diagnostic evaluation of patients with familiar or recurrent dissections include: Marfan syndrome, Ehlers–Danlos syndrome, cystic medial degeneration, fibromuscular dysplasia and syphilitic arteritis. We treat dissections using anticoagulation with the rationale of preventing thrombus propagation and dislodgement through a ruptured intima into the vessel’s lumen. Carotid artery endarterectomy and angioplasty can be associated with benign headaches that begin within hours to a few weeks after the procedure. They may be severe and non-specific or resemble different types of migraine. After carotid endarterectomy the physician should be alert to more severe headaches with associated focal neurological findings or seizures which are indicative of artery thrombosis, dissection or the hyper-perfusion syndrome with leuko-encephalopathy (Lopez-Valdes et al., 1997). These scenarios require specific treatments and management in the intensive care unit.

Venous disease When a diffuse, severe headache occurs associated with convulsions in a young woman taking contraceptive pills, the diagnosis of saggital sinus thrombosis (SST) is likely (Ameri & Bousser, 1992). Recent studies using newer imaging data, have shown a greater incidence than previously suspected of cerebral venous disease manifested by partial SST and venous branch occlusions. It is likely that minimal venous occlusions are frequent but never reach diagnosis because systemic fibrinolysis dissolves the clot before it propagates to cause more significant symptomatology. In the brain, a venous system that bifurcates in closed angles and has no valves in a thromboplastin rich environment, probably predisposes to the occurrence of thrombosis. The most limited occlusions can have a clinical course with little or no headache, making diagnosis difficult. Different situations that predispose to venous thrombosis include use of birth control pills, post partum state, certain drug treatments (-asparaginase, interleukin, etc.), dehydration, air travel, infections, trauma, inflammatory diseases (lupus, Behcet, ulcerative colitis, etc.), clotting factor pathology and other hematological diseases.

Headache is present in 70–80% of patients with venous thrombosis. Onset can be acute within hours of the precipitating event or could take a subacute course spanning over weeks or months. Papilledema, focal motor deficits and changes in mental status are observed in a third of patients. Due to increased intracranial pressure, nausea and vomiting are common. Other findings reflect the etiology of thrombosis (infection, hematological disease, etc.). MRI with phase contrast usually depicts the thrombosed sinus although at times angiography may be necessary (Dormont et al., 1994). Brain imaging reveals ischemic parasagittal areas, in an atypical location for arterial disease, commonly bilateral and associated with a significant hemorrhagic component. Recent randomized studies have shown an improved clinical course and greater recovery in patients treated with anticoagulation (Einhäupl et al., 1991; de Bruijn et al., 1999). This benefit from anticoagulation held equally significant in patients with a hemorrhagic component. Thrombolytics are a consideration in patients that do not respond to anticoagulation. With these treatments, mortality has decreased from 80% to less than 30%.

Antiphospholipid antibodies (APA) Knowledge accumulated in the last decade shows that low titre APA (anticardiolipin antibodies and lupus anticoagulant) are present in up to 12% of the general population and that increased anticardiolipin antibodies are an independent stroke risk factor present in approximately 10% of first stroke patients. Although studies have failed to detect a relation between APA and migraine, based on the high prevalence of both conditions in the young population and role as a stroke risk factor, it seems reasonable to test selected patients with migraine for the presence of these antibodies. Patients with migraine and APA should be advised to avoid hormonal treatments, stop smoking and control other vascular risk factors. Whether this subgroup of migraine–APA is at a higher stroke risk remains to be determined. The precise mechanism of how APA causes thrombosis is unknown but cardioembolic sources (noninfectious vegetations, MVP, endocarditis), associated coagulopathy and endotheliopathy have been proposed. All these mechanisms have also been proposed as potential mechanisms of migrainous infarction (the WARSS, APASS, PICSS and HAS study groups, 1997; The Antiphospholipid Antibodies in Stroke Study Group, 1993).

Mitral valve prolapse (MVP) MVP can be detected in 5% of the general population, but it has been reported in up to 30% of migraineurs. Other

Headache: stroke symptoms and signs

coexistent valvular and cardiac anomalies (redundant leaflets, patent foramen ovale) and hypercoagulable factors (Protein C, antiphospholipid antibodies, platelet adhesiveness alterations) may predispose this population to a greater stroke risk.

other neurological deficits. Pain usually disappears within 2 to 3 days of steroid therapy. Takayasu’s disease (another giant cell arteritis) and other angeitis (periarteritis nodosa, granulomatous arteritis) may have a clinical course with an associated non-specific headache.

Patent foramen ovale (PFO)

Small vessel disease

Anzola et al. (1999) prospectively evaluated a group of patients with migraine with aura (n⫽113), without aura (n ⫽53) and non-migraine controls (n⫽25) to detect the presence of PFO using Transcranial Doppler (TCD) with IV agitated saline. The presence of PFO was significantly more frequent in migraine with aura patients (48% prevalence) compared to migraine without aura (23% prevalence) and controls (20% prevalence). The authors postulate that paradoxical microembolic phenomena in the vertebrobasilar circulation may explain the focal neurological events present in migraine with aura patients. Due to its larger availability, transesophageal echocardiography (TEE) is a good alternative to TCD for PFO detection. Moreover, TEE may reveal embolic sources such as atrial septal aneurysms and aortic arch plaques not detectable with TCD. Future studies should be completed to evaluate further this provocative finding.

Giant cell arteritis Temporal arteritis (TA) – one type of giant cell arteritis – should be considered in the differential diagnosis of all patients older than 55 years with new onset headache. Occurrence of TA in younger patients is very unusual. Headache is present in the majority of patients and is frequently severe. The headache may have migraine features and is usually localized to one or both temples but may be diffuse. Associated systemic and neurological findings such as fever, weight loss, anemia, arthralgia, polymialgia, tender and irregular temporal arteries, and jaw weakness or claudication facilitate the diagnosis but are infrequently found. Visual loss occurs secondary to posterior ciliary or central retinal artery involvement, although the occipital artery and intracranial vessels may be affected as well. The erythrocyte sedimentation rate may reach high values (greater than 60 mm/h) but TA may also occur with normal or only slightly elevated sedimentation rate. The diagnosis is confirmed with biopsy of the temporal artery. Doppler techniques may guide the surgeon to the most affected arterial segment. However, diagnosis should be based more on clinical suspicion than on the presence of a full clinical syndrome or confirmatory laboratory findings. Long-term, high dose corticosteroid treatment should be initiated promptly to avoid irreversible visual loss and

Cadasil Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a nonatherosclerotic, non-amyloid, microangiopathy that affects young people with recurrent infarctions that lead to pseudobulbar palsy and dementia (Bousser & TournierLasserve, 1994). Genetic linkage analysis has mapped the disease locus to chromosome 19 (same chromosome as hemiplegic migraine). Average age of onset is 45 to 50 years and death occurs at an average of 60 years with most patients being demented by that time. Other characteristic clinical features of these patients include neuropsychiatric manifestations, mostly depression and at times mania. Headache is frequently present. The headache manifests as migraine with aura and at times has associated confusion and fever as reported in ‘basilar migraine’. On neuroimaging, all patients (including asymptomatic subjects) show different degrees of periventricular leukoencephalopathy that frequently extends to the centrum semiovale. Chabriat et al. (1995), the authors that reported the original families in whom CADASIL was described, also reported a group of patients with migraine and white matter abnormalities on MRI mapped to the CADASIL locus but without the characteristic recurrent ischemic events. Inheritance of headache in this family followed an autosomal dominant pattern, headache attacks lasted from 2 hours to 2 days, intensity was severe, the pain was usually unilateral, pulsatile in quality, frequently associated with nausea, vomiting and sono-photo phobia and almost always preceded by neurological aura (visual field deficits and paresthesias the most common). Diffuse white matter disease secondary to microangiopathy is frequently observed in the MRIs of elderly symptomatic or asymptomatic people, who do not have any type of headache associated to this condition. Lacunar infarctions also commonly occur without associated headache. Headache in CADASIL is likely part of the genetic disorder and not related to the small vessel alterations per se.

Lacunar disease Different studies have found a wide fluctuation in headache incidence from 3% to 17% of patients with small vessel (lacunar) disease (Mohr et al., 1978; Fisher, 1968,

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Portenoy et al., 1984; Koudstaal et al., 1991). The pain in these cases probably reflects remote hemodynamic or neuronal effects rather than a deep, local origin related to the occluded penetrator vessel. A relatively smaller number of pain-sensitive structures explains that deep hypertensive hemorrhages in the territory of these penetrator vessels also have a much lower headache incidence than their cortical counterparts.

Treatment General measures Independent of migraine type, it has been shown that patients with a prior migrainous stroke are at increased risk of recurrence (Rothrock et al., 1993). In this group of patients, prevention of a new episode is crucial. In patients receiving hormones, estrogens should be discontinued or, if this is not possible, pills with the lowest concentration of estrogen should be used. Vascular risk factors should be aggressively sought and treated. Patients who take antimigraine drugs with vasoconstrictive (ergotamine, triptans) effects should be advised to discontinue and avoid them. Non-steroidal anti-inflammatories should be used as therapy to avoid headaches. Young women with migraine and depression may have a higher stroke risk due to serotonergic-mediated vasoconstriction. Until further data is available, serotonin reuptake inhibitors and abortive medication with vasoconstrictive effects should be avoided in these patients (Singhal et al., 1999). Patients with migraine and preceding episodes of visual field defects, have also shown a higher risk of stroke in the symptomatic PCA territory. Modification of risk factors should be undertaken and preventive medication indicated in those patients with continuing episodes. Although no studies have addressed the issue of primary stroke prevention in migraine patients, the use of aspirin (300 to 500 mg QD) seems intuitively reasonable based on its analgesic and platelet anti-aggregant effect. The indication is especially appropriate for patients with aura in general, auras with significant deficits such as hemianopsia, hemiparesis or language dysfunction, for patients with mitral valve prolapse or other valvular abnormalities and for those with antiphospholipid antibodies. With the rationale of preventing embolization, now supported by the microembolization documented in patients with PFO, anticoagulation has been used in migraine patients (Fragoso, 1997). Medication is not frequently necessary to treat the head-

ache at the time of a stroke. If needed, codeine or antiinflammatory agents are usually effective.

Preventive therapy If episodes occur more than two or three times per month and in patients who have less frequent attacks of migraine with aura, preventive therapy should be considered. Beta blockers, amytriptiline, valproic acid and verapamil are good first-line options decided according to the patient’s individual characteristics. Amytriptiline should be ideally started with a 5 mg bedtime dose and increased slowly to an average 50 mg single dose. This drug should be used with caution – or avoided – in patients with significant cardiac conduction defects. Calcium channel blockers may be especially effective in patients with aura. Young patients with hypertension benefit most from beta-blockers. The elderly hypertensive population that commonly has lower renin, plasma volume and cardiac output with a higher peripheral resistence, benefit more from calcium channel blockers as a ‘double’ antihypertensive and migraine prophylaxis therapy. Only some calcium channel blockers (mostly verapamil) have significant anti-migraine efficacy and, in general, they are less effective than other first line preventive medications (beta-blockers, antidepressants, etc.). Nifedipine, diltiazem, and flunarizine in our experience have modest effect and may cause sideeffects. In elderly patients without hypertension who take other medications with hypotensive properties (levodopa, antidepressants) anti-hypertensive drugs should be used with caution and strict control of orthostatic symptoms. Valproic acid is a good alternative for these patients. Late onset headaches after an ischemic event may not respond to the usual preventive therapies and management may become difficult. Preventive medications should be preferably avoided or used with caution in patients with a recent stroke.

Conclusions (i) A clear interrelationship exists between migraine and cerebral ischemia. The basic mechanism common to both processes encompasses neuronal and chemical changes but is as yet incompletely understood. (ii) Although no definite epidemiologic data is available, there is class III evidence that migraine secondary to ischemia is at least equally frequent (or may even be more common) than migrainous stroke (stroke secondary to migraine). (iii) Migraine is an independent stroke risk factor.

Headache: stroke symptoms and signs

(iv)

(v) (vi)

(vii)

(viii)

(ix) (x)

(xi)

Patients with migraine with aura have a higher risk of ischemic stroke than age-matched people without migraine or with migraine without aura. Thus, strict control of vascular risk factors is especially important in this group. A higher incidence of patent foramen ovale in migraine with aura patients suggests that cardiac microemboli affecting the vertebrobasilar circulation may participate in the migrainous mechanisms of these patients. Non-migrainous headache is also frequent in ischemic and hemorrhagic stroke. Different studies have not defined patterns of headache predictive of specific types of ischemic cerebrovascular disease. Apparently typical attacks of migraine with aura should be considered the potential manifestation of ischemia in patients with first attacks at an advanced age, family history of stroke, and general vascular risk factors. Duplex of neck vessels, transcranial Doppler and MRI/MRA should safely and accurately rule out a significant vascular lesion. Headache is not always typical or present in SAH patients contributing to a significant under-recognition of this disease. Suddenness and maximal intensity at onset are the most predictive features of SAH headache. Patients who develop migraine after stroke should be treated (if justified by frequency of attacks) with preventive medication. Preventive treatment is underused and may be especially appropriate for migraine with aura patients. Daily aspirin should be considered in this patient population.

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Melo, T.P., Pinto, A.N., & Ferro, J.M. (1996). Headache in intracerebral hematomas. Neurology, 47, 494–500. Merikangas, K.R., Fenton, B.T., Cheng, S.H. et al. (1997). Association between migraine and stroke in a large-scale epidemiological study of the United States. Archives in Neurology, 54, 362–8. Mohr, J.P., Caplan, L.R., Melski, J.W. et al. (1978). The Harvard Cooperative Stroke Registry: a Prospective registry. Neurology, 28, 754–62 Moskowitz, M.A. (1984). The neurobiology of vascular head pain. Annals of Neurology, 16, 157–68. Moskowitz, M.A. (1991). The visceral organ brain: implications for the pathophysiology of vascular head pain. Neurology, 41, 182–6. Moskowitz, M., Buzzi, M.G., Sakas, D.E., & Linnik, M.D. (1989). Pain mechanisms underlying vascular headaches. Reviews of Neurology, 145, 181–93. Olesen, J. (1987). The ischemic hypothesis of migraine. Archives of Neurology, 44, 321–2. Olesen, J. (1992). Cerebral blood flow in migraine with aura. Pathological Biology, 40(4), 318–24. Olesen, J., Larsen, B., & Lautitzen, M. (1981). Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Annals of Neurology, 9, 344–52. Olesen, J., Friberg, L., Olsen, T.S. et al. (1993). Ischaemia-induced (symptomatic) migraine attacks may be more frequent than migraine-induced ischemic insults. Brain, 116, 187–202. Osborn, R.E., Alder, D.C., & Mitchell, C.S. (1991). MR imaging of the brain in patients with migraine headaches. American Journal of Neuroradiology, 12, 521–4. Portenoy, R.K., Abissi, C.J., Lipton, R.B. et al. (1984). Headache in cerebrovascular disease. Stroke, 15, 1009–12. Ropper, A.H. & Davies, K.R. (1980). Lobar cerebral hemorrhages: acute clinical syndromes in 26 cases. Annals of Neurology, 8, 141–7. Rothrock, J., North, J., Madden, K. et al. (1993). Migraine and migrainous stroke: risk factors and prognosis. Neurology, 43, 2473–6. Singhal, A.B., Begleiter, A.F., Rordorf, G.A. et al. (1999). Neurology (Suppl. 2), 52, A241. Skyhoj-Olsen, T.S., Friberg, L., & Lassen, N.A. (1987). Ischemia may be the primary cause of the neurologic deficits in classic migraine. Archives of Neurology, 44, 156–61. The antiphospholipid antibodies in stroke study group. (1993). Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology, 43, 2069–73. The WARSS, APASS, PICSS, and HAS study groups. (1997). The feasibility of a collaborative double-blind study using an anticoagulant: the warfarin–aspirin recurrent stroke study (WARSS), the antiphospholipid antibodies and stroke study (APASS), the patent foramen ovale in cryptogenic stroke study (PICSS), and the hemostatic system activation study (HAS). Cerebrovascular Diseases, 7, 100–12. Thie, A., Spitzer, K., Lachenmayer, L. et al. (1988). Prolonged vasospasm in migraine detected by non-invasive transcranial doppler ultrasound. Headache, 28, 183–6. Tzourio, C., Iglesias, S., Hubert, J.B. et al. (1993). Migraine and risk

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Eye movement abnormalities Charles Pierrot-Deseilligny Paul Castaigne Clinic, Pitié-Salpêtrière, Paris, France

Introduction Eye movement commands originate in diverse cerebral hemispheric areas (for saccades and smooth pursuit) or in labyrinths (for the vestibular ocular reflex). They are carried out in the brainstem by the immediate premotor structures and the motor nuclei. Conjugate lateral eye movements are largely organized in the pons, and vertical eye movements and convergence in the midbrain. In the first part of this chapter, we will see the main types of eye movement paralysis resulting from brainstem lesions, and the related physiopathology. Such types of abnormalities are easily detected at bedside by studying three main types of eye movements: saccades, i.e. rapid eye movements made towards a visual target (such as the finger of the examiner); smooth pursuit, elicited by a small visual target moving slowly in front of the subject’s eyes; the vestibular ocular reflex (VOR), tested using the oculocephalic movement, by moving passively the subject’s head. In the second part of this chapter, eye movement disturbances due to cerebellar and cerebral hemispheric lesions, resulting in relatively more subtle syndromes, will be reviewed.

BRAINSTEM

Lateral eye movements Final common pathway The final common pathway of conjugate lateral eye movements begins in the abducens nucleus, which contains: (i) the motor neurones projecting onto the ipsilateral lateral rectus; and (ii) the internuclear neurones, which decussate at the level of the abducens nucleus, run through the medial longitudinal fasciculus (MLF) and project onto the

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medial rectus motor neurones in the contralateral oculomotor nucleus (Fig. 7.1) (for review, see Pierrot-Deseilligny, 1990 and Leigh & Zee, 1999). Lesions affecting the abducens nerve rootlets in the lower basis pontis result in complete paralysis of abduction in the ipsilateral eye, with marked esotropia (Fig. 7.1, syndrome 1). Ipsilateral peripheral facial paralysis, due to damage to the adjacent facial nerve fibres, and contralateral hemiparesis sparing the face, resulting from damage to the adjacent pyramidal tract, are often associated. Lesions affecting the MLF, between the abducens nucleus and the oculomotor nucleus, result in internuclear ophthalmoplegia (INO), which includes: (i) paralysis of adduction in the ipsilateral eye for all conjugate eye movements, usually with preservation of convergence (Fig. 7.1, syndrome 2); (ii) nystagmus in the contralateral eye when this eye is in abduction. INO is often bilateral, as both MLFs are near each other in the dorsal tegmentum (Fig. 7.1, syndrome 2⫹2⬘). The pathophysiology of the nystagmus remains unclear. An adaptive mechanism involving quick phases could partly account for such nystagmus (Zee et al., 1987). Vertical nystagmus is also common in INO, resulting from damage to the vestibulo-oculomotor pathways passing through the MLF (Ranalli & Sharpe, 1988). A skew deviation (vertical tropia relatively constant whatever the gaze direction) may also be observed in INO, due to damage to the central otolithic pathways (Brandt & Dieterich, 1993). After an abducens nucleus lesion, there is paralysis of all ipsilateral eye movements (Pierrot-Deseilligny & Goasguen, 1984) (Fig. 7.1, syndrome 3). Convergence is preserved. As the fibres of the facial nerve are in the immediate vicinity, there is also usually an ipsilateral peripheral facial paralysis. Return saccades from the contralateral position to the midline persist, because phasic inhibition of the contralateral abducens nucleus is still present. This inhibition is under the control of the

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ipsilateral paramedian pontine reticular formation (PPRF) and the inhibitory burst neurones (IBN), both located in the vicinity of the abducens nucleus (Figs. 7.2 and 7.3). In a lesion affecting both the abducens nucleus and the ipsilateral MLF, a ‘one-and-a-half’ syndrome is realized (Fisher, 1967; Pierrot-Deseilligny et al., 1981b) (Fig. 7.1, syndrome 4). This syndrome includes complete paralysis of lateral conjugate eye movements in one direction (abducens nucleus lesion) and INO in the other direction (MLF lesion). Consequently, the eye ipsilateral to the lesion remains immobile during all lateral eye movements, whereas the other eye can only abduct. Abduction nystagmus also exists in the latter. Both eyes can converge and move vertically. Variants of this syndrome exist when the PPRF is damaged, either in addition to, or instead of, the abducens nucleus (see below).

Premotor structures The premotor structure of lateral saccades, i.e. the final common pathway of these saccades (including quick phases of nystagmus) or the generator of horizontal saccadic pulse, is the PPRF (for review, see Leigh & Zee, 1999). This structure is located on each side of the midline in the central paramedian part of the tegmentum, extending from the pontomedullary junction to the pontopeduncular junction (Fig. 7.2). Each PPRF contains excitatory burst neurones (EBN), active just prior to, and during, all types of ipsilateral saccades. The EBN and IBN receive tonic inhibition (ceasing just prior to, and during, saccades) from the omnipause neurones (OPN) (see Fig. 7.3) located close to the midline, between the rootlets of the abducens nerves (Büttner-Ennever et al., 1988). The OPN are involved in saccade triggering, for horizontal gaze but probably also for vertical gaze (see below). The premotor structure of lateral slow eye movements is the medial vestibular nucleus (MVN). This is well established for the VOR, but probably also true for smooth pursuit (for review, see Leigh & Zee, 1999 and PierrotDeseilligny & Gaymard, 1992). The MVN contains excitatory vestibular neurones, projecting onto the contralateral abducens nucleus (Fig. 7.1). The nucleus prepositus hypoglossi (NPH) is another important immediately premotor structure, involved in horizontal eye position. This nucleus is located medially to the vestibular nucleus, below the abducens nucleus (Fig. 7.2). The NPH both receives afferents from, and projects to, the PPRF, the vestibular nuclei and the abducens nuclei (Belknap & McCrea, 1988). Probably in combination with the MVN (Cannon & Robinson, 1987), the NPH appears to be the integrator of lateral eye movements. It could control the ‘step’ necessary to maintain a lateral eccentric position

Fig. 7.1. Clinical characteristics and physiological interpretation of horizontal ocular motor syndromes. 1: basis pontis syndrome; 2: internuclear ophthalmoplegia; 2 ⫹ 2: bilateral internuclear ophthalmoplegia; 3: abducens nucleus syndrome; 4: ‘one-and-ahalf’ syndrome; 5: caudal PPRF syndrome; 6: oculomotor nucleus and paramedian midbrain syndrome; III: oculomotor nucleus; VI: abducens nucleus; VIII: vestibular nerve; A: suprareticular tracts of saccades; B: corticopontine tract of smooth pursuit; C: cerebellum (flocculus and vermis); EBN: excitatory burst neurone; EVN: excitatory vestibular neurone; IN: internuclear neurone; IVN: inhibitory vestibular neurone; L: left; LR: lateral rectus muscle; M: midline; MLF: medial longitudinal fasciculus; MN: motor neurone; MR: medial rectus muscle; MVN: medial vestibular nucleus; P: smooth pursuit; PPRF: paramedian pontine reticular formation; R: right; S: saccade; V: vestibular eye movement; ?: the organization of smooth pursuit circuitry within the cerebellum is still unclear.

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Fig. 7.2. Sagittal view of the brainstem. C: cerebellum; Da: nucleus of Darkschewitsch; INB: inhibitory burst neurone area; iC: interstitial nucleus of Cajal; MLF: medial longitudinal fasciculus; MRF: mesencephalic reticular formation; NPH: nucleus prepositus hypoglossi; NRTP: nucleus reticularis tegmenti pontis; PC: posterior commissure; PN: pontine nuclei; PPRF: paramedian pontine reticular formation; riMLF: rostral interstitial nucleus of the medial longitudinal fasciculus; RN: red nucleus; SC: superior colliculus; Th: thalamus; V: fourth ventricle; VN: vestibular nucleus; III: oculomotor nucleus; IV: trochlear nucleus; VI: abducens nucleus.

obtained after a saccade, and could also be involved in lateral smooth pursuit control. Lesions affecting the premotor structures concern essentially the PPRF, since, in human pathology, no cases of lesions limited to the vestibular nucleus or the NPH have been reported. Lesions affecting both these structures have been reported in the monkey, and resulted in severe impairment of fixation and slow eye movements (Cannon & Robinson, 1987). However, human lesions may involve the region of the MVN in Wallenberg’s syndrome, resulting in disturbances of the VOR and in ipsilateral or contra-

Fig. 7.3. Supranuclear circuitry of horizontal saccades. C: cerebellum (vermis); EBN: excitatory burst neurone; F: fastigial nuclei; FEF: frontal eye field; IBN: inhibitory burst neurone; NRTP: nucleus reticularis tegmenti pontis; P: omnipause neurones; PB: predorsal bundle; PPC: posterior cortex; PPRF: paramedian pontine reticular formation; PT: pyramidal tract; SC: superior colliculus; VI: abducens nucleus.

lateral or bilateral or multidirectional nystagmus (Vuilleumier et al., 1995; Leigh & Zee, 1999). A unilateral PPRF lesion in man results in an absence of all ipsilateral saccades, including quick phases of nystagmus (Fig. 7.1, syndrome 5). Both eyes remain on the midline in attempted ipsilateral saccades, or, when they are in a position contralateral to the lesion, return to the midline very slowly (Pierrot-Deseilligny et al., 1982a). The absence of ipsilateral saccades between the contralateral position and the midline is explained by damage to the pathway controlling phasic inhibition (Fig. 7.3). The VOR ipsilateral to the lesion is preserved after a PPRF lesion (Pierrot-Deseilligny et al., 1982a) – as is also, on occasion, ipsilateral smooth pursuit (Kommerell et al., 1987; Pierrot-Deseilligny et al., 1989) – since the pathways involved in these slow eye movements do not pass through the PPRF. If the lesion affects the caudal part of the PPRF, a sixth nerve palsy is associated (Fig. 7.1, syndrome 5), since the abducens nerve

Eye movement abnormalities

rootlets pass through this part of the PPRF (Fig. 7.2). In the case of a bilateral PPRF lesion, there is a total loss of horizontal saccades, and, at times, a slight slowing of vertical saccades (Pierrot-Deseilligny et al., 1984; Hanson et al., 1986). The latter results from damage to the OPN, which are located between the PPRFs. The OPN could control, during saccade triggering, both the PPRFs and the premotor midbrain reticular formations involved in vertical saccades, i.e. the rostral interstitial nucleus of the medial longitudinal fasciculus (Kaneko, 1989, 1997).

Afferents of the premotor structures The afferents of the premotor structures are multiple. Two suprareticular structures appear to be crucial for saccade triggering: the superior colliculus and the frontal eye field (FEF). The PPRF receives afferents from the contralateral superior colliculus, via the predorsal bundle (located in the paramedian dorsal tegmentum), and from the contralateral frontal eye field, via a tract following the pyramidal tract (Fig. 7.3). The former decussates at the level of the superior colliculus (Meynert decussation), whereas the latter decussates in the upper pons. The superior colliculus, located in the upper part of the brain stem, is an important relay for saccades between the cortical areas and the premotor reticular formations. Furthermore, the premotor reticular formations receive vermian afferents (via the fastigial nuclei) involved in saccade calibration see Leigh & Zee, 1999). Before the cerebellar relays, such a pathway could include a brain stem relay, the nucleus reticularis tegmenti pontis (NRTP). This nucleus, located in the paramedian ventral tegmentum, at the mid-pons level, receives cortical and collicular afferents (Figs. 7.2 and 7.3). The MVN receives afferents from the ipsilateral labyrinth, via the vestibular nerve, but also from the opposite vestibular nucleus, via the vestibular commissure. These pathways are involved during the VOR. The pathways involved in smooth pursuit come from the cerebellum, in particular the ipsilateral flocculus (see Leigh & Zee, 1999) (Figs. 7.1 and 7.5). Before the cerebellar relay, smooth pursuit circuitry includes pontocerebellar and corticopontine neurones. The latter probably originate in the medial superior temporal visual area, pass through the posterior limb of the internal capsule and the ventral part of the upper brain stem (in a region which is not yet well known) and project to the dorsolateral pontine nuclei (DLPN), located in the mid-pons. The DLPN neurones project to the contralateral flocculus and also to the vermis. This circuitry, therefore, includes a double decussation (Figs. 7.1 and 7.5), first at the mid-pons level (pontocerebellar neurone) and secondly in the lower pons (vestibulo-abducens neurone). As the

flocculovestibular neurone is inhibitory, and given that a unilateral lesion up to the floccular level results in ipsilateral smooth pursuit impairment, there is probably another inhibitory neurone, within (interneurone) (Fig. 7.1) or before the flocculus. Lesions may involve the afferents of the premotor structures of saccades and smooth pursuit. A unilateral superior colliculus lesion results in impairment of contralateral reflexive visually-guided saccades (increased latency and decreased accuracy), with preservation of saccades to command and smooth pursuit (Pierrot-Deseilligny et al., 1991a). A lesion affecting the region of the DLPN results in ipsilateral smooth pursuit impairment and contralateral hemiparesis (Thiers et al., 1991; Gaymard et al., 1993). The ipsilateral impairment is, therefore, explained by the existence of a double decussation of smooth pursuit circuitry below the DLPN (see Fig. 7.5). A lesion affecting the paramedian part of the midbrain, including the medial part of the pyramidal tract, results in: contralateral hemiparesis; contralateral paresis of intentional saccades (since the lesion is located above the single decussation of the frontoreticular pathway of saccades); ipsilateral impairment of smooth pursuit (since the lesion is located above the double decussation of smooth pursuit circuitry); and often ipsilateral oculomotor paralysis, due to damage to the third nerve rootlets and nucleus (Zackon & Sharpe 1984; Pierrot-Deseilligny, 1988) (Fig. 7.1, syndrome 6).

Vertical eye movements Final common pathway The final common pathway of vertical eye movements is formed by the oculomotor and trochlear nuclei. The motor neurones of the trochlear nerve decussate in the brainstem, as do those innervating the superior rectus muscle, before passing through the contralateral oculomotor nucleus and rootlets. Lesions affecting the oculomotor rootlets result in ipsilateral oculomotor paralysis. Such paralysis may be isolated (Bogousslavsky et al., 1994; Kiazek et al., 1994; Schwartz et al., 1995) or, more often, combined with contralateral hemiparesis (Weber’s syndrome) or contralateral ataxia (Claude’s syndrome), when the lesion also affects either the pyramidal tract or, a little posteriorly, the red nucleus, respectively (for review, see Bogousslavsky, 1989). When a lesion affects the oculomotor nucleus, there is more or less complete oculomotor paralysis in the ipsilateral eye and isolated paralysis of the superior rectus muscle in the contralateral eye (Pierrot-Deseilligny et al.,

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1981a; Pierrot-Deseilligny, 1990) (Fig. 7.4, syndrome 1). The latter, due to the decussation of the motor neurones of the superior rectus muscle, is combined with a hypotropia of the contralateral eye, resulting from a tonic imbalance with the spared inferior rectus muscle. A lesion in the brainstem may also affect the trochlear nerve nucleus or rootlets (Guy et al., 1989).

Premotor structures and brainstem afferents

Fig. 7.4. Clinical characteristics and physiological interpretation of vertical ocular motor syndromes. 1: oculomotor nucleus syndrome; 2 ⫹ 2: downward saccade paralysis; 3: upward saccade paralysis; 4: monocular elevation paralysis; 5 ⫹ 5: supranuclear upgaze and downgaze paralysis; BC: brachium conjunctivum; D: down; iC: interstitial nucleus of Cajal; IR: inferior rectus muscle; llb: long-lead burst neurone; M: midline; mlb: medium-lead burst neurone; MLF: medial longitudinal fasciculus; NPC: nuclei of the posterior commissure; P: smooth pursuit; PC: posterior commissure; riMLF: rostral interstitial nucleus of the medial longitudinal fasciculus; S: saccade; SR: superior rectus muscle; U: up; V: vestibular eye movement; V: vestibular nucleus; III: oculomotor nucleus (the trochlear nucleus is not shown); ?: a vertical internuclear neurone in the iC is hypothetical; the role of the NPC in upward saccade control and the projections of these nuclei are not yet well defined; the role of damage to the llb in downward saccade paralysis is still uncertain.

The premotor structure of vertical saccades, i.e. the final common pathway of these saccades or the generator of the vertical saccade pulse, is the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), located at the level of the upper pole of the red nucleus (Büttner-Ennever & Büttner, 1988; Horn & Büttner-Ennever, 1998) (Fig. 7.2). This nucleus contains the immediately premotor excitatory neurones (medium-lead burst neurones) involved in upward and downward saccades, both types of neurones being intermingled, perhaps in the mediodorsal part of the nucleus (Nakao et al., 1990) (Fig. 7.4). The axons of these two types of neurones could follow a similar route, through the rostral part of the MLF, before projecting ipsilaterally to the nucleus of Cajal, ipsilaterally to the inferior rectus subdivision of the oculomotor nucleus (downward saccade neurones) or bilaterally to the superior rectus subdivision of this nucleus (upward saccade neurones) (Moschovakis et al., 1991a,b). The riMLF also contains long-lead burst neurones involved in downward saccades, located in its mediocaudal part and probably projecting to the mediumlead burst neurones (Nakao et al., 1990) (Fig. 7.4). The equivalent neurones for upward saccades could be located either in the lateral part of the riMLF (Nakao et al., 1990) or in the nuclei of the posterior commissure (NPC) (Moschovakis et al., 1991a) (Fig. 7.4). The NPC neurones, which receive afferents from the frontal eye field (FEF) and the superior colliculus (Büttner-Ennever & Büttner, 1988), decussate through the posterior commissure and could project to the contralateral riMLF (Moschovakis et al., 1991a). These various findings should be considered when interpreting the different types of vertical gaze paralysis observed in human pathology (see below). The vestibular nuclei (medial, lateral, superior nuclei and y-group) constitute the final common pathway of vertical slow eye movements. They contain excitatory and inhibitory neurones projecting (contralaterally and ipsilaterally, respectively) to the motor nuclei of the midbrain, through the MLF and the brachium conjunctivum (Fig. 7.4). The latter could be involved during vertical smooth pursuit (Chubb & Fuchs, 1982; Pierrot-Deseilligny et al., 1989). The nucleus of Cajal is another premotor structure,

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involved in vertical eye position. It is located between the riMLF and the oculomotor nucleus (Fig. 7.2). It is the integrator of vertical eye movements (i.e. the equivalent for these movements of the NPH for lateral eye movements) (Fukushima et al., 1990), and also an important premotor relay for vertical smooth pursuit. The nucleus of Cajal receives ipsilateral afferents from the riMLF and vestibular nuclei, and projects to the contralateral oculomotor and trochlear nuclei through the posterior commissure (Büttner-Ennever & Büttner, 1988) (Fig. 7.4). The nucleus of Cajal may also contain vertical internuclear neurones, to distribute equally to the opposite oculomotor and trochlear nuclei the different supranuclear inputs (for both downward saccades and vertical slow eye movements) arriving unilaterally in the oculomotor and trochlear nuclei. Clinical syndromes with vertical eye movement paralysis, which may be identified at the bedside, essentially result from different lesions affecting the riMLF region. Bilateral lesions located medially and rostrally to the upper pole of the red nucleus result in downward saccade paralysis, with preservation of the downward VOR and, at times, of downward smooth pursuit (Pierrot-Deseilligny et al., 1982b, 1989) (Fig. 7.4, syndrome 2). These lesions are usually due to a bilateral infarction in the territory of the posterior thalamo-subthalamic paramedian artery, but may also result from a tumour (Büttner-Ennever et al., 1989). A portion of the riMLF, perhaps located between the centre of the nucleus and its medial part, could be damaged by such lesions. As the somas of the medium-lead burst neurones involved in upward and downward saccades appear to be intermingled in the medial part of the riMLF and the axons of these two types of neurones seem to follow very similar routes towards the oculomotor nuclei (see above), lesions affecting this part of the nucleus or its efferents cannot account for downward gaze paralysis alone. On the other hand, such paralysis could result from bilateral damage to the long-lead burst neurones involved in downward saccades, located in the mediocaudal part of the riMLF. Bilateral damage is required for downward saccade paralysis probably because the riMLF efferent involved in downward saccades includes both a direct projection onto the ipsilateral oculomotor and trochlear nuclei and an indirect projection onto the contralateral nuclei, perhaps with a relay in the nucleus of Cajal (Fig. 7.4). A unilateral lesion affecting the posterior commissure or the pretectal region immediately adjacent to this commissure results in upward saccade paralysis with preservation of the upward VOR (Pierrot-Deseilligny et al., 1982b; Ranalli et al., 1988) (Fig. 7.4, syndrome 3). This suggests that fibres involved in upward saccades decussate through the PC. Upward saccade paralysis could result from

damage to the NPC and/or their efferents, decussating through the posterior commissure and perhaps projecting onto the contralateral riMLF (i.e. onto the medium-lead burst neurones involved in upward saccades) (see above). It should be noted that the NPC do receive afferents from the two suprareticular structures important for saccade triggering: the FEF and the superior colliculus. A unilateral lesion affecting the tegmentum above the oculomotor nucleus may result in ‘monocular elevation paralysis’, ipsilateral or contralateral to the lesion (Jampel & Fells, 1968; Lessell, 1975; Bogousslavsky et al., 1983; Viader et al., 1984; Thömke & Hopf, 1992) (Fig. 7.4, syndrome 4). The Bell phenomenon is preserved in these cases, suggesting supranuclear impairment. Such a lesion could affect the supranuclear fibres projecting onto the oculomotor subdivisions controlling the two muscles involved in upward gaze. The dorsal midbrain syndrome – which includes damage to the posterior commissure and, therefore, upward gaze paralysis – may also involve other adjacent structures, resulting in various signs (Leigh & Zee, 1999): lid retraction (Collier’s sign), disturbances of vergence eye movements, convergence spasm (with pseudo-abducens palsy), convergence–retraction nystagmus, skew deviation and pupillary abnormalities (light–near dissociation). A vertical ‘one-and-a-half’ syndrome has also been reported, combining either upward gaze paralysis with monocular downward gaze paralysis (Bogousslavsky & Regli, 1984), or downward gaze paralysis with monocular upward gaze paralysis (Deleu et al., 1989). In this case, damage could also be immediately prenuclear. Large lesions affecting the region of the riMLF on both sides result in paralysis of upward and downward saccades with preservation of the vertical VOR (Büttner-Ennever et al., 1982; Pierrot-Deseilligny et al., 1982b) (Fig. 7.4, syndrome 5). Thus, all the cells of the riMLFs or all the efferent tracts are damaged. Other lesions affecting brainstem premotor structures involved in the control of vertical gaze result in various ocular motor syndromes: a unilateral lesion of the riMLF could result only in a contralateral beating torsional nystagmus (Helmchen et al., 1996), or in a more marked deficit affecting the vertical gaze (Bogousslavsky et al., 1990); unilateral lesions to the nucleus of Cajal could result in a see–saw nystagmus (comprising intorsion and elevation of one eye, with synchronous extorsion and depression of the other) (Halmagyi et al., 1994); bilateral isolated lesions of the nucleus of Cajal are not common in humans but result in vertical gaze paralysis with relative preservation of saccades in monkeys (Helmchen et al., 1998); bilateral medial pontine lesions may also affect vertical gaze, in particular saccade velocity, probably because of damage to the OPNs,

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which are also involved in vertical saccade triggering (Hanson et al., 1986; Toyoda et al., 1992; Leigh & Zee, 1999); larger bilateral pontine lesions, existing usually in unconscious patients, result in ocular bobbing (rapid intermittent downward movement followed by a slower return to the central position) or reverse ocular bobbing (upward deviation), with sometimes a slow centrifugal movement preceding a rapid return movement to the midline (‘inverse’ and ‘converse’ bobbing, respectively) (see Leigh & Zee, 1999); vertical nystagmus (in particular, upwards) is also common in bilateral INO because of damage to the vestibulo-oculomotor pathways (see above); lesions affecting the region of the nucleus intercalatus, located medially in the lower brainstem, result in upbeat nystagmus (Janssen et al., 1998); a skew deviation may be observed in INO (see above) and Wallenberg’s syndrome, due to damage to central otolithic pathways (Dieterich & Brandt, 1992; Vuilleumier et al., 1995).

S U P R A R E T I C U L A R S T RU C T U R E S Outside the brainstem, a number of suprareticular structures, located in the cerebellum and the cerebral hemispheres, control eye movements. Damage to these structures results in saccade and/or smooth pursuit disturbances usually much more subtle than those due to brainstem lesions.

metria, typically hypometria if the vermis alone is involved; and hypermetria if the fastigial nuclei are damaged (Selhorst et al., 1976; Büttner & Straube, 1995; Leigh & Zee, 1999).

Smooth pursuit The cerebellum is crucial for smooth pursuit since this eye movement no longer exists after total cerebellectomy in the monkey (Westheimer & Blair, 1974). The dorsal vermis (lobules VI and VII) and the floccular lobe are involved in the cerebellar control of smooth pursuit (Zee et al., 1981; Keller, 1988; Büttner, 1989) (Fig. 7.5). Vermian and floccular cells discharge during both smooth pursuit and VOR suppression. Alteration of smooth pursuit is observed in patients with a dorsal vermian infarction (Vahedi et al., 1995). The inability to maintain an eccentric eye position, commonly observed in cerebellar lesions, is probably due to a dysfunction of the brainstem neural integrator, which receives floccular afferents. The resulting abnormality is termed gaze-evoked nystagmus. Such a nystagmus and ipsilateral smooth pursuit impairment are observed after a unilateral floccular lesion (Straube et al., 1997). The ipsilateral impairment of smooth pursuit after a floccular lesion, thus similar to that observed after a supra-cerebellar lesion despite a first decussation of the circuitry at the upper pontine level, is explained by the fact that the flocculovestibular tract is ipsilateral and inhibitory (Fig. 7.5).

Cerebral hemispheres Cerebellum The cerebellum is involved in saccade calibration and is a crucial relay for smooth pursuit.

Saccades The cortex of the dorsal vermis (lobules VI and VII), the fastigial nuclei on which the dorsal vermis projects, and some parts of the cerebellar hemispheres are involved in saccades (Mano et al., 1991). The dorsal vermis receives afferents from the cerebral hemispheres, mainly via the NRTP (Fig. 7.3) and has a number of connections (via the fastigial nuclei) with brainstem premotor structures controlling saccades. Saccade dysmetria (hypo- or hypermetria) observed after cerebellectomy suggests that the cerebellum is involved in saccade calibration. The cerebellum also exerts long-term adaptive control of saccade accuracy, allowing compensation of modifications caused by various pathological (stroke, intra-orbital lesions) or physiological (ageing) factors (Leigh & Zee, 1999). Lesions of the dorsal vermis and fastigial nuclei cause saccadic dys-

Saccades and pursuit eye movements are controlled by different cortical areas. Each hemisphere appears to control eye movements in both lateral directions. Consequently, ocular motor impairment resulting from unilateral hemispheral damage can be ascertained only by eye movement recordings.

Saccades Two main cortical areas trigger saccades (for review, see Pierrot-Deseilligny et al. 1997) (Fig. 7.3). The FEF, located in the posterior portion of the middle frontal gyrus and the adjacent motor area (Fox et al., 1985), more particularly at the intersection between the precentral sulcus and the superior frontal sulcus (Paus, 1996), controls intentional saccades. The posterior parietal cortex (PPC), located in humans in the intraparietal sulcus bordering the angular gyrus (Müri et al., 1996), could be mainly involved in the triggering of reflexive saccades (made to suddenly appearing visual targets) (Pierrot-Deseilligny et al., 1991a).

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Therefore, two parallel pathways are involved in saccade triggering. The first originates in the FEF and projects directly to the premotor reticular formations of the brain stem (PPRF and riMLF) (Fig. 7.3). The second originates in the PPC and includes a relay in the superior colliculus before reaching the same reticular formations. It seems that saccades can no longer be triggered after bilateral lesions either affecting both the superior colliculus and the FEF in the monkey (Schiller et al., 1980), or affecting both the PPC and the FEF in man (Pierrot-Deseilligny et al., 1988). As saccade deficits are much less severe after bilateral lesions affecting either of these two pathways, each of them could partially replace the other when necessary. The FEF also projects to the superior colliculus, both directly and through the basal ganglia, the caudate nucleus and the substantia nigra, pars reticulata. These different parallel pathways explain how unilateral cerebral hemispheric lesions result in subtle saccade deficits, involving mainly intentional saccades after a FEF lesion and mainly reflexive saccades after a PPC lesion, with principally increase in saccade latency (PierrotDeseilligny et al., 1997). However, frontal or parietal acute unilateral damage to the cerebral hemisphere may result in ocular conjugate deviation, ipsilateral to the lesion, lasting several hours a day (Tijssen, 1990). During this period, contralateral saccades, as well as smooth pursuit and even at times the VOR, may be performed with some difficulty (because of a tonic imbalance), but do in fact persist. Patients with unilateral cerebral lesions may not have ocular deviation when their eyes are open, but only on forced lid closure. Such deviation is much more often contralateral than ipsilateral to the lesion (Sullivan et al., 1991). The causes of these different forms of ocular deviation observed after unilateral cerebral damage are not yet well understood. Bilateral PPC lesions result in Balint’s syndrome, which includes optic ataxia, peripheral visual inattention and severe deficits of smooth pursuit and reflexive visually guided saccades, whereas intentional saccades persist (Pierrot-Deseilligny et al., 1986). Bilateral lesions affecting both the PPC and the FEF result in acquired ocular motor apraxia, in which the triggering of all saccades (except vestibular quick phases) is severely impaired (PierrotDeseilligny et al., 1988). A typical patient with such a syndrome has a great fixity of gaze, and saccades are rarely observed, only after head movements.

Pursuit eye movements Posterior parietal lesions impair smooth pursuit, predominantly in the ipsilateral direction (Morrow & Sharpe,

Fig. 7.5. Circuitry of horizontal smooth pursuit. DLPN: dorsolateral pontine nuclei; DMPN: dorsomedial pontine nuclei; F: flocculus; FEF: frontal eye field; FN: fastigial nuclei; LGN: lateral geniculate nucleus; M: midline; MST: medial superior temporal area; MT: middle temporal area; MVN: medial vestibular nucleus; NPH: nucleus prepositus hypoglossi; OVA: occipital visual areas; PAN: periabducens nuclei; PPC: posterior parietal cortex; V: vermis; VI: abducens nucleus; 1 and 2: first and second decussation of the circuitry. White neurone: excitatory neurone; black neurone: inhibitory neurone; neurone with dotted line: hypothetical neurone or pathway.

1990). Anatomical and electrophysiological data have clarified how and where the smooth pursuit signal is processed (Fig. 7.5). In the monkey, the middle temporal visual area (MT) is especially sensitive to visual target motion. Area MT sends this motion signal to the ipsilateral and contralateral medial superior temporal visual areas (MST).

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Cells in areas MST respond to visual targets moving towards the ipsilateral side (for review, see Leigh & Zee, 1999). In humans, these two areas could lie adjacent to each other at the parietotemporo-occipital junction (areas 19, 37 and 39 of Brodmann). A unilateral lesion limited to area MT results in contralateral bilateral impairment of smooth pursuit initiation when the target is in the contralateral visual field (Thurston et al., 1988). A unilateral lesion affecting area MST results in a decrease in smooth pursuit gain, bilaterally but more markedly in the movement directed ipsilaterally to the lesion (Thurston et al., 1988). Lastly, lesions affecting the FEF also result in a decrease in ipsilateral smooth pursuit gain (Morrow & Sharpe, 1990; Rivaud et al., 1994). All these cerebral areas project ipsilaterally to the pons (Fig. 7.5), mainly to the DLPN (see above). Therefore, lesions of the posterior limb of the internal capsule also results in ipsilateral smooth pursuit deficit (Pierrot-Deseilligny & Gaymard, 1992).

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and downward saccadic pursuit and vestibular movements with a unilateral midbrain lesion: physiopathologic correlations. Neurology, 38, 114–22. Rivaud, S., Müri, R.M., Gaymard, B., Vermersch, A.I., & PierrotDeseilligny, C. (1994). Eye movement disorders after frontal eye field lesions in humans. Experimental Brain Research, 102, 110–20. Schiller, P.H., True, S.D., & Conway, J.L. (1980). Deficits in eye movements following frontal eye-field and superior colliculus ablations. Journal of Neurophysiology, 44, 1175–89. Schwartz, T.H., Lycette, C.A., Yoon, S.S., & Kargman, D.E. (1995). Clinicodariographic evidence for oculomotor fascicular anatomy. Journal of Neurology, Neurosurgery and Psychiatry, 59, 338–34. Selhorst, J.B., Stark, L., Ochs, A.L., & Hoyt, W.F. (1976). Disorders in cerebellar ocular motor control. I. Saccadic overshoot dysmetria, an oculographic, control system and clinico-anatomical analysis. Brain, 99, 497–508. Straube, A., Scheuerer, W., & Eggert, T. (1997). Unilateral cerebellar lesions affect initiation of ipsilateral smooth pursuit eye movements in humans. Annals of Neurology, 42, 891–8. Sullivan, H.C., Kaminski, H.J., Maas, E.F. et al. (1991). Lateral deviation of the eyes on forced lid closure in patients with cerebral lesions. Archives of Neurology, 48, 310–11. Thiers, P., Bachor, A., Faiss, J. et al. (1991). Selective impairment of smooth pursuit eye movements due to an ischemic lesion of the basal pons. Annals of Neurology, 29, 443–8. Thömke, F. & Hopf, C. (1992). Acquired monocular elevation paresis. Brain, 115, 1901–10. Thurston, S.E., Leigh, R.J., Crawford, T. et al. (1988). Two distinct

deficits of visual tracking caused by unilateral lesions of cerebral cortex in humans. Annals of Neurology, 23, 266–73. Tijssen, C.C. (1990). Conjugate deviation of the eyes in cerebal lesions. In Neurological Organization of Ocular Movement, ed. R.B. Daroff & A. Neetens, pp. 245–58. Amsterdam: KüglerGhedini. Toyoda, K., Hasagawa, Y., Yonehara, T., Oita, J., & Yamaguchi, T. (1992). Bilateral medial medullary infarction with oculomor disorders. Stroke, 23, 1657–9. Vahedi, K., Rivaud, S., Amrenco, P., Pierrot-Deseilligny, C. (1995). Horizontal eye movement disorders after posterior vermis infarctions. Journal of Neurology, Neurosurgery and Psychiatry, 58, 91–4. Viader, F., Masson, M., Marion, M.H., & Cambier, J. (1984). Infarctus cérébral dans le territoire de l’artère choroïdienne antérieure avec trouble oculomoteur. Reviews of Neurology, 140, 668–670 Vuilleumier, P., Bogousslavsky, J., & Regli, F. (1995). Infarction of the lower brainstem. Clinical, aetiological and MRI-topographical correlations. Brain, 118, 1013–25. Westheimer, G. & Blair, S.M. (1974). Functional organization of primate oculomotor system revealed by cerebellectomy. Experimental Brain Research, 21, 463–72. Zackon, D.H. & Sharpe, J.A. (1984). Midbrain paresis of horizontal gaze. Annals of Neurology, 16, 495–504. Zee, D.S., Yamazaki, A., Butler, P.H. & Gücer, G. (1981). Effects of ablation of flocculus and paraflocculus on eye movements in primate. Journal of Neurophysiology, 46, 878–99. Zee, D.S., Hain, T.C., & Carl, J.R. (1987). Abduction nystagmus in internuclear ophthalmoplegia. Annals of Neurology, 21, 383–8.

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Cerebral visual dysfunction Jason J.S. Barton1 and Louis R. Caplan2 Departments of Neurology and 2Ophthalmology Beth Israel Deaconess Medical Center, Boston, USA

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Anatomy, physiology and blood supply Axons of the retinal ganglion cells project through the optic nerves, chiasm and tracts. Each optic tract carries visual information from the contralateral hemifield of both eyes, projecting mainly to the lateral geniculate nucleus. Smaller projections subserving the pupillary light reflex exit just prior to the termination of the tract, heading to the pretectal nuclei, and there are minor projections to hypothalamic circadian nuclei and brainstem ocular motor structures. The tract lies ventral to the brain, coursing just dorsal to the hippocampus. The fibres from the two eyes are not well aligned initially, but the correspondence improves gradually along the course of the tract. The retinotopic map also becomes tilted, so that the macula is represented dorsally, superior quadrant laterally, and inferior quadrant medially (Hoyt & Luis, 1963). The optic tract is supplied by branches of the anterior choroidal artery, which originates from the supraclinoid segment of the internal carotid artery. The anterior choroidal artery courses posterolaterally, at first inferior and lateral to the optic tract, and later on its medial side, giving penetrating branches to the optic tract and to the lateral geniculate nucleus. The lateral geniculate nucleus contains the terminations of the optic tract fibres and the neurons which give rise to the optic radiations. It is not merely a relay nucleus, but receives inputs from visual cortex (Sillito & Murphy, 1988) and brainstem (Harting et al., 1991) that modulate its information transfer. It is a subnucleus in the ventro-posterolateral thalamus. Neighbouring subnuclei are the medial geniculate nucleus ventromedially, the ventral posterior nucleus dorsomedially, and the pulvinar dorsally. The acoustic radiations pass dorsomedially on their way to auditory cortex. The hippocampus and parahippocampal gyrus lie ventral to it, across the ambient cistern and the inferior horn of the lateral ventricle. The lateral geniculate

nucleus is a triangle with six layers. The ventral two layers are the magnocellular layers, the remaining four are the parvocellular component; these differ in the type of retinal ganglion cells providing input and the visual information relayed (Schiller et al., 1990). Fibres from the ipsilateral eye end in layers 2, 3, and 5, and those from the contralateral eye in layers 1, 4, and 6. The retinotopic pattern is similar to that of the distal optic tract. The macula is represented in a dorsal wedge including the hilum and the far periphery is ventral. The inferior visual quadrant is in the medial horn and superior visual quadrant in the lateral horn. The lateral geniculate nucleus has a dual blood supply. The lateral choroidal artery, a branch of the posterior cerebral artery, arising from its ambient segment after the posterior cerebral artery has circled the cerebral peduncle, supplies the hilum and dorsal crest in the midzone (Frisén et al., 1978), and the anterior choroidal artery, a branch of the internal carotid artery, enters inferolaterally and supplies the medial and lateral horns (Frisén, 1979; Helgason et al., 1986). The optic radiations (geniculocalcarine tract) arise from the dorsolateral surface of the lateral geniculate nucleus and project to primary visual cortex in the calcarine fissure. The fibres are initially a compact bundle in the posterior internal capsule. Then, fibres for the superior quadrant first project slightly anterolaterally, coursing dorsal to the temporal horn of the lateral ventricle as Meyer’s loop. As they project posteriorly, they join the fibres from the inferior quadrant, which had projected through inferior parietal white matter, and together stream through the occipitotemporal region to terminate in the calcarine fissure. The origins of the geniculocalcarine tracts in the retrolenticular part of the internal capsule are supplied by the anterior choroidal artery. The temporal and parietal portions of the optic radiation are supplied by branches of the inferior division of the middle cerebral artery. The

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Fig. 8.1. Retinotopic representation of the visual hemifield in striate cortex. Views of medial occipital surface. (a) The horizontal meridian is buried in the depths of the calcarine fissure, and the upper and lower vertical meridians are represented at the inferior and superior boundaries of striate cortex respectively. (b) the eccentricity marches anteriorly from central (foveal) at the occipital pole on the left to the far periphery near the parieto-occipital sulcus, just behind the splenium. Note that about half of all striate cortex is devoted to the central 10 degrees of vision – this concentration on central vision is referred to as ‘cortical magnification’. (From Horton & Hoyt, 1991, with permission.)

distal portions of the radiations in the occipitotemporal lobe are supplied by the posterior cerebral artery. The striate cortex – also known as Brodmann area 17, primary visual cortex, V1, and calcarine cortex – is the entry point for most visual information reaching the cerebral cortex. Striate cortex is located in the upper and lower banks of the calcarine fissure, and can vary between individuals: the parieto-occipital fissure is a reliable anterior boundary, but the posterior limit is more variable, extending from the medial occipital surface over the first one or two centimetres of the posterior surface of the occipital lobe. Striate cortex has a systematic retinotopic map of the contralateral visual field (Fig. 8.1): conclusions from early data from war trauma (Inouye, 1909; Holmes & Lister, 1916; Holmes, 1945) have been corroborated by more recent studies of strokes using magnetic-resonance imaging (Horton & Hoyt, 1991). Central (foveal) vision is located at the posterior occipital pole. These neurons have the most detailed spatial resolution and the smallest receptive fields, and hence the highest number of neurons per degree of visual field. This continues a trend through the visual system, to devote more resources to central vision than peripheral vision: in the striate cortex, over half the area is devoted to the central 10 degrees of vision (Horton & Hoyt, 1991; McFadzean et al., 1994). The far peripheral field is anterior, on the medial occipital surface near the junction of the calcarine and parieto-occipital fissures, with the most anterior part representing the monocular temporal crescent, which is the small rim of vision that lies beyond the limits of the nasal field of the other eye. Most striate cortex lies buried in the depths of the calcarine fissure, with the superior bank representing the inferior visual quadrant and the inferior bank the superior quadrant. There are a large variety of cells in different layers of striate cortex, with selectivities to a wide range of visual dimensions, including orientation, stereodisparity, colour opponency, and some rudimentary forms, among others.

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Fig. 8.2. Visual cortical areas in the macaque. The left diagram (a) shows the lateral surface of the macaque brain, and the middle (b) shows the cortex unfolded, with areas normally hidden in sulci marked by dashed lines. The right diagram (c) shows a simplified version of the projections and hierarchical position of the different visual cortical areas, with areas belonging to the ventral (what) stream on the left and areas of the dorsal (where) stream on the right. (Modified from Felleman & Van Essen, 1991.)

The striate cortex is supplied mainly by the posterior cerebral artery. A parieto-occipital branch supplies the superior calcarine bank and a posterior temporal branch supplies its inferior bank. The occipital pole lies in a watershed between a calcarine branch of the posterior cerebral artery and the middle cerebral artery: cortical and vascular variation between individuals means that foveal vision may be supplied by either artery (Smith & Richardson, 1966). Up to striate cortex, the visual pathway has been primarily a serial relay with clear retinotopic arrangements. Beyond striate cortex, the projections to ‘extra-striate visual cortex’ proliferate in a complex web of parallel projections, back-projections, and interconnections among a large number of specialized cortical modules – over 40 have been identified in the monkey (Felleman & Van Essen, 1991). There is an approximate hierarchy, with early visual areas such as V2, V3, V3A in a peristriate zone surrounding the primary visual area, which receive direct inputs from V1. These regions have zones with differentiated responses to form, colour, depth, and motion (Livingstone & Hubel, 1988). Beyond early visual areas, the extrastriate system has an approximate segregation between a ventral and dorsal system (Ungerleider & Mishkin, 1982) (Fig. 8.2). The ventral or temporal system is sometimes considered spe-

cialized for object recognition (‘what’). It consists of area V4 and the various subregions of inferotemporal cortex in monkeys, which in humans likely occupy ventral parts of Brodmann areas 18 and 19 and the medial occipitotemporal region. The ventral stream is supplied by the posterior cerebral artery. Lesions of the medial occipitotemporal regions can cause dyschromatopsia and a variety of visual agnosias, including prosopagnosia and alexia. The dorsal or parietal system is sometimes considered specialized for spatial aspects of vision (‘where’). It consists of areas V5 (middle temporal or MT), V5a (medial superior temporal), and regions in the posterior parietal cortex. Many of these areas have selective responses to motion, stereodisparity, and spatial attention. Most elements of the dorsal stream lie in the watershed between the middle and posterior or anterior cerebral arteries. Lesions of the cuneus and posterior parietal lobe cause visual–spatial problems, including impaired motion perception, spatial disorientation, and defects in attention. Deficits in visual imagery can parallel this spatial and object dissociation in visual dysfunction also (Levine et al., 1985). The ‘where’ versus ‘what’ dichotomy, though conceptually useful, is clearly an oversimplification, and there are many interactive processes that involve both streams. Also, in humans, many vascular lesions do not correspond

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precisely to the anatomic dichotomy, and the resulting pattern of dysfunction may represent a mixture of dorsal and ventral impairments, which vary between patients.

Visual-field defects Patients may or may not be aware of homonymous visual defects. Those who are may also confuse hemifield loss with monocular loss, believing, for example, that left hemianopia is visual loss in the left eye. Asking patients what they notice with each eye covered in turn may help clarify their visual deficit. The visual fields can be tested at the patient’s bedside by confrontation. Adequate lighting and a non-distracting background behind the examiner are helpful. Each eye is tested separately. As the subject fixates on the examiner’s nose, a quick series of targets of increasing subtlety can be used to probe the four quadrants. First, the examiner holds both hands up, palms facing the patient, in the lower quadrants, and the patient is asked if they can see both hands, and if so, whether the two hands are equally clear. This is then repeated in the upper quadrants. Next, one or two fingers are shown briefly, and the patient is asked to count the fingers seen, in one quadrant at a time, or in two quadrants to test for extinction. Finger motion, or smaller items such as pins with white or red heads can be used next. If at any point a deficit is identified in a quadrant, that target should then be moved towards the more normal areas of visual field and the subject is asked to state exactly when the target improves in appearance. A sudden improvement at the vertical meridian, as the target crosses from one hemifield into the other, is pathognomonic of chiasmal or retrochiasmal defects. Retrochiasmal defects will be homonymous, meaning that they affect the same hemifield. The area of hemifield impairment may be the same in the two eyes (congruous) or different (incongruous). Congruity tends to increase as one passes posteriorly through the retino-geniculocalcarine relay. Lesions anywhere along the retrochiasmal pathway can cause complete contralateral hemianopia. Partial hemianopia is more interesting, since the pattern of defect can localize the lesion. With partial optic tract lesions, the area of contralateral hemifield visual loss is often incongruous between the two eyes (Savino et al., 1978; Newman & Miller, 1983). Because the lesion also interrupts visual input to the pupillary light reflex, there is frequently an associated relative afferent pupillary defect, typically in the eye with the temporal field loss (Bell & Thompson, 1978; Newman & Miller, 1983), since the temporal hemifield has more input to the light reflex than the nasal hemifield. Wernicke’s hemianopic

pupil, in which light shone on the hemiretina corresponding to the hemianopia elicits a much reduced light reflex (Pertuiset et al., 1962), is difficult to demonstrate at the bedside, because of the large intraocular light scatter with most penlights (Savino et al., 1978). With time, the axonal damage with tract lesions will be reflected in partial optic atrophy. Optic tract infarction is rare, and a compressive lesion should first be suspected, particularly if optic atrophy is already evident. lnfarction of the lateral geniculate nucleus in the territory supplied by the posterior choroidal artery causes a sectoranopia. (Fig. 8.3). This is a wedge-shaped defect straddling the horizontal meridian and pointing towards fixation (Frisén et al., 1978). Geniculate infarction in the territory of the anterior choroidal artery produces the mirror-image: sector defects adjacent to the vertical meridian and sparing the zone around the horizontal meridian (Frisén, 1979; Helgason et al., 1986; Luco et al., 1992). Partial optic atrophy will also develop a few months after geniculate infarction, but the pupillary light reflexes are normal, since the fibres subserving this reflex leave the optic tract prior to its termination in the lateral geniculate nucleus. Complete hemianopia from optic radiation infarction can occur with large middle cerebral artery ischemia, in which case there are invariably other signs of major dysfunction, such as hemiparesis, hemisensory loss, and aphasia with left-sided lesions. Complete hemianopia with minimal other neurologic signs is unusual but can occur with anterior choroidal artery infarction of the radiations in the retrolenticular internal capsule, or with posterior cerebral artery infarction of the distal radiations in the occipital lobe, sometimes with associated striate damage. More commonly, ischemia of the optic radiations causes partial hemifield defects, with a milder degree of incongruity than optic tract hemifield defects. Superior quadrantanopia occurs with lesions of the temporal optic radiations in Meyer’s loop and inferior quadrantanopia results from damage to the parietal optic radiation. These quadrantic defects usually abut the vertical meridian and extend a variable amount towards the intact quadrant on the same side, seldom aligning on the horizontal meridian (Jacobson, 1997). Damage to the middle zone of the radiations can cause a sectoranopia that mimics posterior choroidal artery infarction of the lateral geniculate nucleus (Carter et al., 1985) (Fig. 8.4). Infarction of striate cortex occurs with posterior cerebral artery ischemia. In about half of patients the field defect is an isolated finding, but amnesia, prosopagnosia, and color perception defects can also occur (Pessin et al., 1987). A syndrome of agitated delirium and hemianopia may be

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seen with lesions extending to the parahippocampus and hippocampus (Medina et al., 1977). Striate infarctions cause homonymous hemifield defects that are highly congruent. When the hemianopia is complete and involves the macula (Fig. 8.5), the responsible lesion usually damages the optic radiations subcortically also. Striate infarction not uncommonly causes partial field defects, though. If the posterior occipital pole is spared, as may occur after posterior cerebral artery infarction in a patient whose pole is supplied by the middle cerebral artery, a macula-sparing hemianopia results (McAuley & Russell, 1979; Gray et al., 1997). Sparing of this central 5 degree zone is pathognomonic of striate infarction (Fig. 8.6). Similarly, sparing of the monocular temporal crescent, the most anterior portion of striate cortex, is seen only with striate lesions (Benton et al., 1980; Ceccaldi et al., 1993) (Fig. 8.8). The converse, a monocular temporal crescentic scotoma, can occur with a retrosplenial lesion (Chavis et al., 1997), but is hard to detect and likely rare. Partial lesions in the superior–inferior dimension can also occur, with infarction of the lower bank of the calcarine fissure causing superior quadrantanopia and infarction of the upper bank causing inferior quadrantanopia. As with radiation lesions, the horizontal boundary of these defects is variable (Fig. 8.6). Overall, a quadrantic defect is more likely to represent striate damage than radiation damage (Jacobson, 1997). Striate quadrantanopia is more frequently an isolated sign, sometimes associated with other visual dysfunction such as alexia or hemiachromatopsia, whereas optic radiation quadrantanopia usually occurs together with hemiparesis, dysphasia, or amnestic problems (Jacobson, 1997). Small lesions can cause homonymous scotomas. Small occipital pole infarcts can cause hemimacular scotomas (Gray et al., 1997), and more anterior lesions cause peripheral scotomas (Fig. 8.7). These can be missed on routine imaging (McAuley & Russell, 1979) unless coronal MR images are obtained. Bilateral ischemic lesions are unusual, except at the striate cortex or distal optic radiations, because of the shared origin of the two posterior cerebral arteries. These cause bilateral hemianopic defects (Fig. 8.8). Bilateral, large lesions cause complete cerebral blindness (Symonds & MacKenzie, 1957; Aldrich et al., 1987), distinguished from bilateral ocular disease by the normal fundus and normal pupillary light responses. Incomplete bilateral hemianopia can be distinguished from bilateral ocular disease by the congruity of the visual loss and usually a step defect along the vertical meridian which reveals the hemifield nature of the loss (Symonds & McKenzie, 1957). Cerebral blindness is permanent in 25% (Symonds & McKenzie, 1957) and residual visual field defects are

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Fig. 8.3. Visual field defects from lesions at various locations in the geniculo-calcarine pathway. A Posterior choroidal artery infarction of the LGN creates a sectoranopia; A⬘ anterior choroidal artery infarction of the LGN creates the inverse field defect; B mildly incongruous inferior quadrantic defect from parietal optic radiation infarct (inferior division of middle cerebral artery); C mildly incongruous superior quadrantic defect from temporal optic radiation infarct (parietal branches of middle cerebral artery); D missing monocular temporal crescent from small infarct of the most anterior portion of striate cortex; E congruous hemianopia with sparing of monocular temporal crescent on the left and sparing of the macula, indicating infarct of mid-zone of striate cortex, sparing both retro-splenial portion and occipital pole; F small mid-periphery congruous and homonymous scotoma from focal lesion of midzone of striate cortex. (Illustrated by Laurel Cook-Lhowe.)

common in the remainder. Bioccipital lucencies on CT scans carry a poor prognosis for visual recovery, but the presence of abnormal visual evoked potentials does not correlate with severity or outcome (Aldrich et al., 1987). As many as 10% of patients with cerebral blindness deny their visual difficulties and claim that they can see (Anton’s syndrome) (Symonds & McKenzie, 1957; Aldrich et al., 1987). Denial of blindness is likely to be only specific for cerebral blindness if there is no associated encephalopathy or dementia, since similar denial has been reported in

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Fig. 8.4. Sectoranopia. Visual defect in a young man with a hemorrhage affecting the mid-portion of his optic radiation (Reprinted from Neuro-ophthalmology, ed. J.S. Glaser, with permission).

patients with ocular diseases and such concurrent cognitive deficits (Geschwind, 1965). On the other hand, some patients with cerebral blindness or hemianopia are said to possess some remnant visual ability in their blind areas, of which they are not aware, a phenomenon called ‘blindsight’ (Stoerig & Cowey, 1997). This can be demonstrated by having subjects point or look towards a visual target in the blind field, or make ‘forced-choice’ guesses about qualities of the object in the blind field, such as its direction of movement or colour. Subjects with blindsight do better than chance in their blind hemifield, though not usually as well as in their seeing hemifield. Sometimes it can also be shown that stimuli in the blind field influence responses to stimuli in the seeing hemifield (Rafal et al., 1990). It has been hypothesized that blindsight represents the function of remaining inputs to either the superior colliculus or extra-striate cortex (Weiskrantz, 1990), which may receive input from the colliculus via the pulvinar, or direct projections from the lateral geniculate nucleus that bypass striate cortex (Cowey & Stoerig, 1991). Blindsight is of extensive research interest: practically, though, it requires careful controls for light scatter (Campion et al., 1983; Barton & Sharpe, 1997), hence is difficult to show with certainty at the bedside, and has yet to be proved to be of practical value to the subjects who possess it.

Hemi-neglect Patients with hemineglect ignore or fail to attend to stimuli on the side of space contralateral to their lesion. Neglect can be multimodal, in that all stimuli whether auditory, tactile or visual are ignored, though sometimes dissociations between sensory modalities are reported. Often, there is an intentional component as well, in that patients fail to explore a side of space, whether with eye movements or hand responses. Visual neglect represents a complex combination of inattention within different frames of reference. Neglect may occur for the contralateral side of space with respect to the patient’s body. It may occur retinotopically, for the contralateral hemifield, even if the eyes are pointed ipsilaterally, towards the ‘normal’ hemispace. It may also be ‘object-centred’, in that it affects the contralateral side of visual objects, no matter which visual field or side of space the objects are in. This complex interaction is best seen in their reading behaviour, ‘neglect dyslexia’ (Behrmann et al., 1990), in which patients – generally with right-sided lesions – may fail to read words on the left side of the page, and also make omission or substitution errors for the left side of words. Furthermore, as they read further down the page the point at which they start to read on each line may progressively shift rightward. Testing for such hemi-inattention and differentiating it

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from hemianopia can sometimes be difficult, especially since a combination of hemianopia and hemineglect is not uncommon. One can start by asking patients what they see in pictures, in the room, or looking out of a window. Patients with neglect will not report people or objects on the neglected side. Their reading can be tested as above. If the examiner observes their eye movements during a visual scanning task, they will not often look towards the contralateral side. In contrast, patients with hemianopia, particularly those with chronic field defects and who are aware of their field loss, compensate by using lots of eye movements to search the space on the side of their hemianopia, and, in fact, devote more time to their blind side than their good side (Behrmann et al., 1997; Barton et al., 1998). Formal testing for visual neglect starts with observations on performance during confrontational examination of visual fields. Both neglect patients and hemianopia patients may fail to respond to stimuli on the contralateral side. However, neglect stems from a gradient of inattention (Bisiach & Vallar, 1990; Behrmann et al., 1997) rather than the sharp demarcation at the vertical meridian so typical of hemifield visual loss: hence when repeatedly moving a stimulus towards the intact side, the points at which neglect patients declare they see the stimulus are not aligned at the meridian, vary from trial to trial, and vary with the intensity of stimulation and distraction. Several easy bedside tests for neglect exist. When asked to mark the

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Fig. 8.5. Near complete right congruous homonymous hemianopia, not sparing the macula (a), from large left posterior cerebral artery infarction (b). Patient also had alexia without agraphia.

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Fig. 8.6. Left congruous inferior quadrantanopia plus, with sparing of the macula (a), from infarction of the upper bank of the right striate cortex (b), sparing the occipital pole. (Reprinted from Neuro-ophthalmology, ed. J.S. Glaser, with permission.)

midpoint of a line (line bisection), such patients place the mark too far towards the side ipsilateral to the lesion, whereas patients with hemianopia place the mark slightly towards their blind contralateral side (Barton et al., 1998; Barton & Black, 1998). If confronted with a paper covered

with small lines and asked to cross all of them out, they will fail to find the ones on the contralateral side of the page (Albert, 1973). If asked to draw a clock or flower, they may omit contralateral details (Fig. 8.9(a)). Perhaps the most sensitive test is object cancellation (Weintraub & Mesulam, 1987), in which subjects search a page cluttered with symbols for one specific type to circle: many more will be missed on the contralateral side (Fig. 8.9(b)). All studies have found that right cerebral lesions are much more likely to cause neglect than are left-sided lesions (Albert, 1973; Weintraub & Mesulam, 1987). Neglect usually occurs in patients with large right cerebral lesions involving the temporal and parietal lobes, supplied by the posterior cerebral artery, or parietal and frontal lobe structures, supplied by the middle cerebral artery. Parietal lobe neglect is usually attributed to failure to attend to stimuli in contralateral space, and frontal lobe neglect is attributed to a lack of motor exploratory behavior towards contralateral space (Liu et al., 1992). Neglect can also be found in patients with lesions of the upper brainstem that decrease the reticular-activating-system stimulation of the ipsilateral cerebral hemisphere (Mesulam, 1981), or lesions of the thalamus or basal ganglia. In patients with posterior cerebral artery-territory infarction, neglect is usually limited to visual stimuli, but thalamic, frontal, and anterior parietal lobe lesions usually cause multimodality neglect, including visual, auditory, and somatosensory stimuli. Hemianopia and inattention are two distinct, different

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phenomena that often coexist. Infarction or hemorrhage restricted to the occipital lobe will cause hemianopia without neglect. Lesions in the temporal, parietal, and frontal lobes will cause visual neglect without hemianopia if the optic radiations are spared. When lesions involve the striate cortex or the optic radiations as well as the parietal or temporal lobes, both hemianopia and neglect are usually present. Concerning other signs, patients with lesions of the inferior parietal and superior temporal lobes usually fail to blink to a threat from the contralateral hemifield and have impaired smooth pursuit eye movements for stimuli moving towards the side of the lesion (Morrow & Sharpe, 1993; Barton et al., 1996). Frontal and parietal lesions often have associated hemi-sensory loss or hemiparesis. In patients with other visual, motor or sensory defects, neglect may appear a secondary issue, yet it often becomes the major obstacle in the rehabilitation of such stroke patients. Fortunately, many but not all cases of neglect show spontaneous improvement over time.

Abnormal ‘positive’ visual perceptions and distortions Visual hallucinations are reports by individuals of seeing something that other observers do not see. They are frequent accompaniments of patients with altered mental status, from dementia (Lerner et al., 1994), confusional

states or delirium, psychosis, sleep deprivation, or drug intoxication or withdrawal – notoriously alcohol withdrawal (Platz et al., 1995), hallucinogenic street drugs, and dopaminergic agonists (Zoldan et al., 1995). In patients with normal mental state, the three major cerebral causes are migraine, focal visual seizures (Fig. 8.10), and ‘release hallucinations’ related to visual deprivation. Photopsias can also be considered types of visual hallucination: these are transient unformed images of sparks, flashes, lights, blobs, or spots, and are related to diseases of the retina, ocular media, and optic nerves, and hence frequently monocular (Lessell, 1975). Release hallucinations (Charles Bonnet syndrome) are restricted to regions of the visual field with homonymous visual loss. These may occur with bilateral ocular disease or hemianopia from cerebral lesions, and up to half of such patients may have hallucinations (Lepore, 1990; Teunisse et al., 1996). The hallucinations vary widely in content, from simple blurs of colour, streaks and patterns (Kölmel, 1984) to detailed images of people and animals (Lance, 1976). Unlike the case with visual seizures, the visual content has no localizing value – in contrast to the field defect – and may even change over time (Weinberger & Grant, 1940). The variability of their content is often another distinction from the stereotyped nature of repeated visual seizures. Release hallucinations usually start days or weeks after the visual loss, and may stop after a few days or persist indefinitely (Lance, 1976; Teunisse

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et al., 1996). They can be intermittent or continuous. The origins of release hallucinations are probably analogous to the explanations of phantom limb phenomena after amputation, in that the brain has an inherent tendency to generate spontaneous patterns of neural impulses in the absence of sensory input (Schultz & Melzack, 1991). Treatment is rarely required, as most patients are aware that the hallucinations are not real and the content is seldom threatening: reassurance that they are not crazy is often sufficient (Teunisse et al., 1996). Decreasing social isolation may help (Cole, 1992). A less common stroke-related phenomenon is peduncular hallucinosis (van Bogaert, 1927; Lhermitte, 1922). These are complex, detailed hallucinations with varying content, sometimes continuous, sometimes episodic, sometimes accompanied by tactile or auditory hallucinations also (Caplan, 1980; McKee et al., 1990). Patients may or may not have insight into the unreality of their visions. These hallucinations need not be associated with visual field defects, but are invariably accompanied by inversion of the sleep–wake cycle (L’Hermitte, 1922; Noda et al., 1993). Lesions of the cerebral peduncles or paramedian thalamus are seen on imaging (Feinberg & Rapcsak, 1989). The hallucinations may stem from damage to either the reticular activating system (Feinberg & Rapcsak, 1989) or the substantia nigra pars reticulata (McKee et al., 1990), which

may play a role in REM sleep regulation. Vertebrobasilar infarction causing a ‘top of the basilar’ syndrome is the most common cause of this rare problem (Caplan, 1980). Hallucinations can persist indefinitely (McKee et al., 1990), though episodes may become shorter (Noda et al., 1993) or disappear (Feinberg & Rapcsak, 1989). Visual perseverations are the persistence, recurrence or duplication of a real percept, and can take several forms, which may coexist in a given patient (Kinsbourne & Warrington, 1963). All of these are rare phenomena. Palinopsia is visual perseveration in time, in that a recent image either persists after the object disappears, much like an abnormally prolonged afterimage, or else recurs after an interval of minutes or even weeks (Kinsbourne & Warrington, 1963). The palinoptic image can occupy any region of the visual field, and sometimes recurs in a contextually specific manner, in that a previously seen face reappears in the place of other people’s faces, for example (Critchley, 1951; Meadows & Munro, 1977). Almost all patients with palinopsia have visual hemifield defects, in either upper or lower quadrants, or both (Meadows & Munro, 1977), and some have other spatial illusions or complex visual deficits (Critchley, 1951). The localizing value of palinopsia is not clear. The differential includes intoxication with hallucinogenic drugs (including newer antidepressant medications such

Cerebral visual dysfunction

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Fig. 8.9. Left hemineglect in a woman with an extensive right fronto-parietal infarction. (a) When asked to copy a flower, she omits left-sided petals. (b) When asked to circle all the bells in a random array, she misses 2 on the right side and 12 on the left.

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allesthesia in which visual images are projected from the ipsilateral side into contralateral space. Visual distortions alter the sizes and shapes of objects, a complaint familiar to readers of Alice in Wonderland. Again, these are rare. Micropsia is the illusion that objects are smaller than they are. Sometimes this occurs only in the contralateral hemifield – hemimicropsia (Cohen et al., 1994). Lateral or medial occipito-temporal lesions have been reported. The differential includes psychiatric disease, migraine (Abe et al., 1989), and, if monocular, macular edema. Macropsia, the illusion that objects are larger than they are, is even more unusual, but has occurred with occipital infarcts (Ardile et al., 1987). Metamorphopsias are illusions of object distortion. These are far more common with macular disease than with cerebral disease. They have occurred with medial temporooccipital infarction (Imai et al., 1995).

Abnormalities of complex visual perception

Fig. 8.10. Small occipital hemorrhage (arrow) in a man with endocarditis and ictal visual hallucinations, repeated waves of pink or grey hues lasting 10 minutes, triggered by sudden changes in ambient illumination.

as trazadone), psychosis, and non-ketotic hyperglycemia. Palinopsia from stroke can be a transient phase in the progression or resolution of a visual field defect (Bender et al., 1968), but can also persist for years (Kinsbourne & Warrington, 1963; Swash, 1979; Cummings et al., 1982). Anti-convulsants may help some patients (Swash, 1979). Cerebral polyopia, the perseveration of a visual image in space, is less frequent than palinopsia. Unlike diplopia from strabismus, the duplicated image is still seen when one eye is closed. Unlike the monocular diplopia from refractive problems like cataracts, cerebral polyopia is seen with either eye viewing alone and is not eliminated by viewing through a pinhole. The number of images reported can range to over a hundred (Lopez et al., 1993). As with palinopsia, visual field defects are common, and this symptom is often a transient phase in their recovery (Bender, 1945). The localization value is again obscure. Other even rarer perseverative phenomena include illusory visual spread, in which the surface texture or colour of an object exceeds its borders (Critchley, 1951), and visual

Once beyond the striate cortex, lesions create very different effects compared with the findings with lesions of the retino-geniculo-calcarine relay. Visual processing and hence its defects become less specific for the region of visual field affected and more specific for the type of visual information involved. There are also interactions with memory processes and other sensory modalities, as well as effects upon motor responses, particularly eye movements. It must be stressed, though, that in general higher cortical visual dysfunction is diagnosed with the caveat that other cognitive functions are relatively spared or, at least, if affected cannot account for the impaired responses observed. Aphasia and dementia in patients with vascular disease are particular problems in this regard. Furthermore, higher visual dysfunction can only be diagnosed if there is enough sparing of the geniculo-calcarine relay to permit vision that should have been sufficient for the visual task provided. Failure to consider unrelated cognitive and ‘low-level’ visual dysfunctions can lead to misleading conclusions about the nature of complex visual perception in patients – the confusing literature on Bálint’s syndrome is a prominent example (Rizzo, 1993).

Unilateral posterior cerebral hemisphere lesions Unilateral dorsal pathway lesions Functional imaging shows a region sensitive to visual motion in the lateral occipitotemporal cortex. Unilateral

Cerebral visual dysfunction

another way to test for constructional apraxia. Patients with posterior right cerebral hemisphere or thalamic lesions are often impaired on these tasks. Their drawings omit portions of the left sides of figures, have abnormal angles, sizes, and proportions, and fail to improve when copying instead of drawing from memory (Paterson & Zangwill, 1944; Piercy et al. 1960). Large right posterior cerebral artery-territory infarcts, right inferior-division middle cerebral artery infarcts, and deep right occipital and temporo-parietal hematomas are most often responsible (Hier et al. 1983), and there is often left visual hemineglect as well. Some patients with left cerebral and thalamic vascular lesions also show a constructional apraxia of a less severe degree: they draw simple diagrams with normal sizes, angles, and proportions, and their drawings are much improved when they copy figures.

Unilateral ventral pathway lesions

Fig. 8.11. Right lateral occipito-temporal infarction (short arrow) associated with asymptomatic impaired motion perception revealed by psychophysical testing. Impaired smooth pursuit of targets moving to the right was also present, but may have been due more to damage to descending fibres in the posterior internal capsule (long arrow).

lesions of this area (Fig. 8.11) cause hemiakinetopsia, in which there are deficits in motion perception limited to the contralateral hemifield (Plant et al., 1993; Greenlee & Smith, 1997), sometimes with more subtle and partial dysfunction in the central visual field also (Vaina, 1989; Regan et al., 1992; Barton et al., 1995). A right-sided bias was found in one study only (Vaina, 1989). These defects are never symptomatic, and generally are detected only with special psychophysical tests. Impaired smooth pursuit eye movements of targets moving towards the side of the lesion may be the only clinical sign that can be demonstrated, but in the chronic state this abnormality may depend more upon white matter than cortical damage (Fig. 8.11), and is independent of defects in motion perception (Barton et al., 1996). Constructional apraxia is the inability to form figures (arranging, building, drawing, copying), despite sufficient visual perceptual and motor functions judged needed to perform such tasks. This is tested by asking patients to draw figures, such as a clock, bicycle, or house, and to copy complex figures. Making or copying constructions using matches, tongue blades, building blocks, or Koh’s blocks is

Visual agnosia is difficulty in recognizing visual objects despite the preservation of ‘elementary’ sensory functions (Farah, 1990). It is the hallmark deficit of ventral pathway lesions. Lissauer (1890) made the original distinction between two types of visual agnosia. In apperceptive agnosia, complex aspects of visual processing are impaired, causing poor formation of the percept of the object and hence the trouble with recognition. In associative agnosia, a correctly formed percept is poorly matched with stored knowledge based on past visual experience (Caplan & Hedley-White, 1974), as in Teuber’s (1968) famous definition of agnosia as percepts stripped of their meanings. Both groups are unable to name or recognize the character and function of objects seen, but most will readily do so if they can experience the object by hearing, touch, or someone else’s description of the properties of the object (e.g. feeling a cat, hearing a cat meow, or describing a small household pet that likes milk). Combined tactile and visual agnosia can occur, though, probably indicating more anterior extension in the left temporal lobe (Feinberg et al., 1986). The distinction between apperceptive and associative agnosia classically rests upon the patient’s ability to copy drawings, match objects with one another, and trace outlines of drawn objects they cannot recognize. Some visual agnosic patients are able to recognize objects after tracing them with their fingers (Landis et al., 1982). Laboratory studies augment these bedside observations with tests of contrast sensitivity, lightness, shape, and orientation perception (Campion & Latto, 1985; Milner & Heywood, 1989; Milner et al., 1991). Visual agnosia must also be distinguished carefully from visual anomia. In contrast to visual agnosia, patients with visual anomia do recognize the nature and function of the

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visual object. In contrast to anomic aphasia, they can name the object if they hear or touch it. Severe apperceptive agnosia, affecting all classes of objects, is rare and likely requires bilateral occipital injury, often occurring as a residual defect after partial recovery from cerebral blindness (Sparr et al., 1991). The classic cause is carbon monoxide poisoning (Adler, 1950; Benson & Greenberg, 1969; Campion & Latto, 1985; Milner & Heywood, 1989), though it has also been reported after bilateral occipital infarction (Riddoch & Humphreys, 1987). The utility of the apperceptive/associative dichotomy in more restricted forms of visual agnosia – such as pure alexia and prosopagnosia – is more questionable (Farah, 1990). Certainly the distinction is not an all-ornone affair: rather, patients vary on the degree to which impaired visual memory versus perception underlies their disorder. In addition to the apperceptive/associative distinction, visual agnosias range from a generalized agnosia affecting most, if not all, categories of objects, to agnosia selective for certain classes, the most prominent exemplars of which are words (alexia) and faces (prosopagnosia). Selective agnosia is typical of unilateral lesions, whereas generalized agnosia often requires bilateral lesions. Hemiachromatopsia, the loss of colour perception in the contralateral hemifield, may be seen with either left or right-sided lesions of the lingual and fusiform gyri (Albert et al., 1975; Damasio et al., 1980; Kölmel, 1988; Paulson et al., 1994). It is usually asymptomatic and hence likely under-recognized; any patient with an upper quadrantanopia should be tested for colour perception in the remaining contralateral hemifield.

Left-sided ventral lesions Alexia without agraphia (‘pure alexia’ or ‘word blindness’) is the loss of previously fluent reading skill despite preserved ability to write, speak, and comprehend spoken language (Dejerine, 1892). The spectrum ranges from ‘global alexia’ (Binder & Mohr, 1992), in which patients cannot read even single numbers, letters or symbols, to ‘letter-byletter reading’, or ‘spelling dyslexia’ (Black & Behrmann, 1994), a less severe deficit of slowed reading with occasional errors, whose hallmark is a correlation of reading time required with the length of a word (Bub et al., 1989; Coslett et al., 1993). Pure alexia has been explained as a ‘disconnection’ of the left angular gyrus from its visual inputs (Dejerine, 1892; Geschwind, 1965). The left-sided lesion often causes a complete right hemianopia and intercepts information from the right visual cortex in the splenium or callosal fibres (Damasio & Damasio, 1983) (Fig. 8.12). Pure alexia without hemianopia, though rarer, may

occur if the lesion causes a disconnection in the white matter underlying the angular gyrus (Henderson et al., 1985; Iragui et al., 1991). Others argue that pure alexia in some cases is a type of visual agnosia from damage of the medial temporo-occipital regions (Warrington & Shallice, 1980; Rentschler et al., 1994). Besides hemianopia, patients often have colour anomia (Geschwind & Fusillo, 1966; Damasio & Damasio, 1983), anomia for visual objects and photographs, defects of verbal memory, and agnosia for other visual objects (Damasio & Damasio, 1983). A disconnection optic ataxia may occur, in which the right hand has difficulty reaching for objects in the left visual field (Damasio & Damasio, 1983). It must be stressed that reading is a complex performance involving vision, form perception, attention and scanning eye movements, and can be impaired for any of these reasons. Hence patients with impaired fixation or inaccurate saccades from biparietal lesions (Holmes, 1918a; Pierrot-Deseilligny et al., 1986; Husain & Stein, 1988) have trouble reading. Patients with hemineglect will have neglect dyslexia, missing the left side of the page and making errors on the left side of words (Behrmann et al., 1990). Patients with left macula-involving hemianopia, having reached the end of one line, have trouble returning to the beginning of the next, which lies in their blind field (Zihl, 1995). Marking their place with an L-shaped ruler helps. Right macular-splitting hemianopia is even more disabling, because the normal process of reading tends to take in substantial information from areas just forward (rightward) of each fixation. These patients must make more small saccades and longer fixations, creeping slowly along each line (Zihl, 1995; Trauzettel-Klosinski & Brendler, 1998). Pure alexia must also be differentiated from other highlevel reading problems too. These generally stem from linguistic rather than visual dysfunction, and are not ventral pathway visual deficits. Alexia with agraphia is the combination of impaired reading and writing with preserved oral language functions. This is caused by infarcts or hemorrhages involving the left angular gyrus (territory of the lower division of the left middle cerebral artery) or white matter, undercutting this region of the inferior parietal lobe (posterior cerebral artery territory) (Dejerine, 1892; Geschwind, 1965; Benson & Geschwind, 1969). These patients cannot read, write, or spell: an acquired illiteracy. It may be accompanied by other elements of Gerstmann’s syndrome. Literal alexia may occur with left frontal infarcts causing Broca’s aphasia. Patients with this deficit have better comprehension of spoken language than written language (Benson et al., 1971; Benson, 1977). They may have more trouble reading individual letters than whole

Cerebral visual dysfunction

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Fig. 8.12. (a) Dejerine’s diagram of the lesion in pure alexia (without agraphia), interrupting callosal fibres from the right visual cortex as well as damaging the left striate cortex (striped cortical ribbon noted as c). (b) Left lateral occipital-temporal infarction (arrow) associated with pure alexia and right hemianopia.

words (‘letter blindness’). Central dyslexias (Black & Behrmann, 1994) involve problems with accessing word stores or phonological rules: hence some defects are specific to pronouncing words with irregular spelling (i.e. yacht) and others have trouble using language rules to pronounce a nonsense word (i.e. glaster). Reading aloud and for comprehension can be tested with magazines and newspapers, with attention to speed and the performance with long vs. short words. Premorbid intellect must be taken into account. Oral language must be examined to exclude aphasia and writing tested to dictation or spontaneously, not by a signature. Colour anomia is another visual–verbal disconnection symptom (Geschwind & Fusillo, 1966), which only occurs in patients with pure alexia and right hemianopia from lesions of the splenium or adjacent white matter. Despite their naming problems, these patients can perform colour matching or sorting tasks well, in contrast to patients with achromatopsia. They also have normal colour imagery, in that they can describe the usual colours of familiar objects and can colour line drawings of objects with the appropriate colours.

Right-sided ventral lesions Prosopagnosia is the inability to recognize previously familiar faces. Patients usually complain of the social handicap: they cannot recognize individuals except by their voice or idiosyncratic visual features, such as a peculiar hairstyle, glasses, gait, or unusual clothing. They have trouble especially when encountering people out of context (i.e. seeing a teacher at the supermarket). The defect may be so severe that they cannot recognize their family or their own face in a mirror. The specificity of the defect for faces varies among patients: in some, the recognition defect extends to other objects such as individual animals, cars, buildings, food, flowers, coins, handwriting, or personal items of clothing (Damasio et al., 1982), in others the deficit appears more restricted to faces (Bruyer et al., 1983; Farah et al., 1995). Many patients can distinguish sex, estimate age, and recognize expressions from faces (Tranel et al., 1988; Bruyer et al., 1983; Sergent & Poncet, 1990) but some cannot (Campbell et al., 1990). Patients also differ in their ability to match photographs of unknown people, when the views differ in lighting or profile. The performance on such matching tests, as well as

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the ability to perceive age, sex and expression, have been used as an index of face perception, to divide prosopagnosia into apperceptive and associative forms (de Renzi et al., 1991). There are also interesting demonstrations of preserved ‘covert’ knowledge of faces in some, but not all, prosopagnosic patients. Famous faces differ from unfamiliar faces in the eye scanning patterns (Rizzo et al., 1987), galvanic skin responses (Tranel & Damasio, 1985), and P300 evoked potentials (Renault et al., 1989) of some prosopagnosic patients. Some patients even have unconscious access to semantic information about faces, in that their performance on a variety of indirect tasks is influenced by the correct name or occupation belonging to a famous face that they cannot openly recognize (Bauer & Verfaellie, 1988; Sergent & Poncet, 1990; de Haan et al, 1987). Prosopagnosia is caused by lesions in the lingual and fusiform gyri, (Meadows, 1974a; Damasio et al., 1982), occasionally in more anterior temporal cortex (Evans et al., 1995). The most common cause is posterior cerebral artery infarction (Fig. 8.13). Controversy still surrounds the issue of whether prosopagnosia requires bilateral ventral lesions, as claimed in earlier reviews of autopsy data (Meadows, 1974a; Damasio et al., 1982). Neuropsychological data supports a role for both hemispheres in face perception, though the right side is likely dominant. Nevertheless, more recent neuroimaging reports (Landis et al., 1986a; Michel et al., 1989; Takahashi et al., 1995) have documented cases with apparently unilateral right-sided lesions. How bilateral and unilateral cases differ is still not clear. Damasio et al. (1990) hypothesize that unilateral right occipitotemporal lesions may damage the structures needed for perceiving faces, causing an apperceptive prosopagnosia, whereas bilateral anterior temporal lesions may impair the memory for faces, causing an associative prosopagnosia. Prosopagnosia is frequently, but not always, associated with achromatopsia, topographagnosia, and hemifield visual defects. Bilateral upper quadrantanopia is common among those with bilateral temporal lesions and left hemianopia is frequent in those with right-sided lesions (Landis et al., 1986a, Takahashi et al., 1995). Various degrees of visual or verbal memory loss are often found too (Bruyer et al., 1983). Testing for prosopagnosia involves assessing the recognition of faces that should be familiar to them: if images of public figures are used, the likelihood of their familiarity to the patient based on the patient’s interests, education and age needs to be considered. Care should be taken that recognition does not stem from distinctive features (Jimmy Durant’s nose) or props (Winston Churchill’s cigar) that bypass face perception. Face perception, or more correctly recognition of unfamiliar faces, can be

Fig. 8.13. Right medial occipitotemporal infarction associated with left homonymous hemianopia, prosopagnosia and topographagnosia, but no achromatopsia. Note small medial occipital lesion on the left side as well (arrow): whether this also contributes to his prosopagnosia is unclear.

tested with the Benton Face Recognition Test by a neuropsychologist. Topographagnosia (‘disorientation for place’, or ‘environmental agnosia’) is the inability to recognize familiar surroundings (Landis et al., 1986b). These individuals cannot revisualize directions nor describe the relationships of objects in their own rooms or houses or on a standard structure like a baseball or football field. They commonly get lost in their own home or neighbourhood. Some eventually learn to use effortful compensatory strategies, like memorizing the number of turns, doors, or houses on the way to some destination, or peculiar local features like a mailbox or water fountain, reminiscent of the way some prosopagnosic patients rely on distinctive facial features to recognize some people. Most patients have right medial temporo-occipital lesions, but bilateral lesions and right occipito-parietal lesions have been reported also. Prosopagnosia is a frequent companion to this disorder. Disorientation to place, bizarre reports of locale, and daydreaming are also prevalent in patients with rostral brainstem infarcts (Caplan, 1980). A possible related phenomenon is reduplicative paramnesia (Benson & Gardner, 1976). Patients who are other-

Cerebral visual dysfunction

wise alert may duplicate their current location, acknowledging that they are in the hospital but that it is a branch in a distant country. One of our patients in a downtown Boston hospital claimed that he had been in his suburban home during the preceding week of tests, although in reality he had been hospitalized the entire time. He commented that it was very convenient that they had erected the hospital around his home so that he could easily walk back and forth. Reduplicative paramnesia also bears some relation to other misidentification syndromes, such as the Capgras illusion, where patients insist that the familiar person before them is an impostor. Visual amnesia is a modality-specific abnormality of learning and memory. In humans and animals the rightside structures in the Papez circuit (mamillary bodies, medial thalamic nuclei, mamillothalamic tracts, fornices, hippocampi) are specialized for visual-spatial memories, and left-side structures are specialized for languagerelated functions. Patients with right posteromedial thalamic hemorrhages and infarcts have been found to have amnesia especially for visual materials. Selective visual memory deficits can also be found in patients with right or bilateral temporal lobe infarcts (Ross, 1980). Visual hypoemotionality describes reduced affective responses to visual stimuli (Bauer, 1982; Habib, 1986). Flowers, landscapes, and erotic pictures are perceived normally, but no longer elicit the accustomed, expected responses, whereas music, words, and touch do elicit the appropriate, customary affective responses. The reported patients have had right or bilateral temporo-occipital lesions, often with coexistent prosopagnosia.

Bilateral cerebral lesions Bilateral lesions in the posterior portions of the cerebral hemispheres, including the occipital lobes, the posterior temporal lobes, and the inferior posterior parietal lobes, are surprisingly common. The most frequent causes are emboli of the top of the basilar artery and the posterior cerebral arteries (Symonds & MacKenzie, 1957; Caplan, 1980), sequential infarction due to in situ occlusive disease and embolism, sequential intracerebral hematomas, as found in patients with amyloid angiopathy, and borderzone infarctions between the middle cerebral artery and posterior cerebral artery territories. Bilateral embolic infarction affects the medial occipitotemporal regions, whereas border-zone infarction tends to involve lateral occipitotemporal and posterior parietal regions. The very different visual functions subserved by the ventral (temporal) pathway and the dorsal (parietal) pathway make the

deficits of these two different pathologies strikingly different. However, patients are individual entities, and any given person may have a mixture of ventral and dorsal stream deficits, depending upon the extent of their strokes. Also, such strokes often involve the optic radiations or striate cortex, causing ‘low-level’ visual loss as well. Indeed, the likelihood of detecting complex visual deficits depends upon the amount of visual field spared by damage to elements of the geniculo-calcarine relay.

Bilateral ventral (temporal) pathway lesions Cerebral achromatopsia is the loss of colour perception following bilateral cerebral injury (Zeki, 1990). These patients complain bitterly of their impairment, noting that everything appears in shades of grey, the world looks less bright, or has a dirty grey tinge (Meadows, 1974b; Rizzo et al., 1993; Damasio et al., 1980). Rarely, they may complain of a coloured tint to the world (Critchley, 1965). Topographagnosia, prosopagnosia, and upper quadrantic field defects are common accompaniments. Achromatopsic patients have trouble distinguishing colour hue (i.e. blue v. green) and saturation (i.e. red v. pink) but tend to do better along the third dimension of colour space, brightness (Victor et al., 1989; Rizzo et al., 1993). Hue perception can be tested with colour matching or sorting tests, such as the D-15 panel or Farnsworth–Munsell 100-hue test. These patients do poorly across the board, without much selectivity for any particular colour (Rizzo et al., 1993). Despite this severe defect, at least some patients can see the pseudoisochromatic numbers in the Ishihara or AO-14 plates, particularly if viewed from a greater distance (Heywood et al., 1991). This implies that such patients can see boundaries defined by colours even if they cannot name the colours or sort them correctly. This spared colour ability is thought to reflect surviving colour opponent processes in the intact striate cortex (Victor et al., 1989; Heywood et al., 1996). Achromatopsia is due to bilateral lesions of the lingual and fusiform gyri (Damasio et al., 1980; Heywood et al., 1991; Rizzo et al., 1993), of which posterior cerebral artery infarctions are the most common cause. Achromatopsia should be distinguished from the colour anomia that accompanies pure alexia with left-sided lesions. While patients with either defect may not be able to name colours, those with colour anomia can match and sort colours. Also, some patients with milder achromatopsia may be able to name colours approximately, although their discrimination of more subtle colour differences is impaired. Patients with achromatopsia may or may not have preserved colour imagery (Levine et al., 1985; Bartolomeo et al., 1997), so this does not necessarily help.

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As discussed above, some forms of prosopagnosia are associated with bilateral occipitotemporal lesions (Damasio et al., 1982). Bilateral occipital lesions can also cause a severe apperceptive generalized visual agnosia (Riddoch & Humphreys, 1987), and more anterior lesions may cause a generalized associative agnosia, affecting faces, words and other stimuli.

Bilateral dorsal (parietal) pathway lesions Bálint’s syndrome is the classic human dorsal pathway syndrome (Bálint, 1909; Hécaen & de Ajuriaguerra, 1954; Husain & Stein, 1988), though controversy over its validity as a single entity exists (Rizzo, 1993). The three features of Bálint’s syndrome are said to be simultanagnosia, optic ataxia, and apraxia of gaze. As with the ventral pathway syndrome above, these elements are not tightly associated, but can occur independently (Hécaen & de Ajuriaguerra, 1954), suggesting that there is no single mechanism that underlies all elements of the triad. Bálint’s syndrome is typically associated with bilateral angular gyrus lesions (Fig. 8.14), and hence can be associated with other parietal signs such as hemineglect, aphasia or Gerstmann’s syndrome (Benton, 1992). However, similar signs have been found with bifrontal and pulvinar lesions (Ogren et al., 1984), as well as more posterior and inferior occipital regions (Rizzo & Hurtig, 1987; Rizzo & Robin, 1990). Simultanagnosia is the inability to see and interpret an entire visual scene, despite the preserved perception of individual items in that scene (Wolpert, 1924). Thus patients report ‘piecemeal’ vision, with scenes sometimes resembling a jigsaw puzzle with missing pieces. They often report trouble understanding the meaning of pictures. Testing has revealed in simultanagnosia a difficulty with sustaining visuospatial attention over a large array of stimuli; objects often disappear and reappear despite normal visual fixation (Rizzo & Hurtig, 1987; Rizzo & Robin, 1990). At the bedside, simultanagnosia is tested by having a patient freely scan a complex picture with objects in all quadrants, such as the Cookie Theft Picture (Goodglass & Kaplan, 1983), and describe what they see. Omissions should take into account careful prior testing for hemineglect and visual field defects: extensive and patchy holes in peripheral vision can mimic simultanagnosia (Luria, 1959). Optic ataxia refers to poor hand coordination under visual control. Classically, patients should be able to touch parts of their own bodies or point to auditory targets with their eyes shut. However, parietal cortex is a multimodal region, and some patients have trouble reaching for any type of target, visual or otherwise (Holmes & Horrax, 1919).

Fig. 8.14. Sequential bilateral parietal white matter infarctions associated with Bálint’s syndrome.

Holmes (1918a) considered this part of a larger ‘visual disorientation’ disorder, in which judging spatial distance and location is impaired. Such patients have trouble counting objects, walking around obstacles, touching objects with the hands, and looking at stationary or moving objects (Holmes, 1918a; Luria, 1959). To assess optic ataxia, the visual fields must again be assessed first, to ensure that the patient can see the targets. Easily seen tokens are placed at different locations within arm’s reach, and the patient asked to touch or grasp the target. The problem tends to be worse for the hand and hemi-space contralateral to the lesion. The patient is then asked to touch parts of their own bodies. Optic ataxia is differentiated from cerebellar dysmetria by its relative selectivity for visual targets and the lack of intention tremor or dysdiadochokinesia. Apraxia of gaze is a nebulous term that encompasses several different types of saccadic dysfunction in Bálint’s syndrome. ‘Psychic paralysis of gaze’ (Hécaen & de Ajuriaguerra, 1954), or ‘acquired ocular motor apraxia’ (Cogan, 1965) is difficulty in initiating saccades to visual targets on command, though patients may easily make spontaneous scanning saccades or reflex saccades to suddenly appearing stimuli. With ‘spasm of fixation’, patients have trouble tearing their eyes away from a fixated object to saccade to another, doing much better if the first object

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disappears when the second appears (Holmes, 1930; Johnston et al., 1992). Last, when patients can make saccades, their accuracy may be grossly impaired, and the eyes wander in search of the target (Holmes, 1918a; Luria et al., 1962). Because patients cannot direct their fovea to objects appropriately, this renders impossible detailed visual tasks that involve such scanning, such as reading. Impaired saccadic accuracy has been described with bilateral damage to the inferior parietal lobules (PierrotDeseilligny et al., 1986). Acquired ocular motor apraxia is tested clinically by having the subject make saccades to targets on command, and contrasting this with their reflexive saccades to objects or people that suddenly appear or move in the room. Saccadic inaccuracy can be observed with the same simple targets, with care that targets are not placed in known blind regions of the visual field. Cerebral akinetopsia is a rare, relatively recently described condition whose hallmark is impaired motion perception (Zeki, 1991). Only two patients have been well studied. Both had bilateral lesions of lateral occipitotemporal cortex, affecting both cortex and white matter (Zihl et al., 1991; Vaina et al., 1990; Vaina, 1994), consistent with functional imaging reports of a human cortical ‘motion area’ in this region (Tootell et al., 1995; Barton et al., 1996). At least one of the patients had symptoms in her daily life, complaining that objects jumped from place to place instead of moving smoothly (Zihl et al., 1991). On formal laboratory testing, these patients see simple motion of objects relatively well, but fail when small amounts of random motion are added (Baker et al., 1991; Rizzo et al., 1995). Unfortunately, there are no easily available bedside tests for this type of dysfunction. In addition to this more complicated ‘integrative’ motion deficit, they have other problems with spatial and stereoscopic depth perception (Vaina, 1994; Rizzo et al., 1995). Astereopsis is the loss of stereoscopic depth perception. One of the important clues to distance from the observer is the disparity between the retinal images of the object in the two eyes. Patients may complain that the world looks flat and that they cannot tell the depth of objects, and they may misreach for objects in depth but not direction. Yet there are many other clues besides stereopsis to distance, which can be seen with one eye alone, such as relative differences in object size and intensity (which artists exploit), and differences in object motion as the observer’s head moves (motion parallax). It may be that some of these functions are also impaired in these patients, particularly motion parallax. Astereopsis occurs in patients with bilateral occipito-parietal lesions (Holmes & Horrax, 1919; Rizzo & Damasio, 1985). Milder deficits occur with unilateral lesions. Other visuospatial dysfunction may be associated.

Stereotests, which are cards viewed with different polarized or coloured glasses worn by the two eyes, are required to measure deficient stereopsis (Patterson & Fox, 1984): most eye clinics have examples of these at hand.

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9

Visual symptoms (eye) Shirley H. Wray Harvard Medical School, Massachusetts General Hospital, Boston, USA

Transient monocular blindness Temporary loss of vision in one eye, termed transient monocular blindness (TMB), is the most important visual symptom of arteriosclerotic vascular disease, arteritis and states of altered coagulability, and thrombocytosis. In most patients, the visual disturbance during each individual attack of TMB is stereotypic. It may recur over a period of months or over a much briefer span of hours, days, or weeks. A meticulous history of the attack and duration of the visual disturbance will permit classification of the TMB occurrence into one of four types. Type I is due to transient retinal ischemia, type II to retinal vascular insufficiency and type III to vasospasm. Type IV occurs in association with antiphospholipid antibodies but includes cases of unknown etiology (Table 9.1 (Wray, 1988; Burde, 1989)).

TMB type I TMB type I is characterized by a sudden, brief attack of partial or complete dimming or obscuration of vision, lasting seconds to minutes, followed by total recovery. Partial impairment is described as a greyout, or as an ascending or descending curtain or a blind moving sideways across the eye. Occasionally, the patient will describe moving tracks of light. Ipsilateral headache is rare (Wilson et al., 1979). Fisher (1952) drew attention to the association of TMB of this brevity with contralateral hemiplegia. Episodic attacks of fleeting blindness occur as arteriosclerotic plaques progressively narrow the lumen of the ipsilateral internal carotid artery (ICA), leading to periodic reduction in blood flow, reduced pressure in the ophthalmic artery, transient ocular ischemia, or vascular insufficiency. Often, cholesterol crystals or plugs of platelets will detach from an ulcerating plaque in the vessel wall and embolize to distal branches of the carotid and ophthalmic

artery, the central retinal artery (CRA) and/or the posterior ciliary arteries, without causing permanent visual loss. For this reason, TMB is regarded as one variety of carotid artery transient ischemic attack (TIA) and like other TIAs, TMB should be recognized as a warning of an impending stroke. Crescendo TMB occurs in patients with high-grade carotid stenosis or impending CRA occlusion and physical examination of the blood vessels of the head, neck and eyes is key to the detection of signs that can localize the lesion to the ICA.

Clinical signs Retinal emboli A cholesterol embolus is virtually diagnostic of localized ICA disease when a typical ipsilateral carotid bruit is present, when aortic or cardiac disease is absent, and when there is no exogenous source of emboli, as, for example, intravenous drug use, (talc and microcrystalline cellulose), severe trauma, or injection (air) (Table 9.2) Cholesterol emboli (Hollenhorst plaques) appear in the branches of the CRA as bright or shiny bodies whose diameter seems to exceed the intraluminal diameter of the arteriole (Hollenhorst, 1960, 1961). These emboli tend to lodge at arterial bifurcations. They may be invisible except on ocular compression or by varying the incidence angle of the ophthalmoscope light. They may be permanent or quite transient, moving on to the next bifurcation or disappearing before the next examiner can verify them. Cholesterol emboli also produce focal opacification in an arteriole in which they become impacted (Wilson et al., 1979). In an eye with a history of transient visual loss but without visible retinal emboli this sign suggests that an embolus may have been present at one time. The presence of a cholesterol embolus is a poor prognostic sign: 93% of such patients have vascular disease at presentation; 15%

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Table 9.1. Types of TMBa Parameter

Type I

Type II

Type III

Type IV

Onset Visual field

Abrupt All or partial

Less rapid All or partial

Visual loss

May black out completely

Abrupt Resembles Type I, II or III May alternate between eyes

Length

Seconds or minutes Complete No Retinal ischemia, embolus, arteritis

Loss of contrast vision, photopsia, sunlightprovoked Minutes or hours

Abrupt All or progressive contraction May spare fixation, photopsia, scintillating sparkles Minutes Usually complete Often Vasospasm, migraine

Complete No APS, idiopathic

Recovery Pain Mechanism

Complete Rare Retinal hypoperfusion, Carotid occlusive disease

Any length

APS Antiphospholipid antibody syndrome Notes: a Based on 850 personal cases (Wray, 1988) Source: Adapted from Burde (1989), with permission.

Table 9.2. Sources of emboli Type

Patient age

Cardiac valves Rheumatic disease Lupus Acute or subacute endocarditis Floppy mitral valve

Platelet/Calciuma Platelet Marasmic Platelet

Any age Young women Damaged heart Any age; mostly women

Chamber Myxoma Mural thrombus

Myxoma Platelet/clot

Older adult

Carotid artery Ulcerated plaque Stenosis Fibromuscular dysplasia

Platelet/cholesterol ester Platelet Platelet

Young women

Other Amniotic Long bone fractures Chronic i.v. drug users Disseminated intravascular coagulopathya

Debris?a Fata Talca ??

Young women Any age Any age ??

Antiphospholipid antibody(s)

??

Young adult

Note: a Produces retinal infarction; no amaurosis fugax. Source: Adapted from Burde (1989), with permission.

Older adult

Visual symptoms (eye)

Table 9.3. Funduscopic signs in TMB, pupil dilated • • • • • • • •

Normal disc and fundus Retinal emboli BRAO ⫾ visible embolus Retinal infarct (cystoid body) ⫾ hemorrhage Venous stasis retinopathy Asymmetric hypertensive retinopathy A low diastolic ophthalmic artery pressure Ischemic disc swelling

die within the first year, and 55% within 7 years. The cause of death is usually heart disease, 6:1 compared with stroke (Savino et al., 1977). Pale white platelet plugs can also be seen transiently within retinal arteries (Fisher, 1959). In a hypertensive patient, the caliber of the retinal arteries on the side of an ICA stenosis may be reduced and show fewer hypertensive changes than the retinal vessels of the opposite eye. Focal cotton-wool spots (cystoid bodies), in the absence of hypertensive retinopathy, are due to embolic microinfarction and may be seen when no emboli are visible (Table 9.3).

Retinal artery pressure Retinal arterial pressure drops when there is an acute hemodynamically significant lesion in the ipsilateral ICA or ophthalmic artery. Measurements can be by several techniques: by direct use of a hand-held ophthalmodynamometer (ODM) to measure flow in the ophthalmic artery (Toole, 1963); by oculoplethysmography, in which a sensing device is placed on the cornea and measures systolic ophthalmic artery pressure (Gee et al., 1976); by the relative time of arrival of the ocular pulse (Kartchner & McRae, 1977) and by transcranial Doppler ultrasound to measure flow velocities in the ophthalmic artery. Ophthalmodynamometry has the great advantage of being portable and easy to perform. External pressure is applied to the eyeball by the footplate of the dynamometer and is gradually increased while the examiner views the retinal arteries with the ophthalmoscope (Toole, 1963; Ackerman, 1979). When the external pressure applied exceeds the ophthalmic artery diastolic pressure, the arteries on the optic disk will visibly pulsate. When additional pressure is applied to the globe, the systolic arterial pressure will be exceeded, and the arteries will blanch and stop pulsating. The pressures are read from the dynamometer, and the external pressures needed to overcome diastolic and systolic pressures in the two eyes are compared. The ODM

reading will vary with intraocular pressure and the patient’s systemic blood pressure.

Bruit The typical carotid bruit is a high-pitched, long, very focal sound heard loudest over the carotid bifurcation. When a bruit at the bifurcation is also audible over the ipsilateral eye, the neurologist can be confident that the bruit is of ICA origin and that the artery is patent. An ipsilateral ocular bruit alone may indicate stenosis of the intracavernous segment of the ICA. When flow in the ICA is severely diminished no bruit may be audible. A bruit can also arise from the proximal external carotid artery (ECA) in which case it usually radiates towards the jaw and can be diminished by pressure on ECA branches (Reed & Toole, 1981).

Facial pulses Pulsations palpable at the angular, brow, and cheek (ABC) regions may be present when the ICA is occluded or severely stenosed and ECA collaterals feed into the orbit (Fisher, 1970; Caplan, 1973). Embolization from the stump of the occluded ICA is believed to be the mechanism causing TMB in these cases. Absence of the temporal artery pulse, with or without tenderness over the vessel on one or both sides, is indicative of giant-cell arteritis in the elderly patient, until proved otherwise.

Anisocoria Anisocoria, with normal pupil reflexes, is an important sign of ICA dissection. Meiosis and partial ptosis in the ipsilateral eye indicate an oculosympathetic palsy, Horner’s syndrome. Horner’s syndrome results from damage to the autonomic nerve fibres in the ICA sheath in the neck. Facial sweating is preserved, because sympathetic innervation of sweat glands travels along the ECA. Horner’s syndrome is especially common in patients with ICA dissections.

Differential diagnoses Giant-cell arteritis TMB may be the presenting symptom of giant-cell arteritis affecting elderly men and women. This inflammatory disorder typically involves branches of the ECA, especially the superficial temporal and occipital arteries, causing headache, scalp tenderness, claudication of the jaw during chewing, and tenderness over the affected temporal artery. In this systemic disease, TMB usually heralds an ocular stroke. Blindness is a result of an occlusion of the CRA or occlusion of the posterior ciliary arteries, leading to infarction of the optic nerve head. This type of ocular stroke is called anterior ischemic optic neuropathy. Because arte-

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riosclerosis of the carotid arteries in the neck and giant-cell arteritis can coexist in elderly patients, every patient over 55 years of age with TMB should have an immediate measurement of the erythrocyte sedimentation rate (ESR). Characteristic laboratory findings, in addition to a high ESR, include a normochromic or slight hypochromic anemia and increased fibrinogen and alkaline phosphatase levels. If the ESR is elevated, or if the ESR is normal and the fibrinogen level is elevated, treatment with highdosage prednisone must be started pending a temporal artery biopsy – the diagnostic procedure of choice.

Carotid artery dissection The presenting symptom of ICA dissection is pain (Ojemann et al., 1972; Fisher et al., 1978). Ipsilateral neck pain, headache, pain in the face or retro-orbital pain may occur. After a latent interval the patient may have a TIA, such as transient hemiparesis or TMB (Pozzali et al., 1989). TIAs are due to emboli off the top of the dissection into the middle cerebral and/or ophthalmic arteries. TIAs tend to occur more frequently following carotid dissection than in arteriosclerotic ischemia (Ojemann et al., 1972). TMB in some patients with ICA dissection is described as visual scintillations and bright sparkles, very reminiscent of migraine (Caplan, 1993) and migraine may in fact be misdiagnosed if headache is also present. Neck tenderness and bruit are inconstant features, and less common symptoms are pulsatile tinnitus and hypoglossal palsy.

Diffuse disseminated atheroembolism Diffuse disseminated atheroembolism is a rare condition closely related to atherosclerosis (Castleman & McNeely, 1967). Cholesterol-rich atheromatous emboli break off from unusually fragile plaques in the aorta and its major branches and occlude arteries in the brain, retina, kidney, bowel and other organs (Darsee, 1979; Goulet & Mackay, 1963; Coppeto et al., 1984). The diagnosis of diffuse atheroembolism deserves serious consideration in all patients in middle or late life with headache, stroke, TMB, elevated ESR, hypertension, or cholesterol emboli in the retina. Early diagnosis is important because arteriography (Ramirez et al., 1978), endarterectomy, and anticoagulation (Beal et al., 1981) seem to increase the risk for serious, even fatal, embolization in these patients.

Antiphospholipid antibodies The antiphospholipid antibodies (APA) are a group of immunoglobulins, including the lupus anticoagulant (LA) and the anticardiolipin antibody (aCL). These antibodies are found in 1–2% of the general population and in up to 50% of patients with SLE. Patients who are antiphospho-

lipid antibody-positive, without clinical SLE, but with a history of any or all of certain clinical events (recurrent venous or less frequent arterial thromboses in potentially any vascular bed, recurrent spontaneous abortion, thrombocytopenia, and cardiac valvular abnormalities) have a primary antiphospholipid antibody syndrome (Levine & Welch, 1987; Asherson et al., 1989; Coull et al., 1992). In one study of 6 patients, (4 women and 2 men) under the age of 34 yr with episodic TMB, high titres of antiphospholipid antibodies were found (Digre et al., 1989). Patient 1, a 23-year-old woman 20 weeks into her first pregnancy, reported a monocular total visual loss from the bottom up or the top down lasting approximately 2 minutes. She had 20–30 episodes of visual loss over 2 months. Patient 2, a 31-year-old woman in the postpartum period, reported episodic unilateral altitudinal visual loss occurring three to four times in one or other eye every day, each episode lasting 1–5 minutes. Patient 3, a 25-year-old woman with a history of spontaneous abortions, had constriction of the visual field of the right eye at least 20 times each day. At other times, she also had a unilateral central migrating scotoma lasting seconds to minutes at least 20 times each day. Splinter hemorrhages of the nail beds were present in four of the six patients. None had evidence of endocarditis. Some also had neurological symptoms, such as spells of vertigo and diplopia, headache, or an episode of ataxia. Treatment with antiplatelet agents, or anticoagulants, or both, led to significant reduction in the frequency of TMB attacks in five of the patients, but no single therapeutic agent was completely effective. A causal role for antiphospholipid antibodies in thrombogenesis has not been established, despite considerable investigation, but it seems likely, given the increased rate of thrombosis in patients with these antibodies. For this reason, antiphospholipid antibody syndrome (APS) must be a diagnostic consideration in any young patient with arterial or venous occlusive disease with TMB or TIA.

Other non-arteriosclerotic vasculopathies The following non-arteriosclerotic vasculopathies may also give rise to TMB: fibromuscular hyperplasia, granulomatous angiitis, congophilic angiopathy, systemic lupus erythematosus (SLE), Behcet’s syndrome, and moya– moya disease. These rare angiopathies affect small-calibre arteries and collectively must be considered in any patient with a TIA.

Hematological conditions States of altered coagulability and thrombocytosis, such as altered viscosity of the red cells in sickle-cell disease and altered blood viscosity in polycythemia, are associated

Visual symptoms (eye)

with TIAs. TMB associated with antiphospholipid antibodies is discussed in a later section.

TMB type II TMB type II occurs in patients who have extensive extracranial occlusive arterial disease involving both the ipsilateral ICA and ECA due to retinal vascular insufficiency. The visual disturbance differs from that of type I TMB. Typically the attack is less rapid in onset (over 5 min) and longer in duration (minutes to hours), and recovery is gradual (Table 9.1). Visual acuity is not altered significantly during the episode, but contrast acuity is. Bright objects appear brighter, dark objects become more difficult to see, and the edges of bright objects can appear to flicker. When the bright, dazzling sensation is marked, the overall effect is one of overexposure, and the patient may have difficulty reading because of the dazzle of white paper. When sight becomes fragmented and patchy, patients describe the appearance as a photographic negative. Occasionally, they note a transient closing-in of the peripheral vision or a dull pain over the eye. Symptoms of generalized cerebral ischemia (faintness, fatigue, impaired concentration) often coexist, but are mild compared with the visual symptoms. Conditions that provoke attacks of type II TMB are systemic hypotension, venous hypertension and extracerebral steal. The attacks occur on stooping or straining, when venous pressure rises, on standing or during exercise, and on exposure to bright lights or warm surroundings (Furlan et al., 1979; Ross Russell & Page, 1983). This pattern suggests a temporary failure of retinal homeostasis. In the unique case of a man with type II TMB provoked by facial heating with a hair dryer, the mechanism of the visual loss was believed to be diversion of blood to a dilated ECA facial vascular bed, resulting in temporary ocular oligemia on the affected side (Ross Russell & Page, 1983).

Clinical signs Venous stasis retinopathy Type II’s unusual visual symptoms are retinal in origin, and a low retinal arterial pressure is always present. Compensatory retinal venous changes occur, and venous stasis retinopathy develops, indicating that reduction in flow in the ophthalmic artery is severe and longstanding. The early signs of venous stasis retinopathy are microaneurysms, multiple small blot-like intraretinal hemorrhages in the mid-periphery, segmental narrowing and dilation of the veins, spontaneous pulsation of retinal arteries on the disc and ischemic disc swelling (Kearns & Hollenhorst, 1963) (Table 9.4). The fundus appearance resembles dia-

Table 9.4. Funduscopic signs of venous stasis retinopathy Early signs Microaneurysms Dot and blot intraretinal and nerve fibre layer hemorrhages Reduced retinal artery pressure Severe ischemia Dilation and darkening of retinal veins Mild swelling of the optic disc Retinal clouding Spontaneous pulsation retinal arteries on the disc End-stage Ocular ischemic syndrome

betic retinopathy, but is easily distinguished from diabetes by being unilateral. Venous stasis retinopathy occurs ipsilateral to ICA occlusion in 20% of patients. Fundus photographs and a timed fundus fluorescein angiogram, i.e. intravenous use of fluorescein (sodium fluorescein 5%), to study the retinal microcirculation are indicated in most patients to document the severity of impaired retinal perfusion and vascular insufficiency. ECA/ICA transcranial bypass surgery may be helpful when the ECA is not significantly narrowed (Kearns et al., 1979; Edwards et al., 1980).

Ocular ischemic syndrome When the ECA is also stenotic or occluded, signs of anterior-segment ischemia appear; rubeosis of the iris, sluggish reaction of the pupil to light due to ischemia of the iris sphincter or neovascular proliferation on the iris surface, and secondary neovascular glaucoma (Mills, 1989). Ischemic pain, unrelated to glaucoma, is a prominent feature. Pain is felt as a constant ache over the orbit, upper face and temple and is aggravated when the patient is in an upright position (Edwards et al., 1980; Campo & Aaberg, 1983). Ischemic uveitis, present in 18% of eyes with the ocular ischemic syndrome, is typically unresponsive to steroid medication, and posterior synechiae can result. Spontaneous hyphema may also occur, and cataract can be a late complication. At this stage, transcranial bypass is no longer a therapeutic option.

TMB type III Type III is rare. It is due to vasoconstriction (Table 9.1). Temporary vasospasm offers a plausible explanation for TMB in migraineurs, but ocular migraine can be diagnosed only when constriction of the retinal vessels is visualized funduscopically during an attack (Bruno et al., 1990). It may be suspected when all other causes of TMB are

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excluded and examination of the eye yields normal findings. The following is a description of a type III attack in one of our patients with suspected ocular migraine: At the onset, floating bright white lines were present, descending slowly from the top of the visual field over several seconds to involve the entire field. The lines slightly shimmered, but neither pulsed nor flashed on and off. When the lines reached the bottom of the field, the pattern changed to a persistent grey-white, speckled pattern that impaired vision. The patient said this pattern resembled the background design of the Ishihara plates, after being shown the test plate 12, and also mentioned that it resembled the interference pattern on a television screen. At the time, however, believing that her vision was impaired because the eyelid was shut, the patient inspected her eyes in the mirror. No accompanying symptoms occurred – in particular, no eye or head pain. The episode cleared abruptly in seconds, and within 15 min of the onset, and was said to be like ‘a lid lifting off my vision’. Sight returned to normal. Repeated stereotypic attacks occurred twice a day for 9 d, in spite of heparin treatment. A carotid angiogram, ESR, and other investigations showed no abnormality. The patient had a family history of migraine but was not known to have migraines herself.

The clinical profiles of 11 patients with vasospastic TMB are shown in Table 9.5 (Bruno et al., 1990; Burger et al., 1991). Six cases are taken from the literature (Walsh & Hoyt, 1969; Newman et al., 1974; Kline & Kelly, 1980; Ellenberger & Epstein, 1986; Schwartz et al., 1986; Appleton et al., 1988) and 5 new cases are reported. Two patients were teenagers, and three were middle-aged (48–49 years of age). This age distribution is consistent with the previous suggestion that non-embolic transient visual symptoms are not restricted to the young and the healthy (Fisher, 1980). Eight of these patients had 1–12 brief (less than 5 minute) episodes of TMB per day. Nine of the patients had a diffuse or constricting loss of visual field. One 78-year-old woman had an episode of monocular visual loss after she was asked to bend over and stand up. The subsequent ophthalmoscopic examination showed blanching of the CRA, which lasted 3 minutes before suddenly clearing. Fundus photographs taken at the end of the attack showed dilatation of the arteries, but persistent and segmental narrowing of the veins (Burger et al., 1991). The diagnosis in that case was giant-cell arteritis, confirmed by a temporal artery biopsy. Visual loss after bending or exercising has been reported previously (Tomsak & Jergens, 1987; Imes & Hoyt, 1989).

Clinical signs Retinal artery vasospasm In other patients in whom the fundus has been observed during an attack of TMB due to vasospasm, retinal artery and venous narrowing, retinal edema, venous dilatation

and delayed fluorescein filling of retinal vessels have been noted (Burger et al., 1991; Kline & Kelly, 1980; Troost, 1976). Vasospasm initially affects the retinal arteries and then the veins and is relieved first in the arterial bed and subsequently in the venous circulation. Infarction results if retinal ischemia is severe (Wolter & Burchfield, 1971). In rare migrainous patients, vasospastic TMB is complicated by CRA occlusion (Katz, 1986), anterior ischemic optic neuropathy or retinal infarction (Tippin et al., 1989). Vasospastic TMB has also been reported in patients with giant-cell arteritis (Burger et al., 1991), periarteritis nodosa (Newman et al., 1974) and eosinophilic vasculitis (Schwartz et al., 1986).

TMB type IV Cases of TMB type IV include young people with episodic TMB resembling the visual obscurations of type I, except in respect to the duration of the attack, which frequently is too long (30–60 min) or too short (seconds only) (Table 9.1). Occasionally the visual abnormality resembles the temporary loss of contrast vision typical of type II or the photopsias and scintillations of vasospastic type III. In a number of studies (Fisher, 1959; Eadie et al., 1968; Marshall & Meadows, 1968; Carroll, 1970; Corbett, 1983;The Amaurosis Fugax Study Group, 1990) and in our own experience (Wray, 1988; The Amaurosis Fugax Study Group, 1990), no cause has been found to explain recurrent TMB in young adults. One 5-year study of 12 ‘idiopathic’ patients documented benign outcomes for these patients (Eadie et al., 1968), and many investigators regard TMB in healthy children and young adults as benign events (Appleton et al., 1988; Tomsak & Jergens, 1987; Eadie et al., 1968; Carroll, 1970; Longfellow et al., 1962). Others consider TMB in this group of patients as a possible variant of acephalgic migraine (Tomsak & Jergens, 1987; Carroll, 1970; Corbett, 1983).

Clinical signs Antiphospholipid antibodies have been discussed in an earlier section.

Acute monocular blindness Sudden monocular blindness is the major symptom of an ocular stroke causing permanent visual loss. The ocular strokes to be discussed are (i) central retinal artery (CRA) occlusion, (ii) ophthalmic artery (OA) occlusion (iii) branch retinal artery (BRA) occlusion and (iv) ischemic optic neuropathy (ION), which is the result of infarction of the optic nerve.

Table 9.5. Clinical profiles of patients with vasospastic TMB Episode Study

Patient’s age/sex

Pattern of visual

Ellenberger & Epstein (1986) Walsh & Hoyt (1969) Newman et al. (1974) Kline & Kelly (1980) Schwartz et al (1986) Appleton et al. (1988) Present study Present study Present study Present study Present study

? 17/M 48/M 48/M 49/M 19/F 59/M 59/M 65/F 78/F 78/f

? Diffuse Constricting Constricting Diffuse Miscellaneous Constricting Diffuse Diffuse Diffuse Diffuse

Notes: Classified according to the system of Bruno et al. (1990). Photographic documentation of the episode. Source: Adapted from Burger et al. (1991).

a

lossa

Duration

Frequency

Associated condition

5 min Seconds to minutes 5 min 1–2 min 20 min 5–10 min 90 s 1–2 min 15–20 min 3 min 30 s

? 1 in 3 mo 3–12 per day 5 in 5 d 10 in 4 d 1 in 6 wk 30 per day 8 in 24 hr 12 in 11 mo 5 in 4 d 15 in 5 d

? — Periarteritis nodosa Cluster headaches Eosinophilic vasculitis — — — Episodic headaches Temporal arteritis Temporal arteritis

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Central retinal artery occlusion CRA occlusion can occur at any age and is characterized by apoplectic loss of vision. Eye pain is atypical, but when present, it suggests involvement of the ophthalmic artery. TMB may precede the occlusion, and attacks of TMB may increase in frequency over 12–24 h before blindness occurs (i.e., crescendo TMB). The principal causes of CRA occlusion are (i) embolic obstruction, (ii) occlusion in situ, due to thrombosis or hemorrhage into a plaque, (iii) inflammatory arteritis (e.g. giant-cell arteritis)(Cullen, 1963), thromboangiitis obliterans (Gresser, 1932), and polyarteritis nodosa, with involvement of the choroidal and retinal arteries (Goldsmith, 1946), (iv) angiospasm, (e.g. Raynaud’s disease) (Anderson & Gray, 1937) or migraine (Katz, 1986), and (v) arterial occlusion that occurs hydrostatically, with either (a) the high intraocular pressure of glaucoma, (b) the low retinal blood flow of carotid stenosis or the aortic arch syndrome, or (c) severe hypotension. The pathogenesis of a CRA occlusion may be evident if the examination shows a retinal embolus (Table 9.3) hypertension, atrial fibrillation and/or disease of other arteries, notably the ophthalmic, temporal or ipsilateral ICA. Most CRA occlusions occur in the region of the lamina cribrosa, regardless of the cause (Hayreh, 1971). In young patients under the age of 40, retinal arterial occlusions are less likely to be caused by ipsilateral carotid artery stenosis and more likely by cardiac embolism from rheumatic valvular disease, bacterial endocarditis or cardiac myxoma (Cogan & Wray, 1975; Appen et al., 1975) (Table 9.2; Burde, 1989), or to a hypercoagulable state, or vasospasm (Greven et al., 1995). In older patients,TMB type I or II suggests an embolic cause or giant-cell arteritis. The source of the embolus may be cardiac (Zimmerman, 1965) or intra-arterial from atheromatous ulceration of the aorta, ipsilateral ICA dissection, or from the stump of a thrombosed ICA. Trauma is also an important cause. Compression of the globe may be self-inflicted in circumstances involving heavy alcohol use with or without drug consumption followed by stupor (Jayam et al., 1974). Iatrogenic CRA occlusion has been reported in patients undergoing surgery where prolonged pressure to the orbit has occurred inadvertently in association with a period of hypotension during anesthesia (Givner & Jaffe, 1950; Hollenhorst et al., 1954) or as a complication of patient positioning for spinal surgery (Wolfe et al., 1992).

Clinical signs Amaurotic pupil An amaurotic pupil (i.e. absent constriction to light on direct illumination, intact consensual light response, and

intact near response) is present when the eye is completely blind. An afferent pupil defect (i.e. impaired direct-light response) is present if some vision is preserved, even hand motion vision.

Cherry-red spot at the macula Ophthalmoscopy is not often performed within the first hour after a CRA occlusion, and retinal signs are dependent on the time that the fundus is examined. Initial signs are few (i.e. segmentation of the blood column, boxcar segmentation with slow ‘streaming’ of flow in the retinal veins, a normal optic disc and no hemorrhages or exudates). Total obstruction posterior to the laminae cribrosa should be suspected when the retinal arteries on the disc start to pulsate with gentle digital pressure on the globe, indicating a very low retinal diastolic pressure. After an hour or more, the characteristic diagnostic fundus changes are seen. The ischemic retina takes on a white ground-glass appearance, and the normal red colour of the choroid showing through at the fovea accentuates the central cherry-red spot at the macula. Within days of the acute event, the retinal opacification, the cherry-red spot and the nerve fibre layer striations disappear, and optic atrophy of the optic disc of the primary type develops.

Intraocular pressure When the signs of CRA occlusion are secondary to an ophthalmic artery occlusion, the intraocular pressure in the eye is low.

Retinal emboli TMB as a premonitory symptom of CRA occlusion suggests an embolic cause or giant-cell arteritis. The cause is verified when a retinal embolus is visible in a branch artery. However, even in patients with embolic CRA occlusion, an embolus may not be seen initially, because emboli frequently impact behind the inelastic lamina cribrosa. For patients under the age of 40 years the sources of retinal emboli include cardiac disease (particularly rheumatic valvular disease, bacterial endocarditis, and cardiac myxoma) (Cogan & Wray, 1975) and ipsilateral ICA dissection. Over the age of 40 years the sources of emboli include cardiac disease, atheroma of the aorta and diffuse atheromatous embolism, ipsilateral ICA atheromatous disease, and ICA dissection. Calcific emboli can be dislodged by surgical manipulation of calcified heart valves. A cardiac source of embolism accounts for 29 of 103 (28%) patients with CRA occlusion in one series (Wilson et al., 1979). The reported incidences of ICA disease in CRA occlusion have varied, Wilson et al. (1979) found that 12 of 18 patients had carotid

Visual symptoms (eye)

irregularities or stenosis seen on arteriography. Merchut et al. (1988) grouped CRA and BRA occlusions together and noted that 29 of 34 (85%) patients had abnormal ICAs seen on arteriography, of which 12 had occlusion or severe stenosis, and 17 had plaques, ulcers or stenosis of less than 60%. The presence of cholesterol emboli in the fundus increases the likelihood of significant ipsilateral ICA disease. Chawluk et al. (1988) studied patients with CRA occlusion using B-mode ultrasound and integrated pulsed-Doppler ultrasound. Among 17 patients studied, 24% had ICA occlusion, and 36% had occlusive or ulcerated lesions.

Cardiovascular signs The most important additional signs to look for are absence of a temporal artery pulse and/or tenderness over the vessel on palpation. An occlusion of the CRA may be the only symptom of giant-cell arteritis in 5–10% of elderly patients, and the risk for blindness in the fellow eye is extremely high. Physical examination of the vascular system must also focus on angular, brow, and cheek pulses, (Fisher, 1970; Caplan, 1973) auscultation of the head, neck, and eye, and examination for hypertension, atrial fibrillation, and/or peripheral vascular disease.

Ophthalmic artery occlusion Ophthalmic artery (OA) occlusion mimics a CRA occlusion clinically and produces opacification of the infarcted retina. The typical cherry-red spot may be absent or extremely indistinct due to co-existing infarction of the choroid (Burde et al., 1982; Brown et al., 1986; Duker & Brown, 1988). Visual loss is typically severe and permanent with most eyes having no light perception or only bare perception of light (Rafuse et al., 1997). There may be associated eye pain and pupillary dilation from concurrent ischemia to the ciliary ganglion or iris sphincter. The eye may show hypotonous. The retinal vessels are markedly constricted and the optic disc may or may not be swollen. Over time, most patients develop a characteristic fundus appearance characterized by optic atrophy, arterial attenuation and diffuse pigmentary changes. The pathogenesis of OA occlusion is much the same as those of ICA occlusion. The artery may be occluded by a thrombus originating in the artery itself, by a thrombus propagated from an occluded ICA, by an embolus from a distant site, most often the heart, (Rafuse et al., 1997), the common carotid artery or the extracranial portion of the ICA or by an extrinsic process that compresses the vessel (e.g. tumour or aneurysm).

Antiphospholipid antibodies CRA occlusion has been shown to be associated with elevated levels of antiphospholipid antibodies (APA) (Asherson et al., 1989; Englert et al., 1984; Glueck et al., 1985; Shalev et al., 1985; Jonas et al., 1986; The Antiphospholipid Antibodies in Stroke Study Group, 1993). Englert et al.’s case (Englert et al., 1984) was a 36-year-old woman with Degos’ disease, myelopathy, CRA occlusion and bilateral choroidal infarcts. Her partial thromboplastin time (PTT) was normal, but an elevated aCL was demonstrated by radioimmunoassay. Glueck, et al. described a 42-year-old woman with circulating LA and retinal artery thrombosis. Another example is a patient with a CRA occlusion and Sneddon’s disease, a disorder characterized by livedo reticularis, neurologic abnormalities including stroke and labile hypertension. In this case, tests showed a slightly prolonged PTT and elevated aCL (Jonas et al., 1986). Among patients with SLE, persistently positive tests for APA especially LA and aCL characterize a subset of patients with thrombotic tendency (Asherson et al., 1989). In particular, the presence of aCL has been found to be an independent risk factor for ischemic stroke especially among young patients (The Antiphospholipid Antibodies in Stroke Study Group, 1993), and an association between TMB and elevated levels of APA, especially aCL, has been suggested (for review, see Donders et al., 1998).

Clinical signs When only the proximal portion of the OA is occluded, there may be no ocular symptoms or signs because collateral channels from branches of the ECA usually provide sufficient blood to the orbital and ocular vessels normally supplied by the OA. When the occlusion is more extensive, severe visual loss and typical ophthalmoscopic signs are present. Rarely in isolated cases of OA occlusion visual acuity recovers from light perception to 20/30 or from counting fingers at 6 inches to 20/50 with the restoration of retinal and choroidal blood flow (Duker & Brown, 1988). Fundus fluorescein angiography is diagnostic in CRA occlusion or OA occlusion provided that a timed transit is obtained within hours or days of the event, a wide angle lens is used on the fundus camera and the optic disk is photographed in the centre of the picture. In isolated acute CRA occlusion, the choroidal circulation of the eye is normal and there is delay in filling of the branches of the CRA. In OA occlusion there is delayed filling in both the choroidal and the CRA circulation.

Treatment A CRA or OA occlusion requires emergency treatment. The therapeutic goal is to restore circulation to the retina as soon as possible, by abruptly lowering the intraocular

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Table 9.6. Clinical summary of thrombolytic therapy Patient No./ Age (y)/Sexa

Pretreatment visual acuity

Time to therapyb

Thrombolytic agent

Adjunctive therapy

Post-treatment visual acuity

1/56/M 2/74/M 3/61/M

Hand motion Light perception Hand motion

5.5 4.0 2.75

Anistreplase Tissue plasminogen activator Tissue plasminogen activator

Intravenous heparin sodium aspirin 20/60+ Intravenous heparin, warfarin sodium 20/400 Intravenous heparin, warfarin 20/25

Notes: a M, Male; F, female. b Time to initiation of thrombolytic therapy in hours. Source: Data from Mames et al. (1995).

pressure. In eyes that have been blind for less than 24 hours (Stone et al., 1977), the following steps should be taken: place the patient flat, give digital massage to the globe, have the patient rebreath into a paper bag, and give diamox (500 mg) intravenously or mannitol intravenously to reduce intraocular pressure. The patient should then be referred to an ophthalmologist for anterior paracentesis, a procedure that will reduce the intraocular pressure even lower. Prednisone (80 mg daily) is needed immediately for patients suspected of having giant-cell arteritis or in cases of CRA occlusion complicating migraine. Heparin is useful in the treatment of impending CRA occlusion when a patient presents with crescendo TMB or an occlusion of the ophthalmic artery. Unfortunately, however, both medical and surgical approaches have been disappointing (Brown, 1994; Mames et al., for the CRAO Study Group; Mangat, 1995; Atebara et al., 1995). Other medical therapies proposed include sublingual nitroglycerine, oral warfarin sodium, (coumadin) calcium channel blocking agents, vasodilators, antiplatelet agents, intravenous heparin, urokinase or tissue plasminogen activator (TPA), and intra-arterial urokinase or TPA. Schmidt et al. (1992) reported 5 of 14 patients with CRA occlusion had improvement of visual acuity, visual field, or both, following intra-arterial urokinase infusion. In a further five patients, no improvement occurred with this therapy. In these five patients, visual acuity was impaired preoperatively for more than 7 hours. Systemic thrombolytic agents were used in a pilot study involving three consecutive patients with acute CRA occlusion (Mames et al., for the CRAO Study Group, 1995). The selection of the thrombolytic agent, TPA or anistreplase, was at the discretion of the internist. Patients were treated in the hospital emergency department with cardiovascular monitoring. Intravenous heparin sodium and oral coumadin were given as adjuvant therapy after thrombolytic infusion. All three patients noted subjective improvement

within several hours of treatment. The best achieved visual acuity was recorded within 96 h of therapy (Table 9.6; Mames et al., for the CRAO Study Group, 1995). Nevertheless, while the results of these pilot studies are encouraging, it is imperative that the efficacy of thrombolytic therapy in CRA and OA occlusion be tested in a prospective, randomized, clinical trial against conventional modes of therapy.

Differential diagnosis The differential diagnosis of acute persistent blindness includes a number of ophthalmic emergencies; ION (both anterior and posterior ION) due to infarction of the optic nerve, acute central retinal vein occlusion (which is characterized by hemorrhagic retinopathy), detachment of the macula, acute closed-angle glaucoma, sudden vitreous or macula hemorrhage, and factitious visual loss. In the latter condition, the eye claimed to be blind will have a normal brisk pupil response to direct light.

Branch retinal artery occlusion BRA occlusion is due to impaction of an embolus at an arterial bifurcation in a branch of the CRA. The presenting symptom is sudden and permanent loss of a sector of the visual field, with retinal infarction corresponding to the vascular territory of the arteriole blocked. TMB may precede CRA or a BRA occlusion (Table 9.7).

Clinical signs Retinal embolus The ophthalmoscopic appearance of a retinal embolus can provide specific information about the embolic material and its possible source. The commonest emboli are cholesterol, platelet-fibrin and calcific emboli. Less common varieties include tumor emboli from cardiac myxoma and metastatic neoplasms, fat emboli from fractures of long

Visual symptoms (eye)

Table 9.7. Preceding vascular events in occlusion of branch and central retinal arteriesa

Table 9.8. Clinical findings in occlusion of branch and central retinal arteriesa

Retinal artery occlusion

Preceding event

Branchb n⫽68

Centralc n⫽35

Amaurosis fugax Transient cerebral ischemia Stroke Ischemic heart disease Claudication

12 (18) 8 (12) 2 (3) 15 (22) 5 (7)

4 (11) 1 (3) 4 (11) 2 (6) 2 (6)

Notes: a Based on data in Wilson et al., 1979. b 43 male, 25 female patients; mean age 55. c 23 male, 12 female patients; mean age 36. Numbers in parentheses are percentages.

bones, septic emboli, talc emboli and miscellaneous emboli of deposited drugs, silicone or air that occur after injections in the region of the face or scalp (Table 9.2). Cholesterol emboli (Hollenhorst plaques) were discussed in an earlier section. Bruno et al, suggest that these emboli are a marker of systemic arteriosclerosis associated with hypertension, cigarette smoking and bilateral carotid artery disease, and that asymptomatic retinal cholesterol embolism is an independent risk factor for stroke (Bruno et al., 1992, 1995) (Table 9.8). Calcific emboli are characteristically matt-white, nonscintillating, and somewhat wider than the blood column. They may be dislodged by the surgical manipulation of calcified heart valves at the time of valvulotomy or occur spontaneously from rheumatic valvular vegetations and from other disorders of the heart and great vessels that predispose to the formation of calcium (D’Cruz et al., 1977; Guthrie & Fairgrieve, 1963; DiBono & Warlow, 1979; Stefensson et al., 1985). Unlike Hollenhorst plaques and platelet-fibrin emboli calcific emboli tend to lodge permanently in the blood vessels occasionally resulting in the development of collateral vessels forming shunts around the embolic blockage. Patients with these emboli are at significant risk for stroke, heart attack and death (Howard & Ross Russell, 1987). Circulating microemboli that pass through the retina, so called migrant pale emboli, are composed of platelets and associated with thrombocytosis. Emboli that occur after myocardial infarction fall into the category of fibrin plugs. They are especially frequent in patients who have neurological complications after open heart surgery. From the description of Fisher (1959) and

Retinal artery occlusion

Clinical finding

Branch n⫽68

Central n⫽35

Hypertension Carotid bruits Visible retinal embolus Cardiac valvular abnormality

17 (25) 12 (18) 46 (68) 23 (34)

20 (57) 5 (14) 4 (11) 6 (17)

Note: a Based on data in Wilson et al. (1979). Numbers in brackets are percentages.

Ross Russell (1961) platelet-fibrin emboli appear as dull, grey–white plugs that resemble a long white worm slowly passing through the retinal arteries. They become temporarily impacted at bifurcations and then pass on gradually fragmenting and resolve over time.

Treatment The treatment of a patient with BRA occlusion is similar to that for an acute CRA occlusion. Anterior paracentesis and/or medication to lower intraocular pressure are the most common therapeutic approaches. Anticoagulation is advisable in patients with atrial fibrillation. In many instances, however, the BRA occlusion results from lipid, cholesterol or calcific emboli which fail to resolve with anticoagulant therapy. Nevertheless, a patient with a visible retinal embolus, even though having no visual loss, should be investigated urgently because of the risk of a stroke. Arrhythmias are the most common cause of cardiac-related embolic retinal vascular disease, and they may be the most common cause of all emboli to the brain. Abnormal heart rhythms most likely to produce emboli are chronic atrial fibrillation (AF), paroxysmal AF and the abnormal rhythms that develop in patients with disturbances of cardiac conduction. In patients with calcific retinal emboli, the investigative evaluation should focus on the heart valves (Table 9.8). Two-dimensional echocardiogram studies may reveal thickened, calcified valve leaflets or a tight calcified annulus. Transesophageal echocardiography may facilitate cardiac evaluation of patients with suboptimal transthoracic scans such as patients with obesity or emphysema. Compared with transthoracic echocardiography, a transesophageal study is more sensitive for detection of prosthetic valve dysfunction, atrial thrombus and

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other masses, atrial septal defects (especially of the sinus venous type), aortic plaques, aortic dissection and infective endocarditis. To exclude ipsilateral ICA disease as a source of emboli, urgent investigations should include oculopneumoplethysmography, carotid ultrasonography and Doppler studies, and neuroimaging screening with an MRA of the head and neck and/or CT angiography of the neck and brain and when indicated, stroke profile MRI studies including diffusion and perfusion weighted images.

Ischemic optic neuropathy Ischemic optic neuropathy (ION) is the term used for all presumed ischemic causes of optic neuropathy. ION is the commonest cause of sudden persistent visual loss in patients past middle age. There is no significant sex predilection and the average age ranges from 57–65 years with a peak range of 60–69 years (Boghen & Glaser, 1975; The Ischemic Optic Neuropathy Decompression Trial Research Group, 1995). The ophthalmic artery provides the blood supply to the optic nerve by means of two or more posterior ciliary arteries (PCAs), and hypoperfusion of these end arteries is thought to be the commonest mechanism causing infarction of the optic nerve (Onda et al., 1995). The critical region of damage is the prelamina, lamina and immediate retrolaminal portion of the optic nerve. Lessell (1999) suggests that the border zone that determines the site of infarction is between the lamina cribrosa and the centripetal branches of the pial vessels in the retrobulbar segment. Structural and mechanical factors may also render the optic disc more susceptible to vascular damage. The best documented anatomical correlation is with cup–disc ratios. The discs at risk (Burde, 1993) have small cup–disc ratios (Beck et al., 1984) and cross sectional areas (Mansour et al., 1988) which imply that the optic nerve fibres are crowded within the scleral canal. This crowding is probably a contributing factor in the pathogenesis of non-arteritic anterior ischemic optic neuropathy (Doro & Lessell, 1985). The term anterior ischemic optic neuropathy (AION) indicates visible optic disc pathology, swelling of the disc and peripapillary hemorrhages. The term posterior ischemic optic neuropathy (PION) indicates infarction of the retrobulbar or intracranial optic nerve and no disk swelling or other funduscopic signs acutely. AION is far more common than PION, accounting for 90% of cases of ION. The three principal causes of ION are (i) non-arteritic (median age 56 year) occlusive disease, in which the risk factors are diabetes in young patients and hypertension in

older patients, (ii) an arteritic variety due to giant-cell arteritis (median age 74 years), and (iii) embolic obstruction of the PCAs as a complication of cardiac surgery or ipsilateral ICA disease. The clinical characteristics, natural history and management of patients with non-arteritic and arteritic ION are, however, significantly different.

Non-arteritic ischemic optic neuropathy Non-arteritic ION may occur in patients with carotid artery disease as the initial manifestation of an ICA occlusion (Mori et al., 1983). Rarely patients with ICA disease have the simultaneous occurrence of cerebral infarction and ipsilateral ION. This combination is called the opticocerebral syndrome (Bogousslavsky et al., 1987). Three patients described by Bogousslavsky (1987) had AION and cerebral signs. Other patients reported had ICA occlusion or severe stenosis, acute hemispheric stroke and simultaneous monocular blindness caused by PION in the ipsilateral eye (Newman, 1998). Carotid dissections that include the intracranial ICA can also cause this syndrome. No patient gained improvement in vision in the affected eye and all patients developed optic atrophy. The pathogenesis of AION in the setting of disease of the ipsilateral ICA is multifactorial. In some cases, optic nerve infarction results from reduced blood flow secondary to severe ICA stenosis or occlusion, poor collateral blood supply, and local changes in the pial circulation of the optic nerve. In other cases, AION or PION may be due to embolism to the PCAs, pial vessels, or both (Lieberman et al., 1978; Portnoy et al., 1989). In the majority of patients, however, non-arteritic AION is a disease of small vessels and not directly related to carotid artery disease but, rather reflects shared risk factors, such as hypertension, diabetes mellitus or cigarette smoking (Rizzo & Lessell, 1991; Repka et al., 1983; Guyer et al., 1985; Moro et al., 1989; Chung et al., 1994). Non-arteritic AION patients with both hypertension and diabetes have an increased risk of cerebrovascular disease. Furthermore, patients with hypertension, diabetes, cardiovascular disease and cerebrovascular disease have an increased prevalence of subcortical and periventricular white matter lesions on brain MRI, a marker for small vessel (microangiopathic) cerebrovascular disease. Perioperative non-arteritic AION is also the result of multiple factors and occurs in patients who have had various surgical interventions. The two most important factors in conjunction with surgery are hypotension and blood loss (for review, see Williams et al., 1995). Severe anemia alone probably does not cause AION, but even a short episode of hypotension in an already anemic patient may predispose to AION-induced visual loss (Brown et al.,

Visual symptoms (eye)

1994). Williams et al. (1995) emphasized that, because a low hematocrit in the presence of other factors may predispose more surgical patients to visual loss, the current low-level of hemoglobin at which blood transfusion is deemed to be indicated (7–8 g/dl) may not be as safe as previously supposed, especially in patients who become hypotensive. Absolute threshold values for transfusions should, therefore, not be followed when there exists a high risk of operative or postoperative hypovolemia and hypotension. Loss of vision after severe spontaneous hemorrhage is usually bilateral, but it may be unilateral or affect both eyes asymmetrically. The severity ranges from mild or transient blurred vision in one eye to irreversible total blindness in both eyes. The visual loss often occurs at the time of hemorrhage but it may, in rare instances, be delayed beyond 10 days. Most patients are debilitated and over 40 yrs of age. Many have intercurrent systemic illnesses but they do not necessarily have risk factors for arteriosclerosis. Visual loss typically follows repeated hemorrhage although visual loss can occur after a single massive bleed (Kamei et al., 1990). Ophthalmoscopy shows the characteristic changes of AION but the discs can appear normal initially when infarction of the optic nerve(s) occurs in the midorbital portion (Johnson et al., 1987). About 50% of patients who lose vision after an acute bleed have some recovery of vision, but only 10 to 15% recover completely.

Arteritic ischemic optic neuropathy In giant-cell arteritic AION or PION constitutional symptoms of arteritis may be absent and acute visual loss is the herald symptom. The stroke to the optic nerve is caused by inflammatory occlusion of the short posterior ciliary arteries, a process that may also produce sectorial areas of choroidal ischemia. In some cases of arteritic AION constitutional symptoms of giant-cell arteritis are insidious. They include fatigue, anorexia, weight loss and alterations in mental status including depression and memory impairment. Severe persistent headache is present in 40 to 90% of patients with or without tenderness over the temporal arteries or scalp, intermittent claudication of the masseters, and facial swelling. Systemic manifestations include respiratory tract symptoms, myocardial infarction and gastrointerstinal complications due to generalized vasculitis. Acute visual loss is usually unilateral but it may be bilateral and simultaneous, or the second eye may be affected days, weeks or even months after the first eye, particularly if high-dose steroid treatment is not begun immediately or is stopped while the disease is still active. Episodes of TMB may precede persistent visual loss caused by AION, and

occasionally TMB may be induced by exertion or changes in posture. The appearance of the ischemic optic disk in giant-cell arteritis resembles that of nonarteritic AION. Giant-cell arteritis causing PION must always be suspected in acutely blind, elderly patients with a normal appearing optic disc in the affected eye. Infarction of the nerve in these cases may even affect the intracranial portion and in most cases of giant-cell arteritis-associated PION, histopathologic examination reveals inflammatory occlusion of the ophthalmic artery as well as the short posterior ciliary arteries (Hayreh & Podhajsky, 1979). The Westergren method is used to determine the ESR in suspected giant-cell associated INO. The patient age divided by 2 determines the maximum normal ESR for men and the age plus 10 divided by 2 determines the maximum normal ESR for women. It is noteworthy, however, that between 8 and 22% of patients with clinical symptoms consistent with giant-cell arteritis and a positive temporal artery biopsy have an ESR within the normal range.

Clinical signs Visual acuity The loss of vision in ION is usually painless; although some patients (approximately 8%) report discomfort behind and around the eye at the time of visual loss (Rizzo & Lessell, 1991). Visual acuity (VA) data for the initial loss of vision indicates that 31–52% of patients have a VA better than 20/64, whereas 35–54% have a VA worse than 20/200 (Boghen & Glaser, 1975; The Ischemic Neuropathy Decompression Trial Research Group, 1995; Rizzo & Lessell, 1991; Repka et al., 1983). Rarely, visual acuity may drop progressively over 1–7 days. Almost all patients with ION have diminished color perception in the affected eye and a field defect. Altitudinal field defects comprise the most common pattern of visual field loss in 58–80% of cases (Boghen & Glaser, 1975; Rizzo & Lessell, 1991; Repka et al., 1983; Hayreh & Podhajsky, 1979; Ellenberger et al., 1973). Progression of visual loss occurs in some cases (approximately 28%) from 1 to 30 days from onset, with the majority stabilizing in less than 9 days. The best natural history data of ION comes from the IONDT group. The most unexpected and encouraging finding was the high rate of spontaneous improvement of visual acuity observed in the untreated randomized group. At the 6-month evaluation, approximately 43% of patients in this group improved by three or more lines from their baseline evaluation.

Afferent pupil The affected eye has an afferent pupil defect.

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Ischemic papillitis In acute AION, the optic disc is swollen with the swelling being either diffuse (75% patients) or focal (25% patients (The Ischemic Optic Neuropathy Decompression Trial Research Group, 1995)). When diffuse, the swollen disc may simulate the appearance of papilledema. The disc may be pale or hyperemic. Single or multiple flame-shaped hemorrhages are present in the peripapillary region and a few soft exudates. As disc edema begins to subside, optic atrophy develops, and in arteritic AION the optic disc may show increasing cupping mimicking that of glaucoma. AION may also be associated with other signs of ocular ischemia, choroidal infarction, retinal emboli, or iris or anterior chamber neovascularization. AION with iris neovascularization, in the absence of diabetic retinopathy, is a marker for ipsilateral carotid artery occlusive disease. Some patients may develop disc swelling from nonarteritic AION before they have visual symptoms and lose vision up to 2 weeks later. In acute PION due to ischemia of the retrobulbar or intracranial optic nerve (both arteritic and non-arteritic) (Bogden & Glaser, 1975; Hayreh, 1981; Cullen & Duvall, 1983; Isayama et al., 1983; Rizzo & Lessell, 1987; Sawle & Sarkies, 1987; Shimo-Oku & Miyazaki, 1984; Perlman et al., 1994), the optic disc has initially a normal appearance funduscopically. Optic disc pallor subsequently develops, usually within 4–6 weeks. PION is therefore distinguishable from AION by signs of optic nerve dysfunction unassociated with acute ischemic optic disc swelling or retinal hemorrhages.

Treatment High-dosage steroids Temporal artery biopsy must be obtained to confirm the diagnosis of giant-cell arteritis, but it should not delay the initiation of high-dosage steroid treatment. 1 gm/per day of intravenous methylprednisolone or prednisone in a dose of 1–1.5 mg/kg/day should be given until the ESR drops. Prednisone should then be slowly tapered to maintenance doses of 10–15 mg alternate days for 6 months to 1 year. Temporal artery biopsies are likely to remain positive even after 14 days of steroid therapy. In non-arteritic AION or PION high-dosage steroids are of questionable value, and only used by a few physicians when the second eye becomes involved. Numerous other drugs have, however, been tried including anticoagulants, retrobulbar injection of vasodilators, intravenous noradrenaline, and thrombolytic agents. Johnson et al. (1996) reported a combination of levodopa and carbidopa (sinemet) prompted visual recovery in patients with nonarteritic AION of more than 6 months duration. These results have not been confirmed.

Hemodilution has also been described as improving visual function in longstanding non-arteritic AION (Haas et al., 1994) and in AION of less than two weeks duration when combined with pentoxifylline (Wolf et al., 1993). Further verification of this potentially beneficial treatment is required.

Decompression of the optic nerve Direct surgical intervention by optic nerve sheath decompression has been shown in a multicenter randomized trial, to be ineffective and possibly visually harmful (The Ischemic Optic Neuropathy Decompression Trial Research Group, 1995). This surgical procedure is no longer used in the US.

Conclusions In this chapter, the visual symptom of temporary loss of vision in one eye has been reviewed. It has to be emphasized, however, that only a meticulous history of the attack and the duration of the visual episode can permit the physician to classify TMB into one of four types. Immediate investigation of the patient must follow, because TMB is a warning of an impending stroke of the brain or eye. Physical examination of the vascular system and the eye must focus on the following: ii(i) Blood pressure, at rest and standing, heart rate, and cardiac rhythm. i(ii) Palpation of the temporal arteries, and ABC pulses of the face. (iii) Auscultation of the heart, neck, head, and eyes. (iv) A dilated funduscopic examination. i(v) Immediate blood tests: complete blood count, prothrombin time, partial thromboplastin time, platelet count, Westergren ESR, and fibrinogen level. Subsequent studies should include tests for fasting blood sugar, cholesterol, triglyceride and blood lipids, and, when indicated, antiphospholipid antibodies, protein C, protein S and antithrombin III. Non-invasive investigations should utilize: ii(i) A battery of non-invasive carotid artery tests to give information about the presence of a hemodynamic lesion (Doppler ultrasound and oculoplethysmography), and image the artery (B-mode ultrasound). B-mode scans and Doppler colour-flow imaging studies of the carotid origin can help define the nature of plaques, the presence of ulceration, and the dynamics of flow. i(ii) Magnetic resonance angiography (MRA) of the head

Visual symptoms (eye)

and neck and/or CT angiogram of the neck and brain and, when indicated, stroke profile MRI studies including diffusion and perfusion-weighted images. (iii) Cardiac evaluation: two-dimensional transthoracic and transesophageal echocardiogram and Holter monitor. Invasive investigations required in selected patients are: ii(i) A temporal artery biopsy i(ii) A carotid arteriogram if MRA and ultrasound are inadequate to show the lesion and the patient is a candidate for carotid endarterectomy or if an ICA dissection is detected or suspected on a head and neck MRI/MRA. (iii) A timed fundus fluorescein angiogram. We have also discussed in this chapter the clinical presentation and emergency management of ocular strokes due to CRA, OA, or BRA occlusion or due to ischemic optic neuropathy, AION or PION. Because of our growing population of elderly citizens, we must remain alert to symptoms that may herald stroke and direct our attention to reducing and eliminating the identified risk factors.

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Gee, W., Oiler, D. & Wylie, E. (1976). Noninvasive diagnosis of carotid occlusion by ocular plethysmography. Stroke, 7, 18–21. Givner, I. & Jaffe, N. (1950). Occlusion of the central retinal artery following anesthesia. Archives of Ophthalmology, 43, 197–207. Glueck, H.I., Kant, K.S., Weiss, M.A. et al. (1985). Thrombosis in systemic lupus erythematosus: relation to the presence of circulatory anticoagulants. Archives of International Medicine, 145, 1389–95. Goldsmith, J. (1946). Periarteritis nodosa with involvement of the choroidal and retinal arteries. American Journal of Ophthalmology, 29, 435–46. Goulet, Y. & Mackay, C.G. (1963). Athermatous embolism: an entity with polymorphous symptomatology. Canadian Medical Association Journal, 88, 1067–70. Gresser, E.B. (1932). Partial occlusion of retinal vessels in a case of thromboangiitis obliterans. American Journal of Ophthalmology, 15, 235–7. Greven, C.M., Slusher, M.M. & Weaver, R.G. (1995). Retinal arterial occlusions in young adults. American Journal of Ophthalmology, 1995; 120, 776–783. Guthrie, J. & Fairgrieve, J. (1963). Aortic embolism due to myxoid tumor associated with myocardial calcification. British Heart Journal, 25, 137–40. Guyer, D.R., Miller, N.R., Auer, C.I. et al. (1985). The risk of cerebrovascular and cardiovascular disease in patients with anterior ischemic optic neuropathy. Archives of Ophthalmology, 103, 1136–42. Haas, A., Uyguner, I., Sochor, G.E. et al. (1994). Non-arteritic anterior ischemic optic neuropathy. Long-term results after hemodilution therapy. Klinische Monatsblatter Augenheilkunde, 143–6. Hayreh, S.S. (1971). Pathogenesis of occlusion of the central retinal vessels. American Journal of Ophthalmology, 72, 998–1011. Hayreh, S.S. (1981). Posterior ischemic optic neuropathy. Ophthalmologica, 182, 29–41. Hayreh, S.S. & Podhajsky, P. (1979). Visual field defects in anterior ischemic optic neuropathy. Documenta Ophthalmologica Proceedings Series, 19, 53–71. Hollenhorst, R.W. (1960). The ocular manifestations of internal carotid arterial thrombosis. Medical Clinics of North America, 44, 897–908. Hollenhorst R.W. (1961). Significance of bright plaques in the retinal arterioles. Journal of the American Medical Association, 178, 123–9. Hollenhorst, R.W., Svien, H.J. & Benoit, C.F. (1954). Unilateral blindness occurring during anesthesia for neurosurgical operation. Archives of Ophthalmology, 52, 819–30. Howard, R.S. & Ross Russell, R.W. (1987). Prognosis of patients with retinal embolism. Journal of Neurology, Neurosurgery and Psychiatry, 50, 1142–47. Imes, R.K. & Hoyt, W.F. (1989). Exercise-induced transient visual events in young healthy adults. Journal of Clinical Neuroophthalmology, 9, 178–80. Isayama, Y., Takahashi, T., Inoue, M. et al. (1983). Posterior ischemic optic neuropathy: III. Clinical diagnosis. Ophthalmologica, 187, 141–7.

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Jayam, A.V., Hass, W.K., Carr, R.E. & Kumar, A.J. (1974). Saturday night retinopathy. Journal of Neurological Science, 22, 413–18. Johnson, M.W., Kincaid, M.C. & Trobe, J.D. (1987). Bilateral retrobulbar optic nerve infarctions after blood loss and hypotension: a clinicopathologic case. Ophthalmology, 94, 1577–84. Johnson, I.N., Gould, T.J. & Krohel, G.B. (1996). Effect of levodopa and carbidopa on recovery of visual function in patients with nonarteritic anterior ischemic optic neuropathy of longer than six months’ duration. American Journal of Ophthalmology, 121, 77–83. Jonas, J., Kolbe, K., Volcker, H.E. et al. (1986). Central retinal artery occlusion in Sneddon’s disease: association with antiphospholipid antibodies. American Journal of Ophthalmology, 102, 37–40. Kamei, A., Takahashi, Y., Shiwa, T. et al. (1990). Two cases of ischemic optic neuropathy after intestinal hemorrhage. Presented at the VIIIth International Neuro-Ophthalmology Symposium. Winchester, England, June 23–29. Kartchner, M. & McRae, L. (1977). Noninvasive evaluation and management of the asymptomatic carotid bruit. Surgery, 82, 840–7. Katz, B. (1986). Migrainous central retinal artery occlusion. Journal of Clinical Neuro-ophthalmology, 6, 69–75. Kearns, T.P. & Hollenhorst, R.W. (1963). Venous stasis retinopathy of occlusive disease of the carotid artery. Mayo Clinical Proceedings, 38, 304–12. Kearns, T.P., Siekert, R.G. & Sundt, T.M.Jr. (1979). The ocular aspects of bypass surgery of the carotid artery. Mayo Clinical Proceedings, 54, 3–11. Kline, L.B. & Kelly, C.L. (1980). Ocular migraine in a patient with cluster headaches. Headache 20, 253–7. Lessell, S. (1999). Nonarteritic anterior ischemic optic neuropathy. Archives of Ophthalmology, 117, 386–8. Levine, S.R. & Welch, K.M.A. (1987). The spectrum of neurologic disease associated with antiphospholipid antibodies. Archives of Neurology, 44, 876–83. Lieberman, M.F., Shahi, A. & Green, W.R. (1978). Embolic ischemic optic neuropathy. American Journal of Ophthalmology, 86, 206–10. Longfellow, D.W., Davis, F.S. Jr. & Walsh, F.B. (1962). Unilateral intermittent blindness with dilation of retinal veins. Archives of Ophthalmology, 67, 554–5. Mames, R.N., Shugar, J.K., Levy, N. et al. for the CRAO Study Group. (1995). Peripheral thrombolytic therapy for central retinal artery occlusion. Archives of Ophthalmology, 113, 1094. Mangat, H.S. (1995). Retinal artery occlusion. Survey of Ophthalmology, 40, 145–56. Mansour, A.M., Schoch, D. & Logani, S. (1988). Optic disc size in ischemic optic neuropathy. American Journal of Ophthalmology, 106, 587–9. Marshall, J. & Meadows, S. (1968). The natural history of amaurosis fugax. Brain, 91, 419–34. Merchut, M.F., Gupta, S.R. & Naheldy, M.H. (1988). The relation of retinal artery occlusion and carotid artery stenosis. Stroke, 19, 1239–42. Mills, R.P. (1989). Anterior segment ischemia secondary to carotid

occlusive disease. Journal of Clinical Neuro-ophthalmology, 9(3), 200–4. Mori, S., Suzuki, J. & Takeda, M. (1983). A case report of internal carotid occlusion with ischemic optic neuropathy as initial symptom. Japanese Reviews of Clinical Ophthalmology, 77, 1530–3. Moro, F., Doro, D. & Mantovani, E. (1989). Anterior ischemic optic neuropathy and aging. Metabolic Pediatric and Systemic Ophthalmology, 12, 46–57. Newman, N.J. (1998). Cerebrovascular disease. In Clinical Neuroophthalmology, 5th edn ed. N.R. Miller & N.J. Newman, Vol. 3, Chap. 55, p. 3449. Williams and Wilkins. Newman, N.M., Hoyt, W.F. & Spencer, W.H. (1974). Macula-sparing blackouts: clinical and pathologic investigations of intermittent choroidal vascular insufficiency in a case of periarteritis nodosa. Archives of Ophthalmology, 91, 367–70. Ojemann, R.G., Fisher, C.M. & Rich, J.C. (1972). Spontaneous dissecting aneurysms of the internal carotid artery. Stroke, 3, 434–500. Onda, E., Cioffi, G.A., Bacon, D.R. et al. (1995). Microvasculature of the human optic nerve. American Journal of Ophthalmology, 120, 92–102. Perlman, J.I., Forman, S. & Gonzalez, E.R. (1994). Retrobulbar ischemic optic neuropathy associated with sickle cell disease. Journal of Neuro-ophthalmology, 14, 45–8. Portnoy, S.L., Beer, P.M., Packer, A.J. et al. (1989). Embolic anterior ischemic optic neuropathy. Journal of Clinical Neuroophthalmology, 9(1), 21–5. Pozzali, E., Giuliani, G., Poppi, M. et al. (1989). Blunt traumatic carotid dissection with delayed symptoms. Stroke, 20, 412–16. Rafuse, P.E., Nicolle, D.A., Hutnik, C.M.L. et al. (1997). Left atrial myxoma causing ophthalmic artery occlusion. Eye, 11, 25–9. Ramirez, G., O’Neill, Jr. W.M., Lambert, R. et al. (1978). Cholesterol embolization: a complication of angiography. Archives of Internal Medicine, 138, 1430–2. Reed, C. & Toole, J. (1981). Clinical technique for identification of external carotid bruits. Neurology, 31, 744–6. Repka, M.X., Savino, P.J. Schatz, N.J. & Sergott, R.C. (1983). Clinical profile and long-term implications of anterior ischemic optic neuropathy. American Journal of Ophthalmology, 96, 478–83. Rizzo, J.F. III & Lessell, S. (1987). Posterior ischemic optic neuropathy during general surgery. American Journal of Ophthalmology, 103, 808–11. Rizzo, J.F. III & Lessell, S. (1991). Optic neuritis and ischemic optic neuropathy. Overlapping clinical profiles. Archives of Ophthalmology, 109, 1668–72. Ross Russell, R.W. (1961). Observations on the retinal bloodvessels in monocular blindness. Lancet, ii, 1422–8. Ross Russell, R.W. & Page, N.G.R. (1983). Critical perfusion of brain and retina. Brain, 106, 419–34. Savino, P.J., Glaser, J.S. & Cassady, J. (1977). Retinal stroke: is the patient at risk? Archives of Ophthalmology, 95, 1185–9. Sawle, G.V. & Sarkies, N.J.C. (1987). Posterior ischemic optic neuropathy due to internal carotid artery occlusion. Neuroophthalmology, 7, 349–53.

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Schmidt, D, Schumacher, M. & Wakhloo, A.K. (1992). Microcatheter urokinase infusion in central retinal artery occlusion. American Journal of Ophthalmology, 113, 429–34. Schwartz, N.D., So, Y.T., Hollander, H. et al. (1986). Eosinophilic vasculitis leading to amaurosis fugax in a patient with acquired immune deficiency syndrome. Archives of International Medicine, 146, 2059–60. Shalev, Y., Green, L., Pollack, A. et al. (1985). Myocardial infarction with central retinal artery occlusion in a patient with antinuclear antibody-negative systemic lupus erythematosus. Arthritis and Rheumatism, 28, 1185–7. Shimo-Oku M. & Miyazaki, S. (1984). Acute anterior and posterior ischemic optic neuropathy. Japanese Journal of Ophthalmology, 28, 159–70. Stefensson, E., Coin, J.T., Lewis, W.R. III et al. (1985). Central retinal artery occlusion during cardiac catheterization. American Journal of Ophthalmology, 9, 586–9. Stone, R., Zink, H., Klingele, T. & Burde, R.M. (1977). Visual recovery after central retinal artery occlusion: two cases. Annals of Ophthalmology, 9, 445. The Antiphospholipid Antibodies in Stroke Study (APASS) Group. (1993). Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology, 43, 2069–73. The Amaurosis Fugax Study Group. (1990). Current management of amaurosis fugax. Stroke, 21, 201–8. The Ischemic Optic Neuropathy Decompression Trial Research Group. (1995). Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. Journal of the American Medical Association, 273, 625–32. Tippin, J., Corbett, J.J., Kerber, R.E. et al. (1989). Amaurosis fugax and ocular infarction in adolescents and young adults. Annals of Neurology, 26, 69–77.

Tomsak, R.L. & Jergens, P.B. (1987). Benign recurrent transient monocular blindness: a possible variant of acephalgic migraine. Headache, 27, 66–9. Toole, J. (1963). Ophthalmodynamometry. Archives of International Medicine, 112, 219–20. Troost, B.T. (1976). Migraine. In Clinical Ophthalmology, ed. T.D. Duane, Vol. 2. Chapter 19, pp. 11–20, Philadelphia: Harper Medical. Walsh, F.B. & Hoyt, W.F. (1969). Clinical Neuro-ophthalmology. 3rd edn, pp. 1671–73. Baltimore: Williams & Wilkins. Williams, E.L., Hart, Wm. Jr. & Tempelhoff, R. (1995). Postoperative ischemic optic neuropathy. Anesthesia and Analgesia, 80, 1018–29. Wilson, I.A., Warlow, C.P. & Ross Russell, R.W. (1979). Cardiovascular disease in patients with retinal arterial occlusion. Lancet, 1, 1292–4. Wolf, S., Schulte-Strake, U., Bertram, B. et al. (1993). Hemodilution therapy in patients with acute anterior ischemic optic neuropathy. Ophthalmologie, 90, 21–6. Wolfe, S.W., Lospinuso, M.F. & Burke, S.W. (1992). Unilateral blindness as a complication of patient positioning for spinal surgery. Spine, 17(5), 600–5. Wolter, J.R. & Burchfield, W.J. (1971). Ocular migraine in a young man resulting in unilateral transient blindness and retinal edema. Journal of Pediatric Ophthalmology, 8, 173–6. Wray, S.H. (1988). Extracranial internal carotid artery disease. In Amaurosis Fugax, ed. E.F. Bernstein, Chapter 5, pp. 72–80. New York: Springer-Verlag. Zimmerman, L.E. (1965). Embolism of central retinal artery; secondary to myocardial infarction with mural thrombosis. Archives of Ophthalmology, 73, 822–6.

10

Vestibular syndromes and vertigo Marianne Dieterich and Thomas Brandt Ludwig Maximilians University, Munich, Germany

Introduction Vertigo is an unpleasant distortion of static gravitational orientation or an erroneous perception of motion of either the sufferer or the environment. It is not a well-defined disease entity, but rather the outcome of many pathological processes causing a mismatch between the visual, vestibular, and somatosensory systems, all of which subserve both static and dynamic spatial orientation. Physiological and clinical vestibular vertigo syndromes are commonly characterized by a combination of phenomena involving perceptual, ocular motor, postural and vegetative manifestations: vertigo, nystagmus, ataxia and nausea (Brandt & Daroff, 1980). The vertigo itself results from a disturbance of cortical spatial orientation, while nystagmus and ocular deviations are secondary to a direction-specific imbalance in the vestibulo-ocular reflex. Postural imbalance and vestibular ataxia are caused by inappropriate or abnormal inactivation of vestibulospinal pathways. Unpleasant vegetative effects, such as nausea and vomiting, are related to clinical activation of the medullary vomiting centre (Brandt, 1991b). Most of the central vestibular syndromes and some of the peripheral vestibular syndromes may have a vascular etiology (Baloh, 1992; Brandt & Dieterich, 1994a). Ischemia can be responsible for a wide range of vestibular syndromes; most of the central and some of the peripheral vestibular syndromes are listed in Table 10.1. Ischemia will sometimes produce a combination of central and peripheral symptoms, as in anterior inferior cerebellar artery (AICA) infarctions, the territory of which encompasses the labyrinth, pontine, and cerebellar structures (Atkinson, 1949). In migraine and in vertebrobasilar ischemia, it may not be possible to determine whether the vertigo is a symptom of a peripheral or a central vestibu-

lar syndrome. The course and prognosis of the vertigo syndrome are variable. The vertigo itself, which is usually abrupt in onset and frequently transient in ischemic attacks, must be differentiated from the episodic vertigo commonly seen in other conditions, such as Menière’s disease, basilar migraine, vestibular paroxysmia, and vestibular epilepsy. The extreme manifestation of central vascular vertigo is either sudden, incapacitating, severe rotational vertigo or bilateral loss of vestibular function, with intolerance of head motion causing oscillopsia and postural imbalance. Some infarctions cause specific syndromes, such as ipsiversive lateropulsion and ocular tilt reaction (OTR) in lateral medullary infarctions (Wallenberg's syndrome) or contraversive OTR in paramedian thalamic infarctions extending to the interstitial nucleus of Cajal (INC). Hemorrhages, inflammations, or acute space-occupying lesions are, however, other principal causes of the same syndromes. Often, vascular abnormalities are considered only in patients who present with positional nystagmus/vertigo without any corresponding lesions indicated by CT or MRI investigations (Brandt, 1991b). Two interesting vascular pathomechanisms should be mentioned, even though their diagnosis could not be confirmed in the patients affected: neurovascular cross-compression (disabling positional vertigo (Moller et al., 1986) or vestibular paroxysmia (Brandt & Dieterich, 1994a)) and the hyperviscosity syndrome, with venous obstruction of labyrinthine blood flow (Andrews et al., 1988). Decompression sickness is a rare vascular vertigo syndrome (Head, 1984), and labyrinthine hemorrhage can cause perilymph fistulas or delayed endolymphatic hydrops. In the case of perilymph fistulas, provocation of symptoms by various situations helps to establish the diagnosis (Brandt, 1991b).

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Table 10.1. Mechanisms and sites of vascular vertigo Mechanism

Syndrome

Site

Migraine

Basilar migraine

Pontomedullary brainstem

Benign paroxysmal vertigo of childhood Benign recurrent vertigo

Vestibulocerebellum Labyrinth

Vestibular or hearing loss (infarction of AICA or internal auditory artery)

Labyrinth, vestibular nerve

Pseudo ‘vestibular neuritis’ (lacunar or PICA infarct)

Vestibular nerve root or vestibular nuclei

Ocular tilt reaction

Pontomesencephalic (contraversive) Pontomedullary (ipsiversive) Vermis (contraversive)

Lateropulsion (Wallenberg’s syndrome)

Dorsolateral medulla (ipsiversive)

Downbeat nystagmus/vertigo

Commissure of vestibular nuclei or bilateral flocculus

Upbeat nystagmus/vertigo

Pontomesencephalic junction or caudal medulla

Positional downbeat nystagmus

Nodulus?

Thalamic astasia

Posterolateral thalamus

Central positional vertigo

Vestibular nuclei, vestibulocerebellar loop

Neurovascular cross-compression

Vestibular paroxysmia (disabling positional vertigo)

Vestibular nerve

Vascular polyneuropathy

Diabetic vestibular loss

Vestibular nerve, labyrinth?

Hyperviscosity with venous obstruction

Hyperviscosity syndrome with episodic vertigo

Labyrinth

Miscellaneous (secondary signs)

Decompression sickness labyrinthine hemorrhage, perilymph fistula or hydrops, vascular fistula signs

Labyrinth

Infarction/hemorrhage

Strokes affecting peripheral and central vestibular disorders Episodic vertigo and ocular motor abnormalities are common early symptoms of reduced vertebrobasilar blood flow due to the steep pressure gradient from the aorta to the terminal pontine arteries. These long, circumferential arteries provide a highly vulnerable blood supply for the vestibular nuclei (Williams & Wilson, 1962). Symptoms are induced when the head is maximally rotated and/or extended while standing, and they terminate abruptly when the head is returned to a normal upright position. However, they may not only indicate a transient vertebrobasilar ischemia caused by a functional compression of the

vertebral artery (particularly in elderly patients with atheromas, cervical spondylosis or osteophytes that narrow the transverse foramina) but also a neurovascular cross-compression of the eighth nerve. Therefore, we shall restrict the presentation of vascular vestibular syndromes to clearly defined strokes of the labyrinth, the vertebrobasilar and the middle cerebral artery territories. These vascular territories supply the peripheral and central vestibular pathways and integration centers. Vestibular pathways run from the eighth nerve and the vestibular nuclei along the medial longitudinal fasciculus to the oculomotor nuclei and the supranuclear integration centers in the rostral midbrain. From there, they reach several vestibular cortex areas through thalamic projec-

Vestibular syndromes and vertigo

Table 10.2. Classification of some central vestibular syndromes of the brainstem tegmentum according to the three major planes of action of the VOR: yaw, pitch, and rolla Disorders of the VOR in the horizontal (yaw) plane

Horizontal nystagmus: pseudovestibular neuritis (partial AICA/ PICA infarctions; multiple sclerosis plaques)

Disorders of the VOR in the sagittal (pitch) plane

Vertical nystagmus: downbeat nystagmus, upbeat nystagmus

Disorders of the VOR in the frontal (roll) plane

OTR and its components

Note: a Syndromes in roll can include complete OTR or its single components, such as skew deviation, ocular torsion, lateral falls, and SVV tilt. Syndromes in yaw include spontaneous horizontal nystagmus, rotational vertigo, postural imbalance, and lateral falls. Syndromes in pitch include upbeat/downbeat nystagmus, pitch tilt of subjective vertical and fore–aft postural instability.

tions. Most central ischemic vertigo syndromes are secondary to paramedian or lateral tegmental infratentorial lesions. Supratentorial vestibular syndromes are less frequent, and only those of the thalamus and the vestibular cortex are relevant to the present discussion. In the following, we attempt to correlate circumscribed unilateral infarctions of the brainstem, the thalamus, and the temporoparietal cortex with the clinical syndromes and the particular vestibular structures involved. Such a scheme of extended vestibular pathways, with different lesion sites causing characteristic vestibular syndromes, is required for topographic diagnosis. Each pathway that mediates the vestibulo-ocular reflex (VOR) in one of the three major planes of action must run a separate course in order to become individually lesioned (Leigh & Brandt, 1993; Brandt & Dieterich, 1995). A classification has been proposed for central vestibular disorders of the brainstem (Tables 10.2 and 10.3) attributing vestibular syndromes such as downbeat nystagmus, pseudo-vestibular neuritis and OTR to lesional tone imbalances in one of the three major planes of action of the VOR (Brandt, 1991b; Brandt & Dieterich, 1995). This hypothetical classification is based on clinical experience and on animal studies showing that a given syndrome can be elicited by distinct and separate lesions of the pathways at different brainstem levels. Pathways that mediate the VOR in one of the three major planes run separate courses and can become lesioned individually or in combination. Our approach to vestibular syndromes in stroke is based on defined vascular territo-

ries and evaluation of lesional malfunction relative to the perceptional, ocular motor, and postural effects in yaw, pitch, and roll planes.

Anterior inferior cerebellar artery and internal auditory artery The anterior inferior cerebellar artery (AICA) supplies not only the anterolateral pons, the middle cerebellar peduncle and the flocculus but also the inner ear (Atkinson, 1949; Kim et al., 1990). Thus, ischemia of the peripheral labyrinthine receptors, the eighth nerve, the vestibular nucleus, or the vestibulocerebellum could cause vertigo. The clinical spectrum includes brainstem and cerebellar signs and symptoms (Amarenco, 1991), but labyrinthine infarction was also demonstrated histopathologically (Hinojosa & Kohut, 1990). Oas and Baloh (1992) described two patients with clinical features of AICA infarctions who had recurrent attacks of rotatory vertigo. The vertigo initially appeared as an isolated symptom months prior to the brain infarction and recurred at the time of the infarction, accompanied by unilateral hearing loss, tinnitus, facial numbness, and hemiataxia. Unilateral auditory and vestibular dysfunction on the affected side were documented by auditometry and caloric irrigation. Therefore, those authors reasoned that the vertigo attacks preceding the infarction resulted from transient ischemia of the inner ear or the vestibular nerve (Fig. 10.1). Nevertheless, a definitive clinical classification is not possible in individual patients with a labyrinthine, vestibular nerve, or vestibular nucleus lesion responsible for vertigo in AICA infarctions. In patients with both vertigo and hearing loss (which supports labyrinthine or eighthnerve ischemia), a combination of peripheral and central vestibular dysfunction is possible. However, recurrent isolated episodes of vertigo without neurological signs and symptoms are an uncommon manifestation of vertebrobasilar ischemia (Estol et al., 1996). Furthermore, it has been repeatedly demonstrated that small demyelinating plaques (Brandt et al., 1986) or lacunar infarctions (Hopf, 1987) at the root entry zone and/or the vestibular nuclei can mimic vestibular neuritis, in that rotational vertigo and spontaneous nystagmus are combined with abolition of caloric responses on the affected side. These manifestations are combined with masseter paresis, as evidenced by the masseter reflex (Hopf, 1987) or by ocular motor abnormalities such as those of saccadic pursuit (Brandt et al., 1986). If transient ischemic attacks with vertigo, nystagmus, and ataxia occur secondary to vertebral artery compression

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Table 10.3. Vestibular dysfunction in VOR planes

Locus

Roll (unilateral lesions)

Yaw (unilateral lesions)

Pitch (bilateral lesions)

Cortex

Contraversive SVV tilt

?

?

Thalamus Posterolateral Paramedian

Ipsiversive/contraversive SVV tilt Contraversive OTR

? ?

? ?

Mesencephalon

Contraversive OTR

Pons

Ipsiversive/contraversive OTR

Pontomedullary

Ipsiversive OTR

Medulla

Ipsiversive OTR

Upbeat nystagmus

Pseudo-vestibular neuritis

Upbeat nystagmus

Flocculus bilateral Vermis/dentate nucleus

Downbeat nystagmus

Downbeat nystagmus Contraversive OTR

with rotational head motion, this is termed as a syndrome of rotational vertebral artery occlusion (Yang et al., 1985). Vertebral arteries are susceptible to mechanical compression with head rotation, because of muscular and tendinous insertions, osteophytes, and other degenerative changes of cervical spondylosis. When the artery passes through the foramina transversaria of the cervical vertebrae at C2–C6, the patients may be symptomatic on right or left head rotation (Kuether et al., 1997). The correct site of occlusion of the vertebral artery can be demonstrated only by dynamic angiography during stepwise head rotation. It most often occurs at C2 level.

Vertebral artery and posterior inferior cerebellar artery A typical syndrome of occlusions of the vertebral artery or the arteries arising from the vertebral artery (to course through the lateral medullary fossa to supply the lateral medulla), and in rare cases affecting the posterior inferior cerebellar artery (PICA) or posterior spinal arteries, is Wallenberg's syndrome, a lateral medullary infarction that mostly includes the medial, and sometimes the superior, vestibular nucleus. A unilateral ischemic lesion of the medial (or superior) vestibular nucleus usually results in a vestibular tone imbalance in the roll plane. Signs and symptoms of vestibular dysfunction in the roll plane can be detected on the basis of deviations from normal function. In the normal position in the roll plane, the graviceptive input from the otoliths and semicircular canals aligns the subjective visual vertical (SVV) with gravitational vertical and adjusts axes of the eyes and the head

? Pseudo-vestibular neuritis

?

horizontally. A vestibular tone imbalance due to a lesion should result in a syndrome consisting of a perceptual tilt (SVV tilt), head and body tilt, vertical misalignment of the visual axes (skew deviation), and ocular torsion. The OTR comprises several of these features: the synkinesis of head tilt, skew deviation, and ocular torsion (Westheimer & Blair, 1975) associated with a perceived tilt of the vertical (Brandt & Dieterich, 1987). There is convincing evidence that all these signs and symptoms reflect vestibular dysfunction in the roll plane. They may be found in combination or as single components, with varying sensitivity at all brainstem levels. A systematic study of 111 patients with acute unilateral brainstem infarctions revealed that pathological tilts of SVV (94%) and ocular torsion (83%) were the most sensitive signs. Skew deviation was found in one-third of these patients, and a complete OTR in one-fifth. Clinical evaluation of vestibular function in roll therefore includes psychophysical adjustments of SVV, determination of the vertical divergence of the visual axes by use of prisms, and determination of ocular torsion by means of fundus photographs; for methods, see Dieterich and Brandt (1993a). All of the 36 patients with Wallenberg's syndrome we tested exhibited significant tilt of the internal representation of the gravity vector, as indicated by deviation of SVV ipsiversive to the lesion. About one-third of these patients had a complete OTR (Fig. 10.2) (Dieterich & Brandt, 1992); these were the same patients exhibiting the most severe body lateropulsion. OTR in Wallenberg's syndrome is ipsiversive (i.e. ipsilateral ear and eye undermost). Quantitative measures of postural sway by means of posturography demonstrate an increased diagonal sway from right forward to left backward for right-sided lesions and

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(a )

(c )

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(b)

Fig. 10.1. Three zones of AICA supply. Zone 1 is supplied by the recurrent penetrating arteries (RPA) of AICA, zone 2 by the internal auditory artery, and zone 3 by the terminal cerebellar branches of AICA. (a) Rostral pons at the level of the facial and abducens nuclei (vertical dotted line represents the mid-sagittal line). Zone 1A and zone 1B represent the arterial supply to areas supplied by a premeatal and postmeatal RPA. Often a single RPA, originating from the premeatal or postmeatal AICA, supplies all of zone 1. The cross-hatched area represents the root entry zone of the facial and vestibulocochlear nerves. (b) Zone 2 represents the arterial supply to the inner ear (modified from Schuknecht, 1974). (c) Cerebellum, anterior view. Zone 3 represents the arterial supply from the terminal cerebellar branches of AICA. (ASC ⫽ anterior semicircular canal, AVA ⫽ anterior vestibular artery, CCA ⫽ common cochlear artery, HSC ⫽ horizontal semicircular canal, IAA ⫽ internal auditory artery, MCP ⫽ middle cerebellar peduncle, PSC ⫽ posterior semicircular canal, V ⫽ spinal trigeminal tract and nucleus, VI ⫽ abducens nucleus, VII ⫽ facial nerve, VIII ⫽ vestibulocochlear nerve). Adapted from Oas & Baloh, 1992, with permission.

from left forward to right backward for left-sided lesions. Body lateropulsion is correlated with SVV tilt (i.e. the more pronounced the lateropulsion, the greater the SVV tilt). We hypothesize that deviation of SVV, lateropulsion of the body, skew deviation, and ocular torsion of the eyes are the perceptual, postural, and ocular motor consequences of a common lesion of the vestibular pathways that subserve VOR in the roll plane (Dieterich & Brandt, 1993a, c). Most patients have disconjugate ocular torsion, usually of the eye ipsilateral to the brainstem lesion, which suggests involvement of posterior semicircular canal pathways (Fig. 10.2). If anterior and posterior semicircular canal pathways are affected, the OTR in Wallenberg's syndrome is manifest as binocular ocular torsion. In rare cases with monocular incyclotropia of the uppermost eye, involvement of anterior semicircular canal pathways can only be assumed. Where is the most probable site of the lesion of graviceptive pathways in roll in Wallenberg's syndrome? Projection of ischemic lesions demonstrated by CT and MRI onto the appropriate sections of a stereotaxic brainstem atlas (Olszewski & Baxter, 1982) allows identification of the medial (and/or superior ?) vestibular nucleus as the critical vestibular structure (Fig. 10.3). The medial and/or superior vestibular nuclei were included in the ischemic areas in the cases of Wallenberg's syndrome with OTR. The blood supply to these structures originates from the PICA, from

the branches of the vertebral artery, or from the branches of the AICA. Our studies on the OTR, lateropulsion, and SVV tilts were concerned with static effects of vestibular dysfunction in roll, which persist for days to weeks, during which time they gradually and spontaneously subside. Additional dynamic signs and symptoms consisting of lateral rotational vertigo and torsional nystagmus occur in the acute stage of infarction (Morrow & Sharpe, 1988; Lopez et al., 1992). Fast phases of rotational nystagmus are contraversive, whereas the slow phases correspond in direction to the static deviation. The combination of static and dynamic effects is not surprising if one considers the functional corroboration of vertical semicircular canals and otolithic input based on neuronal convergence at the second-order vestibular nuclei neurons (Angelaki et al., 1993). We have left out, to a great degree, consideration of the cerebellum in this vestibular chapter. It seems likely that ischemic lesions of the vestibular vermis structures (uvula, nodulus), the flocculus, the fastigial nucleus, the dentate nucleus, and the the middle cerebellar peduncle can cause vertigo or related vestibular syndromes, whereas this is unlikely in infarctions of the cerebellar hemispheres only. From animal experiments it is known that the cerebellar nodulus and uvula receive visual and vestibular (otolith and semicircular canal) information via the climbing fiber

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(a )

(b)

Fig. 10.2. (a) Patient with a right lateral medullary infarction (Wallenberg’s syndrome) presenting with a OTR to the right. OTR consists of ipsiversive head tilt of 20° (bottom), skew deviation of 4° (middle) and ocular torsion of the undermost eye of about 20° (excyclotropia; counterclockwise from the viewpoint of the observer; top), whereas the uppermost eye shows a normal position in roll (5° excyclotropia). (b) Hypothetical explanation of OTR due to lesions of the vertical semicircular canal pathways. Schematic drawing of the three-neuron vestibuloocular reflex arc between the posterior semicircular canal and the extraocular eye muscles. An excitatory ascending pathway is linked from the posterior semicircular canal to the ipsilateral superior oblique and the contralateral inferior rectus muscle; an inhibitory ascending pathway is linked to the ipsilateral inferior oblique and the contralateral superior rectus muscles (Graf et al., 1983; Graf & Ezure, 1986). A lesion of these pathways causes excyclotropia of the ipsilateral and hypertropia of the contralateral eye (AC, PC, HC ⫽ anterior, posterior and horizontal semicircular canal; MLF ⫽ medial longitudinal fasciculus; OS and OI ⫽ superior oblique and inferior oblique muscles; RS and RI ⫽ superior and inferior rectus muscles; III ⫽ oculomotor nucleus; IV ⫽ trochlear nucleus; VIII ⫽ vestibular nucleus).

pathways, especially from the dorso-medial cell column and the beta nucleus of the inferior olive and the vestibular nuclei (Takeda & Maekava, 1989; Barmack, 1996). In two patients with acute cerebellar lesions (one hemorrhage, one PICA infarction) – in which an affection of the nodulus was discussed – contraversive partial OTR with ocular torsion of both eyes but without head tilt was reported (Mossman & Halmagyi, 1997). We saw more than 15 patients with complete or incomplete OTR presenting with acute PICA infarctions or hemorrhages of the vermis, particularly of the uvula (Fig. 10.4), or with cavernoma of the

dentate nucleus and the middle cerebellar peduncle (Fig. 10.5). In contrast to lesions of the pontomedullary brainstem, which always induce an ipsiversive tilt of the signs in the roll plane, tilts in vermal and dentate nucleus lesions were all contraversive due to a loss of cerebellar inhibition of otolith neurons in the ipsilateral vestibular nucleus (resulting in an increase of tonic resting activity). Moreover, it was reported that experimental nodulus lesions in cats cause positional downbeat nystagmus (Fernandez et al., 1960; Fernandez & Fredrickson, 1964), which was less convincingly confirmed in patients by

Vestibular syndromes and vertigo

Kattah et al. (1984) and Sakata et al. (1987). Furthermore, it is our own experience that severe central positional vertigo is usually induced by lesions located dorsolateral to the fourth ventricle. The differentiation between brainstem and cerebellar lesions is impossible in most clinical cases of infarctions, because the major infratentorial arteries supply both brainstem and cerebellum.

Basilar artery and paramedian pontine and mesencephalic arteries

Fig. 10.3. Unilateral pontomedullary infarctions causing vestibular dysfunction in the roll plane presenting either as ocular tilt reaction or its components; head tilt, skew deviation, ocular torsion and tilt of subjective visual vertical. Schematic representation of two transverse sections (XVI, XXIV) of the stereotaxic brainstem atlas of Olszewski and Baxter (1982) with typical lesioned areas in four patients with unilateral medullary and pontine infarctions as taken from MRI scans and projected onto the appropriate transverse section. In the lateral medullary infarctions (Wallenberg’s syndrome; bottom) – within the territories of the vertebral arteries, the PICA or posterior spinal arteries – vestibular dysfunction with ipsiversive tilts results from involvement of the medial vestibular nucleus (VIIIm). In pontine infarctions, vestibular dysfunction in roll results either from involvement of the superior vestibular nucleus (VIIIs) or the MLF within the territories of the AICA or paramedian arteries from the basilar artery, respectively (top). Occlusions of the AICA may involve the superior vestibular nucleus and cause ipsiversive OTR, whereas MLF lesions cause contraversive OTR.

Unilateral ischemic lesions of the pontomesencephalic vestibular pathways, which run along the MLF, predominantly cause vestibular tone imbalance in the roll plane, which is demonstrated by the frequency of SVV tilts, skew torsion, and OTR in affected patients. The direction of the perceptual, ocular motor, and head tilt may be helpful for determining the level as well as the side of the brainstem lesion. All tilts are ipsiversive (i.e. ipsilateral eye undermost) with caudal pontomedullary lesions and contraversive (contralateral eye undermost) with rostral pontomesencephalic lesions. These directionspecific findings of vestibular dysfunction in roll can be explained by unilateral lesions of a ‘graviceptive’ pathway that crosses the midline at the upper pontine level (Figs. 10.6; 10.7; Brandt & Dieterich, 1993, 1994b), running along the MLF and reaching the INC, a well-known integration center for eye-head coordination in roll (Anderson, 1981; Fukushima, 1987). If the level of the brainstem damage is known from the clinical syndrome, an SVV tilt, OTR, or skew torsion will indicate the side more severely affected. If, on the other hand, the side of the damage is clear from the clinical syndrome, the level of the brainstem damage will be indicated by the tilt direction of these signs (i.e. caudal with ipsiversive tilt and rostral with contraversive tilt). Thus, the diagnostic topographic value of a static vestibular dysfunction in roll is similar to that of cranial nerve lesions, but is more sensitive. One of the most striking findings, previously unreported, was that all of our patients with skew deviations also had ocular torsion (OT) toward the undermost eye. The direction-specific coincidence of skew and OT is helpful for clinical differentiation between supranuclear (mesencephalic) skew and nuclear or fascicular oculomotor or trochlear palsies. A unilateral oculomotor or trochlear palsy causes OT of the paretic eye only, whereas mesencephalic skew can be identified most often by a binocular, conjugated OT. Even in patients with bilateral third- or fourth-nerve palsies, a skew can be differentiated by the

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Fig. 10.4. Unilateral cerebellar lesion causing contraversive OTR. Schematic representation of two transverse sections (106, 107) of the human brainstem and cerebellum atlas of Duvernoy (1995) with typical lesioned areas (right) as taken from MRI scans (left) and projected onto the appropriate section. The patient (SK49M) presented with incomplete OTR to the right (body and head tilt to the right of 15°, minimal alternating skew deviation of 1° at lateral gaze, bilateral ocular torsion with excyclotropia of 0° of the left and 12° of the right eye, tilts of SVV of 10–16° to the right) which resulted from a small medial PICA infarction affecting the left tonsil (22) and uvula (16) of the cerebellar vermis. (12 ⫽ facial nerve, 13 ⫽ vestibulocochlear nerve, 16 ⫽ uvula, 19 ⫽ inferior semilunar lobule, 20 ⫽ superior semilunar lobule, 21 ⫽ flocculus, 22 ⫽ tonsil, 23 ⫽ pyramid of vermis, 24 ⫽ tuber of vermis).

Fig. 10.5. Schematic representation of a transverse section (112) of the human brainstem and cerebellum atlas of Duvernoy (1995) with a lesioned area of a patient (LA25F) presenting with a ‘pseudo-vestibular neuritis’ and incomplete contraversive OTR to the right (strong rotational vertigo, spontaneous horizontal–rotatory nystagmus to the left of 38°/s, caloric hyporesponsiveness of the right ear, ocular torsion with an incyclotropia of 2.5° of the left eye and excyclotropia of 13° of the right eye, tilts of SVV of 8° to the right). The syndrome was caused by a small hemorrhage in a cavernoma lateral to the fourth ventricle affecting the left middle cerebellar peduncle (10) and the left dentate nucleus (18). (10 ⫽ middle cerebellar peduncle, 11 ⫽ trigeminal nerve, 14 ⫽ simple lobule, 15 ⫽ declive, 16 ⫽ uvula, 17 ⫽ nodulus, 18 ⫽ dentate nucleus, 19 ⫽ inferior semilunar lobule, 20 ⫽ superior semilunar lobule).

(d )

(d )

(c )

(c )

(b) (b)

(a ) (a )

Fig. 10.6. Typical lesioned areas in four patients with unilateral pontomedullary infarctions showing ocular skew torsion sign to the left (left eye undermost). Ischemic areas were taken from MRI scans and projected onto the appropriate transverse sections of the stereotaxic brainstem atlas of Olszewski and Baxter (1982). In medullary lesions involving the medial and superior vestibular nuclei (VIIIm in sections XIV and XVI, VIIIs in section XXIV) skew torsion sign was ipsiversive (a), (b), (c). Ocular skew torsion sign was contraversive if the medial longitudinal fasciculus (Flom in section XXIV) was involved with the vestibular nuclei spared (d); same section as in (c). Opposite directions of ocular skew torsion sign in same-sided lesions at pontine level (c), (d) indicate crossing of graviceptive pathways mediating eye position in roll plane. In (c) ipsilateral pathways were affected; in (d) contralateral pathways were affected.

Fig. 10.7. Ischemic areas in four patients with right pontine and mesencephalic infarctions causing contraversive ocular skew torsion sign to the left. Lesions indicated either involvement of the medial longitudinal fasciculus (F lo m in sections XXVIII, XXX, XXXVI) at different pontomesencephalic levels (a), (b), (c) or the rostral midbrain tegmentum including the interstitial nucleus of Cajal (iC in section XXXVIII) (d). The latter seems to be the most rostral brainstem structure to elicit the ocular skew torsion sign.

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Downbeat nystagmus in the primary gaze position, especially in lateral gaze, is often accompanied by oscillopsia and postural instability, with increased fore–aft body sway. Upbeat nystagmus – the directional pendant of downbeat nystagmus – can be induced by two separate and distinct brainstem lesions, located either at the pontomedullary junction near the perihypoglossal nucleus or at the pontomesencephalic junction (Fisher et al., 1983). Transitions between upbeat and downbeat nystagmus are possible, depending on the level of brainstem ischemia. Pontomesencephalic brainstem lesions, whether unilateral or bilateral, may therefore cause a vestibular tone imbalance in roll or pitch, but not in yaw (Brandt & Dieterich, 1995). A tone imbalance in the yaw plane indicates pontomedullary lesions near the root entry zone of the eighth nerve or the vestibular nuclei. Fig. 10.8. Schematic drawing of circumscribed brainstem lesions causing vestibular syndromes in the three major planes of action of the VOR, yaw, pitch and roll. Vestibular syndromes in yaw plane are caused only by unilateral ponto-medullary lesions including the vestibular nuclei (VN) and the root entry zone of the vestibular nerve. Vestibular syndromes in pitch plane are either caused by midline lesions of the ponto-medullary or ponto-mesencephalic junction or bilateral dysfunction of the flocculus. Vestibular syndromes in roll are caused by unilateral graviceptive pathway lesions, e.g. the medial longitudinal fasciculus (MLF), from the vestibular nuclei to the interstitial nucleus of Cajal (INC). These pathways cross at pontine level.

direction of OT, which is disconjugate in the peripheral nerve palsies (i.e. bilaterally excyclotropic in bilateral trochlear palsies and bilaterally incyclotropic in bilateral oculomotor palsies). Therefore, determination of skew and OT (by fundus photographs) can be recommended for routine neuro-ophthalmological investigation in suspected brainstem dysfunction (Dieterich & Brandt, 1993b). Furthermore, a reliable differentiation between dysfunction in the roll plane in central brainstem lesions and OT and SVV tilt caused by extraocular eye muscle paresis is possible, because the latter are not associated with SVV tilts under binocular viewing conditions. A vestibular tone imbalance in the pitch plane typically results from bilateral paramedian lesions (Table 10.3, Fig 10.8) of the vestibular pathways (e.g. basilar artery thrombosis). A tone imbalance in the pitch plane can cause a downbeating nystagmus if the lesion is located at the level of the vestibular nuclei, affecting commissural fibers at the floor of the fourth ventricle (Baloh & Spooner, 1981).

Thalamic infarctions Unilateral thalamic infarctions may cause contralateral falling, astasia (Masdeu & Gorelick, 1988), or contralateral OTR (Halmagyi et al., 1990). SVV, OT, skew deviation, and lateral head tilt were measured in 35 patients with acute thalamic infarctions (14 paramedian, 17 posterolateral, 4 polar) (Dieterich & Brandt, 1993c) and in five patients with mesodiencephalic hemorrhages, in order to determine their differential tonic effects on vestibular function in the roll plane. Eight of 14 patients with paramedian infarctions had complete OTR with contraversive head tilt, skew deviation, OT, and SVV tilt. Projections of infarcted areas in CT scans or MR images onto appropriate transverse sections of cytoarchitectonic atlases clearly showed that OTR was due to concurrent ischemia of the rostral midbrain tegmentum, including the INC (Fig. 10.9). The blood supplies to the two regions may have a common origin in the paramedian thalamic and paramedian mesencephalic arteries. Thus, OTR is not thalamic, and INC (and the rostral interstitial nucleus of the MLF) is obviously the most rostral brainstem structure that mediates eye–head coordination in roll. Eleven of 17 patients with posterolateral infarctions exhibited moderate but significant SVV tilts, which could either be ipsiversive or contraversive (Fig. 10.10). In those cases, thalamic subnuclei (Vim, Vce, Dc) were involved, which are known from animal experiments to convey vestibular and somatosensory information to the cortex. Infarctions were more ventromedial in the remaining cases without SVV tilts. Polar infarctions did not affect vestibular

Vestibular syndromes and vertigo

function in roll. Even if thalamic infarction includes the vestibular subnuclei, it does not result in ocular motor signs such as spontaneous nystagmus or skew deviation.

Cortical infarctions

Fig. 10.9. Collective presentation of lesions taken from MRIs and projected onto the appropriate transverse thalamic and midbrain sections of a stereotaxic thalamus atlas (Van Buren & Borke 1972); 9.7 mm and 0.9 mm above the anterior commissure–posterior commissure [AC–PC] line) (top and middle) and midbrain atlas (Olszewski & Baxter, 1982; plate XXXVIII) (bottom). The AC–PC interval is 25 mm. In the seven ischemic patients with complete contraversive OTR, the infarction involves the rostral midbrain tegmentum in the region of the interstitial nucleus of Cajal (iC ⫽ INC) and the adjacent area of the rostral interstitial nucleus of the MLF. (EW ⫽ Edinger–Westphal nucleus; IIIpr ⫽ nucleus oculomotorius principalis; Icp ⫽ nucleus intracapsularis).

Several distinct and separate areas of the parietal and temporal cortex have been identified in animal studies as receiving vestibular afferents, such as area 2v at the tip of the intraparietal sulcus (Fredrickson et al., 1966; Schwarz & Fredrickson, 1971; Büttner & Buettner, 1978), area 3aV (neck, trunk, and vestibular region of area 3a) in the central sulcus (Ödkvist et al., 1974), the parieto-insular vestibular cortex (PIVC) at the posterior end of the insula (Grüsser et al., 1982, 1990a,b), and area 7 in the inferior parietal lobule (Faugier-Grimaud and Ventre, 1989) (Fig. 10.11). Our knowledge about vestibular cortex function in humans is less precise, derived mainly from stimulation experiments reported anecdotally in the older literature. It is not always possible to extrapolate from monkey species to human cortex, as Anderson and Gnadt (1989) have demonstrated for Brodmann’s area 7 in rhesus monkey and humans. Area 2v corresponds best to the vestibular cortex, as described by Foerster in 1936. PIVC corresponds best to a region from which Penfield and Jasper (1954) were able to induce vestibular sensations by electrical stimulation with a depth electrode within the Sylvian fissure, medial to the primary acoustic cortex. This region was found to be activated during caloric vestibular stimulation as assessed by focal increase of cortical blood flow (Friberg et al., 1985; Bottini et al., 1994), and during electrical vestibular stimulation, as assessed by functional MRI (Bucher et al., 1998). What is the clinical significance of the vestibular cortex? Vertigo has long been recognized as a manifestation of epileptic seizures (Foerster, 1936; Penfield & Jasper, 1954; Schneider et al., 1968). This vertigo is secondary to unilateral focal discharges from the vestibular cortex, whereas functional deficits of this area, such as those caused by infarctions of the medial cerebral artery, do not typically manifest with vertigo. In our study, a reliable test was required for determination of the functional deficit of vestibular cortex lesions in patients with acute ischemic stroke. SVV was chosen as one mode of testing vestibular function, because it provides a sensitive and direction-specific means for measurement of unilateral peripheral (Friedmann, 1971; Curthoys et al., 1991) and central (Dieterich & Brandt, 1993a) vestibular dysfunctions. We systematically investigated 71 patients with infarctions of the middle, posterior and anterior cerebral artery

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Fig. 10.10. Collective presentation of infarcted areas taken from MRI scans and projected onto the appropriate transverse sections (9.7 mm and 0.9 mm above AC–PC line) of the atlas of Duvernoy (1991) in nine patients with posterolateral infarctions that caused either ipsiversive (i; n ⫽ 6) or contraversive (c; n ⫽ 3) tilts of SVV. The overlap area involves the thalamic nuclei Vce, Dc, Vim, Vci, and less frequently Voe, independent of the direction of induced tilt of internal representation of gravity. Black areas represent six overlaps; hatched areas represent five overlaps on the left and three on the right side.

Fig. 10.11. Schematic representation of a monkey brain with the experimentally established areas that receive vestibular input: area 2v at the anterior part of the intraparietal sulcus, area 3aV in the central sulcus, post arcuate area 6, multisensory area 7 a, b at the inferior parietal cortex, and area PIVC, the parieto-insular vestibular cortex, deep in the posterior end of the insula. The visual temporal sylvian area (VTS) at the posterior end of PIVC receives mainly visual input and only minor vestibular input. (c ⫽ central sulcus, ip ⫽ intraparietal sulcus, 1 ⫽ lateral Sylvian sulcus, ts ⫽ superior temporal sulcus).

Vestibular syndromes and vertigo

Fig. 10.12. Collective presentation of infarcted areas taken from MRI scans and projected onto the appropriate transverse sections of the atlas of Duvernoy (1991) in seven patients with clearly demarcated infarctions of the MCA which caused significant contraversive tilts of perceived vertical. Overlapping areas of infarctions (seven of seven in black) in the section ⫹16 mm above the AC–PC line are centred at the posterior part of the insula, involving the long insular gyrus with the adjacent short insular gyrus, the transverse temporal gyrus and the superior temporal gyrus. This area could represent the human homologue of the PIVC in monkey (see Fig. 10.10).

for their visual ability to adjust a test line to vertical. Skew deviation and OT were also evaluated in order to complete perceptual and ocular motor testing of vestibular function in the roll plane. Infarcted areas shown on CT and MRI were projected onto corresponding transverse sections of the atlas of Duvernoy (1991) to identify the critical structures involved. The aim of the study was to address the following three questions: Are there (one or several) distinct supratentorial areas, a lesion of which causes a directionspecific tilt of the SVV? Is it possible to relate these areas to known vestibular structures as identified in animal experiments? Are pathological tilts of the SVV in supratentorial lesions associated with skew deviation and ocular torsion toward the perceptual tilt? Seventy-one patients with unilateral supratentorial infarctions were evaluated with respect to static vestibular function in the roll plane, including determinations of the SVV, skew deviation, and OT. Infarctions in the territories of the posterior and anterior cerebral arteries did not affect static vestibular function in roll. Twenty-three of 52 patients with infarctions in the middle cerebral artery (MCA) territory showed significant, mostly contraversive, pathological SVV tilts. The overlapping area of these infarctions centered on the posterior insula, probably homologous to the PIVC in the monkey (Fig. 10.12). Although

electrophysiological and cytoarchitectonic data in animals demonstrate several multisensory areas, rather than a single primary vestibular cortex, the PIVC seems to represent the integration centre of the multisensory vestibular cortex areas within the parietal lobe. This is in agreement with recent functional imaging data in humans during caloric and galvanic vestibular stimulation (Bucher et al., 1998; Dieterich & Brandt, 2000).

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Auditory disorders in stroke Robert A. Levine1 and Rudolf Häusler2 1 2

Massachusetts Eye and Ear Infirmary, Harvard University, Boston, USA Department of ENT, Head and Neck Surgery, Inselspital, University of Bern, Switzerland

The auditory and vestibular systems share the same end organ and cranial nerve, yet vestibular signs and symptoms are common with stroke, whereas hearing disturbances are much less frequent. Several reasons would appear to account for this striking dissimilarity. One is that the auditory pathway is less ubiquitous than the vestibular pathways (Nieuwenhuys et al., 1988). The likelihood that a stroke involves the auditory pathway is, therefore, less on this basis alone. A second difference, to our knowledge not previously reported, is that the auditory pathway is often spared by the most common strokes. This is because major parts of the auditory pathways, such as the cochlear nucleus, the inferior colliculus and the medial geniculate body have multiple sources of blood supply (Duvernoy, 1978). A third well-recognized factor is the redundancy of the central auditory system and its strong bilateral representation above the level of the cochlear nuclei (Webster, 1992). Consequently, rostral to the cochlear nuclei, gross deficits in hearing, such as measured by standard pure-tone audiometry and speech discrimination only occur if lesions are bilateral. Furthermore, widespread bilateral lesions of the auditory system typically render the patient unable to respond or are incompatible with life. In contrast, language disorders are more frequent because language is usually unilaterally represented in the cortex. Certainly, cerebral stroke often includes the auditory system, resulting in various types of auditory disorders, but most hemispheral lesions produce subtle hearing dysfunctions that can only be detected with sophisticated psychoacoustical and electrophysiological testing. The purpose of this chapter is to provide an overview of the auditory system and its blood supply and to review how auditory processing can be affected by stroke. Psychoacoustic and electrophysiological test procedures for identifying lesions in the central auditory system are

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described. The literature of hearing disorders due to stroke is reviewed and illustrative cases are presented.

The auditory system and its blood supply Fig. 11.1 is a schematic representation of the afferent central auditory system. Sound passes through the external and middle ear to reach the inner ear, where sensory transduction occurs. The inner ear performs a frequency decomposition of the auditory signal so that the auditory nerve fibres innervating the inner hair cells are frequency selective. Type I auditory nerve fibres, which comprise 95% of all nerve fibres, are excited by inner hair cells. At low or moderate stimulus levels, the approximately 32 000 auditory nerve fibres are tonotopically organized within the cochlear nerve, and this tonotopic organization is a fundamental organizational property throughout the classically described auditory neurological pathway. Those from the base of the cochlea are preferentially responsive to highfrequency components of a sound. The further away a nerve fibre is from the base of the cochlea, the lower the frequency of preferential sensitivity (‘best frequency’). Nerve fibres or cell bodies with similar best frequencies are adjacent, and a systematic distribution of best frequencies is found within any nucleus or fibre tract as well as the auditory cortex. The internal auditory artery is the exclusive arterial supply to the inner ear (Axelsson, 1974; Kim et al., 1990), and in 80% of people, is a branch of the anterior inferior cerebellar artery (AICA). It sometimes emerges directly from the basilar artery, and in about 2–3% of cases it is a branch of the posterior inferior cerebellar artery (PICA). In the internal auditory canal, the auditory nerve also receives collaterals from arteries supplying the dura mater and petrous bone. In the cerebellopontine angle and in the root entry zone, a network of anastamosing vessels

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2 1

3

6 4 8

7 5

10 9 11 12 14 13 15

16 17 18 19

22

20

21 23

24

Fig. 11.1. Schematic depiction of the ascending central auditory system. 1. Planum temporale. 2. Transverse temporal gyrus. 3. Auditory radiations. 4, 5, 6. Medial geniculate body; dorsal, ventral, and medial divisions, respectively. 7. Brachium of inferior colliculus. 8. Superior colliculus. 9. Inferior colliculus, lateral zone. 10. Commissure of the inferior colliculus. 11. Central nucleus of inferior colliculus. 12, 13. Nuclei of lateral lemniscus, dorsal and ventral, respectively. 14. Commissure of Probst. 15. Lateral lemniscus. 16, 17, 18, 19. Superior olivary complex with periolivary, medial, lateral, and trapezoid body nuclei respectively. 20. Trapezoid body. 21. Auditory nerve. 22, 23. Cochlear nuclei, ventral and dorsal, respectively. (From Nieuwenhuys et al., 1988, with permission © Springer–Verlag.)

from the AICA, PICA, and vertebral arteries (e.g. the inferior lateral pontine artery and lateral medullary artery) provide the nerve’s blood supply (Kim et al., 1990; Mazzoni, 1972). The auditory nerve enters the lateral brainstem at the pontomedullary junction. Every type I nerve fibre terminates by splitting into two branches, one for each of the two divisions of the cochlear nucleus: the dorsal cochlear nucleus located dorsolaterally to the restiform body and the ventral cochlear nucleus located ventrolateral to the restiform body. The outputs from the dorsal cochlear nucleus project through the dorsal acoustic stria to the contralateral inferior colliculus; whereas, the ventral cochlear nucleus has multiple projections via the intermediate and ventral acoustic striae, both ipsilaterally and contralaterally, including the opposite cochlear nucleus, the superior olivary complex bilaterally, both lateral lemnisci and the inferior colliculi. The richness of connections of the ventral cochlear nucleus suggests that many auditory functions are processed there. Behavioural studies in experimental animals have thus far found difficulties only with vertical sound localization with lesions of the dorsal cochlear nucleus (Sutherland et al., 1998). The cochlear nuclei receive a rich blood supply from multiple sources including branches of AICA and PICA (Oas & Baloh, 1992). The trapezoid body and superior olivary complex are rostral and medial to the cochlear nuclei in the tegmentum of the lower third of the pons just dorsal to the base of the pons. The superior olivary complex is involved in binaural processing and is composed of several nuclei, the most prominent of which is the medial superior olive (MSO). The MSO receives inputs from both ventral cochlear nuclei and is sensitive to differences in the timing of sounds at the two ears. As the lowest part of the auditory system to receive major inputs from the two sides, the superior olivary complex is also involved in an initial assessment of the intensity differences of the sounds being received from the two sides (Furst et al., 2000). Penetrating branches of the basilar artery or anterior inferior cerebellar artery provide this region’s blood supply (Duvernoy, 1978). Outputs of the superior olivary complex project both ipsilaterally and contralaterally. Some project to the inferior colliculus through the lateral lemnisci while others terminate in one of the nuclei of the lateral lemniscus. The lateral lemnisci extend from the lateral and rostral trapezoid body in the midpons to the inferior colliculi of the tectum of the midbrain. Virtually all ascending and descending auditory tracts synapse in the inferior colliculus. The commissure of the inferior colliculi connects the two inferior colliculi across the quadrigeminal plate, while

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the commissure of Probst connects the dorsal nucleus of the lateral lemniscus to the opposite inferior colliculus. The blood supply of this region is from penetrating branches of the basilar, for the caudal lateral lemniscus and more rostrally from branches of both the superior cerebellar artery and posterior cerebral artery (Duvernoy, 1978). The brachium of the inferior colliculus is a pathway carrying fibres between the inferior colliculus and the ipsilateral medial geniculate body, located in the metathalamus, the caudal subpial portion of the thalamus. This region receives its blood supply through the thalamo-geniculate and posterior choroidal arteries. The auditory radiations pass either through the posterior limb of the internal capsule or sublenticularly to reach the auditory cortex of the temporal lobe (Percheron, 1973). The primary auditory cortex occupies the region of Heschl’s gyrus of the superior temporal lobe. For different individuals, there are likely to be variations in its exact location. Surrounding the primary auditory cortex area are the association cortices extending medially nearly to the insula, posteriorly to the parietal operculum, and anteriorly nearly to the orbitofrontal cortex (Galaburda & Friedrich, 1980; Pandya, 1995). Branches of the middle cerebral artery supply this part of the temporal lobe. Interhemispheric fibres connecting the right and left auditory cortices pass through the posterior corpus callosum, whose blood supply is via the pericallosal artery, a branch of the anterior cerebral artery (Damasio & Damasio, 1979). Paralleling the afferent auditory pathway at all levels is a descending auditory pathway extending from the cortex to the cochlea. These two systems interact at multiple levels (Brodal & Osen, 1981).

Auditory complaints and hearing evaluation Auditory complaints (Table 11.1) It is a common experience that stroke patients seldom complain about hearing. In the vast majority of cases, hearing disorders – even when they are present – are subtle, involving tinnitus, auditory hallucinations, or loss of auditory sensitivity. Patients rarely complain about difficulties with sound localization. In many cases, hearing complaints are overshadowed by more prominent complaints involving other neurological systems; therefore, every patient should be directly questioned for each of the above auditory symptoms. When explicit auditory complaints occur, they may be of diagnostic value. Unilateral

or bilateral deafness may suggest AICA or basilar artery ischemia (Applebaum & Ferguson, 1975; Huang et al., 1993). Hearing deficits are also noted in extensive bilateral lesions of the ascending pathways and in bilateral temporal lobe lesions (Graham et al., 1980; Jerger et al., 1972). Often, hearing loss becomes clinically evident only after sequential infarctions involving both sides have occurred. While hearing loss or tinnitus can be the first symptom of stroke or appear with a latency up to several days, they are rarely symptoms of a transient ischemic attack. Auditory hallucinations have been noted in brainstem (Cambier et al., 1987; Murata et al., 1994) and cortical lesions (Berrios, 1990). Probably the most frequent auditory symptom spontaneously reported by stroke patients is tinnitus. It occurs ipsilaterally with brainstem lesions caudal to the trapezoid body and bilaterally with higher-level lesions. Hyperacusis may occur with midbrain ischemia. Sometimes gross central auditory disorders in stroke are initially mistaken for acute psychosis, aphasia, or peripheral deafness (Case Report 3).

Standard pure tone audiometry and speech discrimination In patients with stroke, hearing evaluation is often restricted to procedures that can be done at the patient’s bedside. When there is suspicion of a hearing problem following a stroke, pure-tone audiometry and speech discrimination tests should be performed, together with the regular otologic examination. One has to bear in mind that, in addition to the neurological event, a peripheral hearing or otologic problem could have been pre-existing. Sometimes unilateral or bilateral hearing impairment or total deafness can result from AICA or basilar ischemia (Huang et al., 1993; Kitamura & Berreby, 1983). A major increase in pure-tone thresholds and a deterioration of speech discrimination scores also can occur in bilateral subcortical and cortical temporal lobe lesions (Case Report 2).

Psychoacoustic methods for the evaluation of central auditory function (Table 11.2) Auditory dysfunction resulting from stroke syndromes varies with the location and extent of auditory pathway infarction. Even if pure tone audiometry and speech discrimination are normal, abnormalities may be present (i) for other types of functions requiring binaural fusion, such as sound localization, or (ii) for more difficult monaural pure-tone or speech tests, such as recognizing distorted

Auditory disorders in stroke

Table 11.1. Auditory symptoms reported in strokes Symptom

Location of ischemia

Hearing loss – Unilateral

Ipsilateral

Cochlea Auditory nerve Cochlear nucleus Acoustic striae

Hearing loss – Bilateral

Bilateral

Cochleae Auditory nerves Cochlear nuclei Acoustic striae Superior olivary complexes Lateral lemnisci Inferior colliculi Brachia of inferior colliculus Medial geniculate bodies Auditory radiations Primary auditory cortices and/or subcortical white matter

Tinnitus – Unilateral

Ipsilateral

Cochlea Auditory nerve Cochlea nucleus Acoustic striae

Tinnitus – Bilateral

Bilateral

Cochleae Auditory nerves Cochlear nuclei Acoustic striae Inferior colliculus (transient)

Unilateral Hallucinations

Pontine tegmentum Midbrain (‘peduncular’) Non-dominant temporal lobe (musical)

Hyperacusis

Unilateral inferior colliculus

stimuli or understanding speech in noise, or (iii) for tests involving competing stimuli to the two ears.

Sound localization and binaural sound lateralization tests Sound localization is based upon (i) differences in the sounds that arrive at the two ears, so called interaural differences, (e.g. differences in the time of arrival or in the intensity of a sound at the two ears) or (ii) upon monaural cues (e.g. the spectral filtering of a sound due to the auricle). Interaural differences or binaural cues are mainly used for left/right localization, while monaural cues are used for vertical and back/front localization. For interaural time or interaural intensity differences, tests under head phones can (i) measure the smallest such difference that a subject can detect reliably (‘just noticeable difference’ or

JND) and (ii) assess a subject’s ability to lateralize (Furst et al., 1995). Patients with brainstem lesions often have highly pathological results in these binaural tests (Furst et al., 2000; Häusler et al., 1983; Häusler & Levine, 1980). Patients with cochlear hearing losses or with unilateral or bilateral cortical lesions usually perform normally. Free-field tests using speakers can also assess sound localization (Häusler et al., 1983). Patients with cortical lesions can have impaired sound localization for the sound field contralateral to the lesion and also with sound localization in the vertical plane (Bocca et al., 1954; Häusler et al., 1983; Pinek et al., 1989; Poirier et al., 1994).

Masking level difference An important binaural function is the detection of one sound in the presence of competing sounds (‘the cock-

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Table 11.2. Psychoacoustic tests of central auditory function Name

Description

I. Tests of brainstem processing (binaural evaluation of fusion) Lateralization of sounds Sounds with interaural time or intensity differences (König, 1964; Häusler & Levine, 1980; Häusler et al., 1983; Furst et al. 1995) Masking level difference (Release from masking). (Hirsch, 1948; Olsen & Noffsinger, 1976)

Speech or pure tone in phase at the two ears plus noise out of phase at the two ears

Binaural fusion (Matzker, 1959)

Low-pass filtered words to one ear and high-pass filtered words presented to the other ear

Alternating speech (Vox alternans) (Hennebert, 1955)

Continuous monaural speech switched from ear to ear every 300 milliseconds

II. Tests of cortical processing (a) Stimulus distortion (monaural evaluation of redundancy) Speech in noise Speech together with background noise at various signal-to(Morales-Garcia & Poole, 1972; Olsen et al., 1975) noise ratios and levels Accelerated speech (Bocca & Calearo, 1963; Beasley et al., 1972)

Time-compressed speech

Retarded speech (Tato & Quiros, 1960)

Time-expanded speech

Filtered speech (Bocca et al., 1954; Willeford, 1987)

Low-pass filtered speech

(b) Competing stimuli (evaluation of ear extinction or hemispheric dominance) Dichotic Listening Test (Vox simultanea) Different stimuli simultaneously at the two ears (consonants, (Feldman, 1960; Kimura, 1961; Fifer & Jerger, 1983; vowels, digits, words, sentences, music etc.) Bergmann et al., 1987; Willeford, 1987)

tail party effect’). The masking level difference, which is measured under headphones, can assess this function by comparing the threshold of a tone presented binaurally in the presence of identical noise at the two ears under two conditions: (a) with the tone in phase at the two ears and (b) out of phase at the two ears. In normal subjects, there is a major improvement in threshold for the out of phase condition. Masking level difference can be abnormal for brainstem lesions (Levine et al., 1994).

Other fusion tests Evaluation of fusion ability can also be tested by presenting non-redundant complementary auditory information to the two ears, e.g. (a) by presenting low-pass filtered words to one ear and the same high-pass filtered words simultaneously to the other ear or (b) by switching a monaural sentence between the two ears every 300 milliseconds. Normal patients are able to fuse the auditory

signals from the two ears and understand the content of the auditory stimulus. This binaural fusion ability is impaired in brainstem lesions and seems to be closely related to the ability to lateralize sounds with interaural differences in time and intensity (König, 1968; Blauert, 1997).

Distorted stimuli Listening tasks with distorted stimuli such as accelerated (Bocca et al., 1954), retarded or decelerated (Tato & Quiros, 1960), and filtered (Matzker, 1959) speech are often poorly performed in patients with temporal lobe lesions, even when pure-tone audiometry and speech discrimination ability are normal. Time-compressed speech recognition has also been reported to be impaired for the ear contralateral to an inferior colliculus lesion, whereas the ability to recognize tone order is preserved (Durrant et al., 1994). Also, speech discrimination in noise typically is impaired

Auditory disorders in stroke

in patients with cortical lesions (Morales-Garcia & Poole, 1972; Olsen et al., 1975).

Competing stimuli Dichotic listening tests consist of simultaneously delivering different stimuli, such as words, sentences or musical stimuli, to the two ears (Feldmann, 1960; Kimura, 1961; König, 1968). Dichotic stimulation creates a perceptual conflict between the two ears. In normal subjects, this test can reveal the dominant hemisphere. In patients with stroke, unilateral lesions of the auditory radiations or cortex typically produce contralateral ear extinction in dichotic testing (Eustache et al., 1990). However, lesions of the dominant hemisphere can sometimes disconnect the auditory areas of the two hemispheres, and thereby produce an ipsilateral, so-called ‘paradoxical’, ear extinction (Damasio & Damasio, 1979).

Extensive psychophysical evaluation of central hearing function Specialized laboratories perform in-depth psychophysical analysis of impairments of pitch, duration or rhythm perception, and more complex percepts such as phonemes, musical and environmental sounds (Keith, 1994). Higher level auditory processing including lexical, semantic and syntactic capacities or even aesthetic features, can also be studied. Deficits in performance have been correlated with specific regions of infarctions (Eustache et al., 1994; Praamstra et al., 1991; Peretz, 1985).

Electrophysiological evaluation of central auditory function Acoustically evoked potentials and electroacoustic tests such as stapedial muscle reflex measurements and otoacoustic emissions provide an objective measure of central auditory function. These electrophysiologic measurements are especially informative when used in association with psychoacoustic test procedures.

responses (BAERs) consist of up to seven waves occurring within 10 milliseconds of the click stimuli (Jewett et al., 1970). Waves I, III and V are the most reliable. These waves reflect mainly neuronal activity in the auditory nerve (wave I), the spherical cell projection from the ventral cochlear nucleus to the superior olivary complex (wave III), and the contralateral lateral lemniscus or inferior colliculus (wave V) (Durrant et al., 1994; Levine et al., 1993b; Melcher & Kiang, 1996). BAERs can distinguish between pathologies of the middle and the inner ear, the auditory nerve, as well as brainstem lesions. Waves may be absent due to nonresponsive or desynchronized neurons. It is interesting to note that a close relationship exists between these electrophysiological measurements and psychoacoustic functions that require precise neuronal timing. For instance, the synchronization and latencies of the BAER waves are closely related to the ability to discriminate interaural time differences, suggesting that acoustic timing information is contained in the precise latencies of the brainstem potentials (Häusler & Levine, 1980). Middle latency responses (MLR) are recorded with a latency of between 10 and 50 milliseconds (Geisler et al., 1958). In part, they are generated by the auditory cortex. Long latency cortical responses (LLR) occur between 50 and 500 milliseconds following the stimulus and are mainly generated in the auditory cortex. MLR and cortical responses are abolished when the cortical or subcortical auditory areas are damaged bilaterally, giving rise to the clinical picture of central deafness. In unilateral or partial bilateral lesions, they usually remain normal. Special stimulus paradigms permit the recording of ‘endogenous’ long latency responses, which appear to relate to specific higher auditory processing. Attention to acoustic stimuli can be evaluated by the ‘cognitive potential’ (P-300) occurring at a latency of about 300 milliseconds after the stimulus (Sutton et al., 1965). P-300 is very sensitive to diffuse ischemia even when there is no overt cognitive decline (Jacobson et al., 1997).

Stapedius reflex measurements Auditory evoked potentials Electrical brain activity elicited by acoustical stimuli, the so-called auditory evoked potentials (AEP), can be measured with electrodes placed on the surface of the head (Kiang, 1961). AEPs consist of a series of waves that are classified into early, middle and late responses according to their latency after the acoustic stimulus. They are generated by subpopulations of neurons that respond synchronously to the acoustic stimulus. Early potentials, also called brainstem auditory evoked

With electroacoustic impedance measurements, stapedius muscle contractions can be readily detected in response to ipsilateral or contralateral sound. Thus, within minutes, objective information about the functional state of the middle ear, the inner ear, the auditory nerve, the facial nerve, and the central auditory pathways in the lower brainstem can be obtained. Ipsilateral and contralateral measurements can distinguish between right, left and mid-line lesions involving the lower brainstem (Hayes & Jerger, 1981).

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Otoacoustic emissions A microphone within the external auditory canal can detect acoustic output from the cochlea in response to either transient or continuous sounds. These ‘evoked otoacoustic emissions’ can be modulated by sounds presented to the opposite ear via the auditory efferent system of the caudal pons including the olivocochlear bundle, which reaches the cochlea via the vestibular nerve. Contralateral modulation of otoacoustic emissions can be abolished by brainstem lesions (Probst & Harris, 1997).

Stroke syndromes involving the auditory pathways (Table 11.3) Auditory symptoms in brainstem strokes The auditory symptoms associated with brainstem stroke include hearing loss, phantom auditory perceptions (tinnitus/hallucinations), and hyperacusis. These may be associated with widespread ischemia due to vertebrobasilar occlusive disease or large hemorrhage or with focal disease due to penetrating artery occlusion or small hemorrhage. Hyperacusis, which means increased sensitivity to sounds, is always bilateral, but hearing loss or tinnitus can be either bilateral or unilateral. Because the trapezoid body is a major auditory decussation, ischemia at or rostral to the trapezoid body generally will result in non-lateralized symptoms, whereas symptoms related to more caudal ischemia, due to lesions of the acoustic striae, cochlear nucleus, auditory nerve, or cochlea, will be strictly localized to the ipsilateral ear. Hyperacusis is the least common of the auditory complaints; it has been reported for a patient with a bilateral tectal midbrain hemorrhage (Sand et al., 1986) and transiently in a case with a stroke presumably involving the medial caudal pontine tegmentum including the trapezoid body (Cambier et al., 1987). By contrast, ‘in lower brainstem ischemia due to vertebro-basilar disease and in other processes as well, assorted auditory hallucinations of a minor nature are not rare (Fisher & Tapia, 1987)’. Phantom auditory perceptions that have been associated with brainstem ischemia have been described as either tinnitus or auditory hallucinations. Aside from when they are musical, the distinction between tinnitus and hallucinations would appear to be largely semantic, since the ‘hallucinations’ have been described in terms similar to those used to describe the tinnitus resulting from ear or auditory nerve disease such as ‘buzzing bees’, ‘organ notes’, ‘seashell’, ‘bells chiming’, ‘grinding noises’, or ‘roaring’ (Cascino & Adams, 1986; Fisher & Tapia, 1987). A few cases of musical

hallucinations, occasionally with verbal hallucinations, have been reported with brainstem stroke (Cambier et al., 1987; Lanska et al., 1987; Murata et al., 1994). All were transient, and most involved the caudal pontine tegmentum unilaterally with ischemia or hemorrhage. One case has been clinically localized to the region of the inferior colliculus (Cambier et al., 1987). Peduncular hallucinations can occur with midbrain strokes, but they are predominantly visual with an occasional minor auditory component, such as seeing people who are ‘whispering’ (Cambier et al., 1987; Kolmel, 1991).

Large vessel occlusion Tinnitus and hearing loss can occur with vertebro-basilar disease. Sudden onset of unilateral or bilateral deafness usually accompanied by dizziness or vertigo can be a sign of basilar artery occlusive disease. However, transient ischemic attacks involving auditory symptoms with hearing loss or tinnitus would appear not to occur, rather hearing loss is followed by other symptoms within a week (Huang et al., 1993; Oas & Baloh, 1992). Bilateral sudden hearing loss with vertigo and tinnitus has a poor prognosis, whereas without vertigo, especially if the hearing loss is mild, the prognosis is more favorable (Huang et al., 1993). Sudden unilateral hearing loss with vertigo frequently occurs with anterior inferior cerebellar artery occlusion proximal to the internal auditory artery. Incomplete hearing loss or hearing loss without vertigo is probably not due to internal auditory artery occlusion (Huang et al., 1993; Oas & Baloh, 1992). Posterior inferior cerebellar artery ischemia generally does not produce any auditory symptoms because PICA generally does not perfuse any of the auditory pathway (Fisher & Tapia, 1987). The ‘classical’ case of superior cerebellar artery occlusion includes the description that ‘on the other side [there was] deafness (Mills, 1912)’. However, no subsequent reports have described deafness from strokes involving the superior cerebellar artery. In fact, despite lateral lemniscus or inferior colliculus infarction in more than half the reported cases of superior cerebellar artery occlusion, no auditory complaints have been described (Amarenco & Hauw, 1990). Similarly, posterior cerebral artery ischemia can involve the brachium of the inferior colliculus or medial geniculate body, but auditory symptoms have not been reported (Tatemichi et al., 1992).

Hemorrhage Sudden unilateral deafness and intense vertigo can be signs of an intralabyrinthine hemorrhage. These can occur in the setting of a bleeding diathesis such as leukemia (Paparella et al., 1973).

Table 11.3. Hearing abnormalities that may occur as related to level of auditory system involvement in stroke Speech Location

Evoked

Stapedius

Otoacoustic

Audiogram

discrimination

Psychoacoustic testing

potentials

reflex

emissions

Hearing loss (I)

Elevated

Impaired (I, ⫹/⫺)

Distortion tests impaired (I)

Absent (I)

Absent (I)

Absent (I)

Tinnitus (I, ⫹/⫺)

Thresholds (I)

Reported symptoms

Unilateral Cochlea Auditory nerve Cochlear nucleus Superior olivary complex

Hearing loss (I)

Elevated

Tinnitus (I, ⫹/⫺)

Thresholds (I)

Hearing loss (I)

Elevated

Tinnitus (I, ⫹/⫺)

Thresholds (I)

Hearing loss (I)

Elevated

Tinnitus (I, transient)

Thresholds (I, ⫹/⫺)

Fusion & dichotic (⫹/⫺) Impaired (I) Impaired (I) Impaired (I, ⫹/⫺)

Present (C)

Distortion tests impaired (I)

I normal (⫹/⫺)

Absent (I)

Present (I)

Fusion & dichotic impaired

III, V abnormal (I)

Present (C)

Present (C)

Distortion tests impaired (I)

I normal

Absent (I)

Present (I)

Fusion & dichotic impaired

III, V abnormal (I)

Present (C)

Present (C)

Fusion

I normal;

Impaired (⫹/⫺) Present (I)

impaired

III, V abnormal (I)

Fusion

V abnormal

Normal (I)

Normal (I)

impaired

bilaterally

Absent (C)

Abnormal (C)

Fusion

V abnormal (C)

Normal

Normal

V abnormal (C)

Normal

Normal

BAERs normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Abnormal (C)

Hallucinations (⫹/⫺) Trapezoid body Lateral lemniscus

None None

Normal Normal

Normal Normal

impaired Inferior colliculus

Tinnitus (⫹/⫺)

Normal

Normal

Hyperacusis (⫹/⫺) Brachium of IC and

None

Fusion impaired

Normal

Normal

medial geniculate body Auditory radiations and auditory cortex

MLR abnormal Difficulties in

Fusion normal

BAERs normal

adverse listening

Normal

Normal (⫹/⫺)

Dichotic & distortion tests

MLR abnormal

conditions

abnormal (C)

LLR abnormal

Normal or

Dichotic

BAERs normal

Unable

impaired

MLR abnormal

Hallucinations (⫹/⫺) Intrahemispheric connections

Speech, music

Normal

or environmental sound (⫹/⫺)

LLR abnormal

Bilateral Lateral lemniscus and

Deaf

inferior colliculus

Elevated

Unable

Thresholds

Bilaterally

Unable

I, III normal; V abnormal MLR abnormal LLR abnormal

Brachium of IC,

Deaf

medial geniculate body and

Elevated

Unable

Unable

Thresholds

MLR abnormal

primary auditory cortex Interhemispheric connections

BAERs normal LLR abnormal

Difficulties in

Normal

adverse listening conditions

Notes: I ⫽ ipsilateral. C ⫽ contralateral. ⫹/⫺ ⫽ sometimes.

Normal

Dichotic

BAERs normal

impaired

MLR normal LLR normal

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Smaller brainstem hemorrhages, in which alertness is maintained, may be associated with hearing loss, hallucinations (usually musical) and tinnitus (Obach & Obach, 1996). Those involving the caudal pons can have hearing impairment and hallucinations that can be either unilateral or bilateral (Cascino & Adams, 1986; Lanska et al., 1987). The hallucinations are usually lateralized only when the hearing loss is unilateral. Sound localization is frequently impaired (Cambier et al., 1987; Lanska et al., 1987). Typically, the auditory symptoms are transient. Wave V of the BAERs is always abnormal and sometimes wave III is abnormal on the side with the hearing loss (Lanska et al., 1987). The contralaterally evoked stapedial reflexes are abnormal (Egan et al., 1995). While no detailed analyses of hemorrhage location and auditory findings have been reported, studies with other types of lesions and animal studies suggest that the more lateral lesions are associated with unilateral hearing loss and affect wave III from involvement of the superior olivary complex and/or the auditory striae. Some patients with midbrain hemorrhages involving the tectum report either bilateral tinnitus or bilateral hyperacusis, even with unilateral tectal involvement. The tinnitus has always been reported as transient and the hyperacusis persistent (Link et al., 1993; Sand et al., 1986). Right posteromedial thalamic hemorrhages have been associated with transient left auditory neglect (Motomura et al., 1986).

Small vessel occlusion Internal auditory artery The arterial blood supply to the inner ear is provided by a single vessel, the internal auditory artery arising from AICA in most cases (Kim et al., 1990; Mazzoni, 1972). Experimental transitory occlusion of the internal auditory artery produces complete cessation of auditory function within minutes (Levine et al., 1993a) and irreversible degeneration of the cochlea. The apical cochlear region is particularly vulnerable (reflected as low frequency loss) and the vestibular end organ is somewhat more resistant (Perlman et al., 1959; Schuknecht, 1993). While bilateral sudden deafness with vestibular symptoms often is a sign of vertebrobasilar occlusive disease (Huang et al., 1993), unilateral sudden deafness as an isolated neurological event is rarely due to internal auditory artery or vertebrobasilar occlusion. Most patients with sudden deafness are young or middle-aged and have no risk factors for vascular disease. Pathologic inner ear studies of unilateral sudden deafness typically show alterations similar to those seen after viral infections, such as mumps or measles, with atrophy of the sensory organ and

without vascular occlusion (Schuknecht et al., 1973). Only isolated pathological reports of sudden deafness have identified a vascular occlusion of the internal auditory artery (Kitamura & Berreby, 1983). Unilateral sudden deafness can be produced by vascular lesions in association with systemic vascular disease, such as leukemia (Schuknecht et al., 1965), Buerger’s disease with thromboangitiis obliterans (Kirikae et al., 1962), macroglobulinemia (Ruben et al., 1969), or fat emboli and hypercoagulation (Jaffe, 1970). Sudden deafness has also been reported as a presumably embolic phenomenon following cardiac and abdominal surgery (Guillemin et al., 1988).

Penetrating branches Penetrating branch artery disease results in small limited subcortical infarcts. Auditory complaints in general are infrequently reported for these strokes. One reason appears to be the richness of collateral blood supply to the regions of the auditory nerves, cochlear nuclei, inferior colliculi, brachia of the inferior colliculus, and medial geniculate bodies. Consequently, single small vessel occlusions generally spare these regions (Bassetti et al., 1996). We are not aware of any well-established cases with small vessel occlusion affecting the cochlear nucleus. One case has been studied pathologically with a lateral medullary infarct extending into the lower pons in the region ‘just medial to the 7th nerve nucleus and lateral to the position of the 6th nerve nucleus which actually lay slightly rostral to the superior border of the infarct (Fisher & Tapia, 1987)’. This patient, who survived only 2 days, presented with intermittent roaring and impaired hearing of the ipsilateral ear. This description suggests the infarct involved the ventral acoustic striae and/or the superior olivary complex. Infarcts of the pons involving the trapezoid body or lateral lemniscus have not been reported to be associated with auditory complaints (Bassetti et al., 1996) or abnormal audiometry (Aharonson et al., 1998), yet tests of sound lateralization are abnormal (see Case Report 1). Patients with infarcts involving the trapezoid body tend to hear all sounds towards the middle (‘centre-biased’), while patients with infarcts involving the lateral lemniscus tend to hear all sounds toward the sides (‘side-biased’) (Furst et al., 2000). While isolated ischemic infarcts of the midbrain have not been reported to involve the inferior colliculus (Bogousslavsky et al., 1994), one case of unilateral necrosis of the right inferior colliculus has been described in a woman with an arteriovenous malformation that had bled

Auditory disorders in stroke

and subsequently was irradiated. She complained of difficulty using the telephone with her contralateral ear. A battery of hearing tests were normal including pure tone thresholds and speech discrimination. All testing of her ipsilateral ear was normal. Wave V of her BAERs was abnormal for contralateral ear stimulation (Durrant et al., 1994). Another case of small traumatic hemorrhage to the right inferior colliculus has recently been reported. Wave V was similarly abnormal. Suppression of the perception of echoes (‘the precedence effect’) was degraded and freefield sound localization was abnormal for the contralateral sound field only (Litovsky et al., 2000). The brachium of the inferior colliculus has been involved by small infarcts, but no auditory symptoms have been reported (Tatemichi et al., 1992). We have not found reports of small infarcts involving the medial geniculate body.

Auditory syndromes in hemispherical strokes Syndromes of elementary central auditory disorders such as cortical deafness (Lichtheim, 1885), pure word deafness (Kussmaul, 1877a,b), auditory agnosia for environmental sounds (Freud, 1953) and amusia (Steinhals, 1871) have been recognized for more than a century on the basis of clinical observations and post mortem studies. More systematic evaluation of central auditory dysfunction became possible in the middle of the twentieth century when electroacoustic equipment became available (Jerger, 1960a,b). In the 1970s, electrophysiological tests were introduced in the clinic, especially the technique of auditory evoked potentials, which allowed one to distinguish a peripheral from a central auditory disorder and also provided some localization of the lesion. CT scanning became available about the same time and allowed anatomical localization of lesions. This was followed a decade later by MRI scanning, which has provided very precise central nervous system anatomy. Presently, newer imaging techniques such as PET and functional MRI confer precise functional and anatomical insights into central auditory processing in normal and pathologic states (Melcher et al., 1999; Zatorre et al., 1992).

Cortical deafness Cortical deafness is a rare condition occurring with bilateral temporal lobe lesions (Wernicke & Friedländer, 1883) or with bilateral subcortical lesions interrupting the ascending auditory pathways (Musiek & Lee, 1998). In cortical deafness, patients appear deaf, though some reflex responses such as turning toward a sudden loud sound

may be preserved. With time, some auditory capacities may re-emerge. Other patients remain permanently deaf (see Case Report 2). LLR are abolished in cortical deafness. MLR are usually also abolished or impaired. BAERs and acoustic reflexes are preserved.

Hemianacusia Unilateral cortical temporal strokes produce subtle hearing dysfunction. Pure-tone thresholds and speech discrimination remain largely preserved; dysfunction becomes apparent in tests with distorted and dichotic stimuli. Unilateral cortical lesions produce contralateral ear extinction. Sound localization is impaired in the sound field contralateral to the impaired temporal lobe and also in the vertical plane (Häusler et al., 1983). There exist, in addition, differences between right and left lesions. Eustache et al. (1990) observed, in a patient with a left temporoparietal ischemic lesion, difficulties in understanding verbal stimuli and in identifying melodies in addition to right ear extinction to dichotic testing. Another patient with right internal capsule and frontal lesions had great difficulty discriminating environmental sounds and melodies. He also had left ear extinction with dichotic testing, but intact naming and identification. Robin et al. (1990) describe a series of patients with unilateral temporal lobe infarcts. Those with left temporal infarcts had normal spectral performance but impaired temporal discrimination, and those with right temporal infarcts had normal temporal discrimination but impaired spectral performance. BAERs, MLR and LLR are generally preserved in unilateral cortical lesions.

Auditory agnosia In its most general sense, auditory agnosia refers to impaired perception restricted to certain classes of sounds. For example, word (or verbal) deafness, the most striking type of auditory agnosia, is the incapacity to recognize speech sounds. Pure word deafness (i.e. word deafness without other features of aphasia) is rare. Patients rely on lip-reading and writing for communication. Tonal audiometry is usually preserved, but speech discrimination is abolished. BAERs, MLR, and LLR are preserved. An example of pure word deafness is presented in Case Report 3. Word deafness mostly occurs from bilateral temporal lesions interrupting the connections from the two primary auditory cortices to Wernicke’s area. Occasionally, pure word deafness is produced by a posterior unilateral temporal lobe lesion, when the lesion isolates Wernicke’s area from bilateral primary auditory cortex input (Kanter et al., 1986; Praamstra et al., 1991). Phonagnosia describes the inability

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(a)

(c)

(b)

(d)

Fig. 11.2. Sound lateralization centre-biased with trapezoid body stroke. Imaging, electrophysiological and behavioral studies from an audiometrically normal 80-year-old man, one year following a pontine penetrating branch infarct. He had no auditory complaints, yet his ability to lateralize sounds was markedly impaired. (a) Axial and sagittal T2-weighted MRI sections through the mid-pons, showing the infarct (outlined by open arrowheads). (b) Location of the infarct vis-à-vis the auditory pathway. Schematic coronal projection of the pontine auditory pathway with region of infarct (left trapezoid body) shaded. (c) Right and left BAERs normal. Monaural 65 dB SL alternating polarity clicks; nasion–inion recordings. (d) Position of sound as indicated by patient’s selection of one of the nine possible locations (y-axis) vs. the nine presented interaural level differences for low-frequency narrow-band noise (x-axis) for 56 trials. Each small dot represents a trial. Unlike normal subjects whose responses fall on or near the diagonal (shaded region), this patient’s responses (solid circles) were highly abnormal; he always indicated that sounds were perceived at or near the center (Furst et al., 2000).

to identify a speaker by his/her voice. Amusia refers to a disorder of music perception, such as impaired ability to recognize melodies. Well-documented amusia with preserved perception of tone, pitch and intensity is only exceptionally reported. More often, amusia is associated with other types of auditory agnosia. Amusia is commonly associated with right temporal lesions, but left-sided impairments also may

produce musical perception disorders, in particular, in professional musicians, especially melody and written music identification. There are reports of professional musicians who, following a left-sided hemispherical stroke with Wernicke’s aphasia, retained their pre-morbid musical capacities (Peretz, 1985; Eustache et al., 1994). Finally, sometimes the term auditory agnosia is used to refer to an

Auditory disorders in stroke

impaired ability to hear various types of environmental sounds (Eustache et al., 1994). Such agnosia usually results from non-dominant or bilateral temporal lobe damage.

C A S E R E P O RTS Case report 1 Impaired sound lateralization in a patient with a lower pontine lacunar infarct involving the trapezoid body; all sounds were heard toward the middle (‘centre bias’). An 80-year-old man presented with sudden onset of vertigo and vomiting. On examination, he was found to have a left gaze palsy, dysphagia, dysarthria, and a right hemiplegia that included only the lower face. He had no auditory complaints, and his bedside hearing evaluation was unremarkable. An MRI scan revealed a pontine infarct. A year later, he was evaluated with a battery of hearing tests and a repeat MRI scan (Fig. 11.2). Despite an age appropriate audiogram and normal BAERs, all fusion tests were abnormal for the three stimuli used (clicks, low-pass noise, and high-pass noise) and for interaural time or level disparities. Just noticeable differences were highly abnormal, and regardless of the size or type of interaural disparity, the patient indicated that everything sounded as though it were coming from or near the center of his head. Unlike normal subjects, nothing was heard coming from the far right or left. When mapped onto an atlas of the auditory pathway, his infarct was localized to the left trapezoid body (Aharonson et al., 1998; Furst et al., 2000). Case report 2 Cortical deafness in a patient with traumatic bilateral internal capsule hemorrhages A 20-year-old man was referred for cochlear implants because of bilateral deafness following a motorcycle accident two years earlier. He was initially comatose and CT showed hemorrhagic lesions involving both internal capsules (Fig. 11.3). After several weeks of coma, he awoke quadriparetic, cognitively impaired, and totally deaf. However, he occasionally turned his head towards a sudden loud sound. He used lip-reading for communication. He was able to read and write. Speech was dysarthric, but comprehensible. Pure tone audiometry and speech discrimination measurements confirmed total deafness (Fig. 11.4). Normal tympanograms and stapedial reflexes suggested, however, that the middle and inner ear, and the auditory nerve were intact. A normally functioning inner ear and auditory nerve were also confirmed by evoked responses with normal auditory nerve potentials (N-1 of the

Fig. 11.3. Axial CT scan sections of a patient (male, 20 years; case report 2) with cortical deafness showing a hyper dense lesion at the level of both internal capsules due to traumatic hemorrhages. Psychoacoustical and electrophysiological test results of this patient are shown in Fig. 11.4.

electrocochleogram) with a threshold estimate of 10 dB nHL bilaterally. BAERs showed normal Waves I–III, but an abnormal complex IV–V, suggesting functioning auditory pathways in the lower brainstem and a lesion in the midbrain. Late cortical responses were abolished. Based on these findings, it was concluded that the patient had cortical deafness due to bilateral interruption of the ascending auditory pathway associated with hemorrhagic lesions of both internal capsules. Cochlear implantation was not performed. Case Report 3 ‘Pure’ word deafness in a patient with bilateral temporal lobe infarctions A 64-year-old woman with a history of several minor strokes was admitted to psychiatry because of the onset of sudden agitation and failure to respond to speech despite hearing and responding to other sounds appropriately. She was able to write spontaneously and

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Fig. 11.4. Psychoacoustical and electrophysiological hearing evaluation of a patient (male, 20 years; case report 2) with cortical deafness following traumatic bilateral capsula interna hemorrhages. The pure-tone audiogram shows bilateral, complete deafness. The tympanogram as well as the stapedial reflex thresholds are normal and there is a normal auditory nerve potential on electrocochleography (ECochG) on both sides, suggesting a normally functioning middle ear and normally functioning cochlea and auditory nerves. BAERs have normal waves I–III, but an abnormal complex IV–V on both sides, suggesting normal functioning auditory pathways in the lower brain stem and a lesion in the mid-brain and the diencephalon. Late cortical responses are abolished. Based on these findings, it was concluded that the patient had cortical deafness due to bilateral interruption of the ascending auditory pathways, compatible with the hemorrhagic lesions of the internal capsulas, as observed on the CT scan shown in Fig. 11.3.

Auditory disorders in stroke

Fig. 11.5. Results of hearing tests and AEP recordings of a 64-year-old woman (case report 3) presenting pure word deafness due to sequential bilateral temporal lobe infarctions. Despite nearly normal pure tone thresholds, speech discrimination is 0% in both ears. BAERs and late cortical responses are normal, suggesting a functioning inner ear and functioning ascending auditory pathways, up to the auditory cortex. CT scan section of the same patient is shown in Fig. 11.6.

read with comprehension. Speech was fluent but accompanied by a moderate phonemic paraphasia. Repetition of words and writing to dictation could not be done. She used lip-reading for communication. The result of the hearing tests performed and the AEP recordings are shown in Fig. 11.5. Despite nearly normal pure tone thresholds, speech discrimination was 0% in both ears. Normal stapedial reflexes, BAERs and cortical AEPs,

suggested a functioning inner ear and functioning ascending auditory pathway up to the auditory cortex. Cognitive evoked potentials (P-300) for each ear were abnormal. A CT scan showed extensive hypo dense lesions in both temporal lobes (Fig. 11.6). It was concluded that the patient had an auditory agnosia for speech (⫽pure word deafness) due to her bilateral temporal lobe infarcts.

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iAcknowledgmentsi We would like to express our gratitude for secretarial help to E. Clamann and B. Norris. We acknowledge the help of Norris in making Fig. 11.2. We thank Drs Furst, Aharonson, Pratt and Korczyn for providing the clinical details of Case Report 1.

iReferencesi

Fig. 11.6. Axial CT scan section of a 64-year-old woman (case report 3) suffering pure word deafness due to sequential, bilateral temporal lobe infarctions. The CT scan shows extensive hypo dense lesions in both temporal lobes. Auditory test results and AEP recordings of the same patient are shown in Fig. 11.5.

Conclusions The auditory symptoms and findings for unilateral and bilateral strokes involving different levels of the auditory pathway are summarized in the Tables 11.1 and 11.3. These tables are based on cases reported in the literature and our personal observations. The entries in these tables, however, must be considered provisional as more and more systematic observations of the neurology of hearing expand our knowledge.

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Abnormal movements Joseph Ghika and Julien Bogousslavsky Department of Neurology, University of Lausanne, Switzerland

Introduction Acute, paroxysmal, recurrent, transient, permanent, or delayed movement disorders have been occasionally reported in the acute phase of stroke as well as after a delay up to months or years. Almost any type of hyperkinetic or hypokinetic movement disorder has been reported, most commonly as hemi- or focal dyskinesia. Only isolated case reports or very small series can be found in the literature, and few epidemiologic studies (D’Olhaberriague et al., 1995; Ghika-Schmid et al., 1997) have been performed in order to estimate the prevalence of movement disorders in cerebrovascular disease. However, what is clear in all studies, is the demonstration that any kind of dyskinesia can be found in lesions at any level of the motor frontosubcortical circuits of Alexander et al. (1986), including the sensorimotor cortex, caudate, putamen, pallidum, subthalamic nuclei, thalamus and brainstem and interconnecting pathways (for review, see Bhatia & Marsden, 1994).

Hypokinetic movement disorders Parkinsonism associated with small vessel disease (‘vascular parkinsonism’) Parkinsonism of vascular origin is a controversial entity. Only 2% of patients with cerebral infarcts may have a parkinsonian syndrome (De Reuck et al., 1980; Struck et al., 1990; Takeuchi et al. 1992). Hypertension is found in 22% of patients with parkinsonism (Marttila & Rinne, 1976, 1977). The association of ‘arteriosclerosis’ and parkinsonism has been studied, but does not seem to be significant (Eadie & Sutherland, 1964; Escourolle et al., 1970; Marttila & Rinne, 1976; Schneider et al., 1977; Kim et al., 1981; Horner et al., 1997; Homann & Ott, 1997). Critchley (1929) introduced

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the concept of ‘arteriosclerotic parkinsonism’, characterized by clinical and pathologic criteria, but his definition of this ‘disorder of the pallidal system’ with ‘general rigidity of non-pyramidal type, weakness and slowness of movement’ is somewhat different from what is accepted in the definition of the parkinsonian syndrome (requiring at least two items of bradykinesia, tremor, rigidity and loss of balance or postural responses). In the 1960s and 1970s, the concept of vascular parkinsonism was discarded (for review, see Schwab & England 1968; Parkes et al., 1974). However it is well recognized (since CT and MRI are available), that diffuse lesions of the hemispheric white and/or grey matter, lacunar states, senile or hypertensive leukoencephalopathy, or multiple infarcts can present with bradykinesia, akinesia, mixed features of rigidity and spasticity, loss of balance or gait disorder, which can be easily confused with a parkinsonian syndrome. As pointed out by Critchley (1929), ‘incomplete forms are more common’, and generalized rigidity (‘arteriosclerotic rigidity’ of Foerster 1909), pure akinesia or bradykinesia can be found. The ‘syndrome strié du vieillard’ of Lhermitte (1922), or ‘arteriosclerotic pseudoparkinsonism’ (Critchley, 1981) has also been widely reported by others (see Critchley, 1929 for summary) (Foerster, 1909; Hughes et al., 1954; Schwab & England, 1968; Parkes et al., 1974; Fahn, 1977; De Reuck et al., 1980; Koller et al., 1983; Tolosa & Santamaria, 1984; Kinkel et al., 1985; Friedman et al., 1986; Steingart et al., 1987; Thompson & Marsden, 1987, Dubinsky & Jankovic, 1987; Fitzgerald & Jankovic, 1989; Murrow et al., 1990; Chang et al., 1992; Tison et al., 1993; Bhatia & Marsden, 1994; Inzelberg et al., 1994; Zijlmans et al., 1994, 1995, Scott & Jankovic, 1996, Yamanouchi & Nagura, 1997; van Zagten et al., 1998), but the limit between this entity and ill-defined ‘senile gait disorders’ or ‘lower body parkinsonism’ still remains to be delimited (Fitzgerald & Jankovic, 1989; Achiron et al., 1993; Atchison

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et al., 1993; Nutt et al., 1993). Strategic infarcts or hemorrhage in the mesencephalon can lead to true vascular parkinsonism (Inoue et al., 1997). The parkinsonism reported in association with cerebrovascular lesions correspond to a clinical entity, which is different from the parkinsonian syndrome of degenerative origin. Generally the symptoms tend to be generalized and not lateralized initially, with ictal, slowly progressive, stepwise or insidious onset or progression. Pseudobulbar signs (‘pseudobulbar parkinsonism’ or ‘progressive pyramido-pallidal degeneration’ of Lhermitte (1921), brisk reflexes, Babinski signs, sphincter incontinence and dementia are commonly associated, but ataxia is less frequent. Tremor is characteristically absent (‘sine agitatione’) unless the patient has essential tremor (Critchley, 1929, 1981), but has been reported (Holmes, 1904). The rigidity is generally ‘sticky’ or ‘lead pipe type’ with no cogwheel, characteristically variable in degree (with paratonia or gegenhalten), and the topographic distribution of the hypertonia is more suggestive of spastic antigravity muscles than in parkinsonism. Bradykinesia, akinesia, and hypokinesia are typically found. Micrography has also been reported but, when performing rapid alternating movements, frequent synkineses or mirror movements are common. Hypophonic, dysarthric, monotonous, monosyllabic or elliptic speech may be present, and sometimes frank mutism. Features of bulbar speech can be found. A ‘mask facies with an expression of bewilderment, elevated eyebrows, retracted lids and gaping mouth, accounting for a mixture of spastic and extrapyramidal face’ (Critchley, 1929) has been reported, but sebaceous secretion is generally absent. The ‘marche à petits pas’ or Petren gait (Petren, 1901, 1902) can sometimes be confused with parkinsonian gait; however, stooped posture and excessive flexion of hip and knee are usually absent, both arms are frequently held rigidly away from the sides, with variable loss of armswing. Associated movement occurs at the shoulder joint, and en-bloc turn is present, the steps being exceptionally short (‘one toe advances in front of the other’) and the feet are not lifted from the ground, but festination and propulsion generally do not occur, and the base is not massively increased. Apraxia and magnetism of the feet to the ground can be found. Tandem gait is generally impossible. Retropulsion can be massive. The overall extrapyramidal syndrome predominates in the lower body (‘lower body parkinsonism’, Fitzgerald & Jankovic, 1989) and in the proximal segments of the limbs, usually symmetrically. Dubinsky and Jankovic, (1987) and Winitaker and Jankovic (1994) described a syndrome resembling progressive supranuclear palsy in a patient with a multiinfarct state. A history of hypertension and/or diabetes is present in

Fig. 12.1. Parkinsonism and gait disorders. Synopsis of reported lesions.

most patients and the CT or MRI images clearly show multiple small deep infarcts and white matter changes. Some dilatation of the ventricles and cerebral atrophy are often observed. Convincing cases of sudden parkinsonian syndrome of vascular etiology with bilateral basal ganglia ischemic lesions include patients with bilateral thalamic infarcts (Denny-Brown, 1962; De Reuck et al., 1980; Tolosa & Santamaria, 1984), bilateral putaminal infarcts (Lhermitte & Cornil, 1921; Lhermitte, 1922; Friedman et al., 1986; Tolosa & Santamaria, 1984), bilateral caudate infarcts (Tolosa & Santamaria, 1984; Hughes et al., 1954). In any event, while the clinical picture of atypical parkinsonian syndromes in a patient with multiple vascular lesions on CT and MRI does exist, the diagnosis of vascular parkinsonism is essentially made by exclusion, and the final diagnosis can only be made on pathological examination (Fig. 12.1). Few pathological studies show ischemic involvement of the substantia nigra in status cribrosus, multilacunar state, hypertensive or senile leukoencephalopathy, but the striatum is generally involved (Escourolle et al., 1970; De Reuck et al., 1980). Denny-Brown (1962) reported vascular lesions in the putamen in one-third of patients with ‘diffuse microangiopathic disease’. In other studies, however, there were Lewy bodies in the substantia nigra of patients with cerebrovascular disease and parkinsonism, showing difficulty in separating both entities without pathological studies (Escourolle et al., 1970). The absence of response to antiparkinsonian medication relates to postsynaptic damage with involvement of striato-pallidal structures, making it difficult to differentiate this condition from multiple system atrophy.

Senile gait disorders Higher level gait disorders (Sudarsky & Ronthal, 1983; Thompson & Marsden, 1987, Nutt et al., 1993; Thajeb, 1993) can be found in patients with generalized small vessel disease.

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‘Subcortical disequilibrium’ is characterized by disequilibrium with absent or inefficient postural responses with hyperextension of axial muscles with retropulsion, but stepping is possible. Astasia-abasia, thalamic astasia (Masdeu & Gorelick, 1988) or tottering are synonymous for this type of gait disorder, which can be acute or insidious with lesions in basal ganglia, thalamus, and midbrain. ‘Frontal disequilibrium’ or trunk or gait apraxia, frontal apraxia of Bruns, or astasia–abasia is defined by disequilibrium, inappropriate or counterproductive postural and locomotor synergies, inability to stand, to sit, or to rise from a chair, with severe retropulsion, and crossing of the legs. These patients cannot walk and step or turn. Bilateral corticospinal signs, corticobulbar and frontal syndromes as well as incontinence are frequently associated. In ‘isolated gait ignition failure’ (Atchison et al., 1993) or gait apraxia, magnetic gait, slipping clutch gait, lower body parkinsonism (Fitzgerald & Jankovic 1989), trepidant abasia, Petren’s gait (1901, 1902), or isolated progressive freezing (Atchison et al., 1993) the steps are short, shuffling is present, with hesitation in starting and turning, variable freezing and variable base. Once this difficulty in starting to walk has been overcome, the gait is almost normal, with normal posture, stride base, stride length and armswing, until the need to turn or the meeting with an obstacle. Isolated freezing, start hesitation or turn hesitation can be found. ‘Frontal gait disorder’ or marche à petits pas, magnetic gait apraxia, lower body parkinsonism is characterized by variable base, hesitation in starting, turning, short steps with shuffling and disequilibrium. Apraxia of sitting can be isolated. Cautious gait (elderly gait or senile gait) is defined by shortened stride, with slowing, mild disequilibrium, difficulty in balancing on one foot, normal or wide base, en bloc turn but no hesitation, shuffling or freezing. The stance phase is longer, with short swing phase, increased number of steps and antero-posterior swinging, preserved rhythm but loss of postural responses. Mixed peripheral and central nervous system disorders are frequently found. Posture, standing from a sitting position, equilibrium, postural reflexes, and protective reactions are normal. On MRI, multiple white matter lesions are usually present (Atchison et al., 1993).

in parietal (Ghika et al., 1998) and less often in frontal or striatal strokes (Saposnik et al., 1998), the patient maintaining for minutes postures passively produced by the examiner or actively performed, even though these are uncomfortable. Hemihypokinesia is also found in right hemispheric strokes (Heilman & Valenstein, 1972; Watson et al., 1981; Laplane & Degos, 1983; Coslett & Heilman, 1989; Von Giesen et al., 1994) as part of motor hemineglect, but can be found in basal ganglia strokes (Damasio et al., 1980; Von Giesen et al., 1994), including the thalamus (Laplane et al., 1986, Verret & Lapresle, 1986), and catatonia in biparietal infarcts (Howard & Low-Beer, 1989). Isolated micrographia has been described in a lenticular hematoma (Martinez-Vila et al., 1988). Athymormia, loss of self autoactivation, apathy, abulia and other akinetic syndromes like akinetic mutism can be found in association with generally bilateral basal ganglia infarcts, hemorrhage or deep venous thrombosis (Laplane et al., 1982, 1984, 1988; Richfield et al., 1987; Habib & Poncet, 1988; Habib et al., 1991; Croisile et al., 1989; Haley et al., 1989; Caplan et al., 1990; Desi et al., 1990; Laplane, 1990; Laplane & Dubois, 1998; De Smet et al., 1990; Macucci et al., 1991; Lehembre & Graux, 1992; Tei et al., 1993; Baron, 1994; Bhatia & Marsden,1994; Milandre et al., 1995, Piccirilli et al., 1995; Tatemichi et al., 1995; Mega & Cohenour, 1997) thalamic (Lhermitte et al., 1963; Ogata et al., 1966; Kuriyama et al., 1997, Szirmai et al., 1977; Tomimoto et al., 1984; Tanaka et al., 1986; Bogousslavsky et al., 1991), unior bilateral capsular genu infarcts (Terao et al., 1991; Hara et al., 1992; Tatemichi et al., 1993; Yamanaka et al., 1996), midbrain infarcts or hemorrhage (Cravioto et al., 1960; Kemper & Romanul, 1967; Segawa, 1970; Castaigne et al., 1981; Price et al., 1983; Tomimoto et al., 1984; Hochman et al., 1985; Robles et al. 1995; de Oliveira-Souza et al., 1995; Von Domburg et al., 1996) or bilateral cingulate (Faris, 1969; Freeman, 1971; Buge et al., 1975; Laplane et al., 1981; Habib & Poncet, 1988; Gugliotta et al., 1989; Borggreve et al., 1994; Miyashi et al., 1995), basal forebrain (Okawa et al., 1980) or frontal strokes (Gautier et al., 1983; Calvanio et al., 1993).

Asymmetric catalepsy, motor neglect and hypokinesia and other akinetic syndromes (abulia, athymormia, akinetic mutism, catatonia)

Hemichorea-hemiballism

Asymmetric cataleptic posturing, more prominent in the left side, was found in a patient with a large fronto-parietal infarct (Saver et al., 1993) and can be frequently observed

Hyperkinetic movement disorders

Acute hemichorea-hemiballism Hemichorea-hemiballism is certainly the most frequently reported movement disorder in acute stroke. Hemiballism is defined as a severe, involuntary, very fast, arrhythmic, explosive, large amplitude excursion of the

Abnormal movements

limb at proximal joints, with an element of rotation in the movement, possibly present at rest, but increased by any attempt to move. Patients may attempt to fixate the affected limb with the uninvolved side, and can be exhausted by these explosive motions, especially if they have chronic cardiac failure. The movements generally predominate in one limb and may be strictly unilateral. They disappear during sleep. Hemichorea is characterized by unilateral rapid involuntary motion with flexion and extension, rotation or crossing, which may involve all body parts, but predominantly distally, with fluent distal-to-proximal or proximalto-distal march. There may be some grimacing of the face, tongue protrusion and vocalization. Patients frequently use the involuntary movement in a semi-purposeful manner as if they were hiding them, or hold the moving limb with the good one. Kase et al. (1981) proposed the name of hemichorea-hemiballism. As a mixture of both, the motion has a flinging character, increased on stress. Some degree of dystonia (persistent postures in overflexion, overextension or torsion), and athetosis (inability to maintain fixed postures with slow snake-like motions) can be added. Cases with associated cortico-spinal, sensory, ataxic or neuropsychological or even psychiatric features (like mania) have been reported (Kulisevsky et al., 1993b). The syndrome of hemichorea-hemiballism is generally transient, lasting a few days, less commonly weeks (Hyland & Forman, 1957; Reimer & Knüppel, 1963) but rarely it is persistent (Lang, 1985) or recurring (Goldblatt et al., 1974). It responds generally well to neuroleptics (Klawans et al., 1976). Classically, acute hemichorea and its variants is found after an acute small deep infarct or hemorrhage in the contralateral subthalamic nucleus (Martin, 1927, 1957; Schwartz & Burrows, 1960; Barraquer-Bordas & PeresSerra, 1965; Melamed et al., 1978; Calzetti et al., 1980; Lang, 1985; Cecotti et al., 1986; Maruyama et al., 1992; Bhatia & Marsden, 1994; Bhatia et al., 1994; Lee & Marsden, 1994), sometimes ipsilaterally (Borgohain et al., 1995; Crozier et al., 1996), but any location in the motor frontosubcortical circuit of Alexander et al., (1986), i.e from the caudate to putamen, pallidum (Freund & Vogt, 1912; Martin, 1927; Austregesilo & Galotti, 1924, Davison & Godhart, 1940; Papez et al., 1942; Meyers et al., 1950; Hyland & Forman, 1957, Martin, 1957; Sandyk, 1960; Reimer & Knüppel, 1963; Avenarius et al., 1964; Gioino et al., 1966; Antin et al., 1967; Goldblatt et al., 1974; Lobos-Antunes et al., 1974; Johnson & Fahn, 1977; Calzetti et al., 1980; Kase et al., 1981; Folstein et al., 1981; Lodder & Baard, 1981; Fisher, 1982; Margolin & Marsden, 1982; Becker & Lal, 1983; Saris, 1983; Jones &

Fig. 12.2. Hemichorea–hemiballism. Synopsis of reported lesions.

Baker, 1985; Tabaton et al., 1985; Buruma & Lakke, 1986; Biller et al., 1986; Tognetti & Donati, 1986; Mas et al., 1987; Sethi et al., 1987; Srinivas et al., 1987; Tamaoka et al., 1987; Kawamura et al., 1988; Mempel, 1988; Dewey & Jankovic, 1989; Lopez-Arlandis et al., 1989; Altafullah et al., 1990; Destée et al., 1990; Defebvre et al., 1990; Friedman & Ambler, 1990; Lownie & Gilbert, 1990; Sethi & Patel, 1990; Ghika et al., 1991; Rumi et al., 1992; Bhatia & Marsden, 1994; Bhatia et al., 1994; Borgohain et al., 1995; Deldovici et al., 1995; Lin et al., 1995; D’Olhaberriague et al., 1995; Patel et al., 1995; Takamatsu et al., 1995; Cava et al., 1996; Scott & Jankovic 1996; Ghika-Schmid et al., 1997; Vila & Chamorro, 1997; Dragasevic et al., 1998; Karsidag et al., 1998; Shan et al., 1998), but also in the thalamus (Martin, 1957; Hyland & Forman, 1957; Graff-Radford et al., 1985; Verret & Lapresle, 1986; Bogousslavsky et al., 1988a,b; Camac et al., 1990; Maruyama et al., 1992; Nijssen & Tijssen, 1992; Kulisevsky et al., 1993; Milandre et al., 1993; Lee & Marsden, 1994; Moroo et al., 1994, D’Olhaberriague et al., 1995; GhikaSchmid et al., 1997; Lee et al., 1998) and pathways interconnecting these nuclei, including corona radiata (Barinagarrementeria et al., 1989) also in the frontal lobe (Martin, 1957; Papez et al., 1942) (Fig. 12.2). Cases with primary hemorrhage or hemorrhagic infarcts in the same loci are less frequent than ischemic strokes (Melamed et al., 1978; Lodder & Baard, 1981; Giroud & Dumas, 1988; Jones & Baker, 1985; Cecotti et al., 1986; Srinivas et al., 1987; Giroud & Dumas, 1988; Altafullah et al., 1990; Waragi et al., 1992; Maruyama et al., 1992; Lee & Marsden, 1994; Cava et al., 1996; Ghika-Schmid et al., 1997). Exceptionally, an angioma can be discovered (Avenarius et al., 1964; LobosAntunes et al., 1974; Tamaoka et al., 1987). Transient or paroxysmal hemiballism has been considered as a vertebro-basilar TIA by a few authors (Gänshirt et al., 1978; Margolin & Marsden, 1982) and a case of transient hemiballismus associated with subclavian steal syndrome has been reported (Calzetti et al., 1980). Paroxysmal

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complex dyskinesias have been described in latero-posterior thalamic infarcts (Camac et al., 1990; Nijssen & Tijssen, 1992). Paraballism, bi- or diballism or generalized choreoballism has been reported in patients with bilateral deep hemorrhage (Hoogstratten et al., 1977; Lodder & Baard, 1981), and bilateral deep infarcts (Tabaton et al., 1985; Sethi et al., 1987). One patient presented a clinical picture suggestive of Huntington’s disease (Folstein et al., 1981). On postmortem examination, he had multiple small infarcts in the caudate, putamen and internal capsule. Monoballism confined to one limb has been reported (Davison & Goodhart, 1940; Hyland & Forman, 1957).

Delayed hemichorea Delayed posthemiplegic hemichorea is a rare entity. It has been reported years after a stroke involving the basal ganglia (Dooling & Adams, 1975). It may be considered in patients with transient hemichorea.

Athetosis and pseudoathetosis Athetosis is rarely found in association with stroke. Delayed syndromes after perinatal anoxia are well recognized (Dooling & Adams, 1975). Pseudoathetosis can be found in association with lesions in the parietal lobe, thalamus, brainstem or spinal cord causing severe proprioceptive deficits (Sharp et al., 1994; Waragi et al., 1992; Ghika et al., 1995, 1998).

Dystonia Acute dystonia Dystonia is defined as a persistent inappropriate posture at rest or on action, in overflexion, overextension or rotation by prolonged cocontraction of antagonist muscles or simply tonic contraction of focal muscles (dystonic posture), sometimes associated with various movements (dystonic movements) such as tremor like jerky motion (dystonic tremor) or athetotic snake-like movements (athetotic dystonia or athetosis), or muscle jerks (dystonic myoclonus). Acute hemidystonia has been reported in association with an acute stroke. On CT, MRI, or pathology, large parietal or frontal infarcts or generalized hemiatrophy of perinatal origin have been reported (Marsden et al., 1985). Small infarcts or hematomas have also been found in the motor fronto-subcortical circuit including the caudate and lenticular nuclei (pallidum and putamen) (Lopez Aydillo & Sanz Ibanez, 1956; Burke et al., 1980; Brisson et al., 1981; Grimes et al., 1982; Traub & Ridley, 1982; Demierre & Rondot, 1983; Russo, 1983; Burton et al., 1984; Marsden et

al., 1985; Giroud & Dumas, 1988; Picard et al., 1989; Bhatia & Marsden, 1994; D’Olhaberriague et al., 1995), but preferentially in the putamen (Lopez Aydillo & Sanz Ibanaz, 1956; Oppenheimer, 1967, Zeman & Whitlock, 1968; Burton et al., 1984; Marsden et al., 1985; Merchut & Brumlik, 1986; Berkovic et al., 1987; Fross et al., 1987; Lopez-Arlandis et al., 1989; Midgard et al., 1989; Picard et al., 1989; Choi et al., 1993; Ferraz & Andrade, 1992; Inagaki et al., 1992; Molho & Factor, 1993; Bhatia & Marsden, 1994; Casas-Parera et al., 1994; Girlanda et al., 1997). Lesions in posterior and lateral thalamic nuclei have also been reported (Garcin, 1955; Grimes et al., 1982; Solomon et al., 1982; Gordon & Lendon, 1985; Marsden et al., 1985; Milandre et al., 1993; Lee & Marsden, 1994; Bhatia & Marsden ,1994; Ghika et al., 1994; D’Olhaberriague et al., 1995; Gille et al., 1996; Ghika-Schmid et al., 1997; Motoi et al., 1997; Karsidag et al., 1998; Ghika et al., 1998) as well as in the parietal and frontal cortex (Ferbert et al., 1990; Ghika-Schmid et al., 1997; Ghika et al., 1998) and brainstem (Day et al., 1986; Kulisevky et al., 1993a). Focal hand or foot dystonia has been found in patients with lacunar infarctions in the lenticular or caudate nuclei (Sterling, 1929; Lopez Aydillo & Sans Ibanaz, 1956; Brisson et al., 1981; Traub & Ridley, 1982; Lovis & Russo, 1983; Russo, 1983; Obeso et al., 1984; Pettigrew & Jankovic, 1985; Quinn et al., 1985; Nakashima et al., 1989; Yoshimura et al., 1992; Bhatia & Marsden, 1994; Scott & Jankovic, 1996; Thajeb, 1996; Ghika-Schmid et al., 1997; Rousseaux et al., 1998) or in the thalamus (the ‘thalamic hand or ‘signe de la main creuse’) (Garcin, 1955; Marsden et al., 1985; Karsidag et al., 1998; Ghika-Schmid et al., 1997) and in superficial parietal lobe infarcts (Critchley, 1953; Ferbert et al., 1990; Ghika-Schmid et al., 1997; Ghika et al., 1998). One patient with focal facial and lingual dystonia was reported by Zeman & Whitlock (1968), another one with cephalic dystonia (Meige syndrome) has also been reported in association with a brainstem infarct (Day et al., 1986) and jaw dystonia has been found together with basilar artery thrombosis (Nishi et al., 1985). Two patients with cervical dystonia of acute onset with lacunar infarcts in the basal ganglia were also recently described (Molho & Factor, 1993). Keane & Young (1985) reported a blepharospasm in bilateral basal ganglia infarctions and Powers (1985) reported a patient with a unilateral diencephalic infarction and another one in a thalamo-mesencephalic stroke (Kulisevsky et al., 1993). Generalized dystonia after a stroke is reported, with or without concomitant choreoathetosis (Sterling, 1929; Lopez Aydillo & Sanz Ibanez, 1956; Zeman & Whitlock, 1968). Painful repetitive tonic spasms, described as ‘sudden,

Abnormal movements

vigorous muscle spasm, preceded or accompanied by pain in the same limb’, ‘usually unilateral’, affecting the arm more often than the leg although they may simulatenously be affected, and facial grimacing, lasting a few seconds to minutes, have been reported in patients with putaminal infarcts from various etiologies (lupus erythematosus, anticardiolipin, other vasculitis) (Merchut & Brumlik, 1986). The spasms can be spontaneous or triggered by various stimuli (anxiety, hyperventilation, physical activity or sensory stimuli). Various generalized ‘tetanic postures’ of the limb can be found during the spasm. Progressive dystonia has also been reported after putaminal infarcts (Berkovic et al., 1987) and internal cerebral vein thrombosis (Solomon et al., 1982) ‘Virtual dystonia’, i.e ‘mental dystonia’ has been reported in association with a posterior ventrolateral infarct (de Oliveira et al., 1996). Paroxysmal kinesigenic dystonia has been described in a medullary infarct (Riley, 1996) and action-induced rythmic dystonia in a thalamic stroke (Sunohara et al., 1984).

Delayed hemidystonia Posthemiplegic hemidystonia may develop months or years after hemiplegia of vascular origin (Hammond, 1871; Solomon et al., 1970; Dooling & Adams, 1975; Quaglieri et al., 1977; Nardocci et al., 1996) in association with putamino-caudate infarcts on CT (Grimes et al., 1982; Burke et al., 1980; Burton et al., 1984; Traub & Ridley, 1982; Obeso et al., 1984; Marsden et al., 1985; Picard et al., 1989; Choi et al., 1993) and on MRI (Burton et al., 1984), less frequently with capsulo-thalamic lesions (Marsden et al., 1985; Ghika et al., 1995; Ghika-Schmid et al., 1997; Fig. 12.3).

Tremor

Fig. 12.3. Hemidystonia. Synopsis of reported lesions.

1988a,b; Caplan et al., 1990, 1998; Kim, 1992; Ferbert & Gernig, 1993; Lee et al., 1993; Mano et al., 1993; Milandre et al., 1993; Mossuto-Agatiello et al., 1993; Bhatia & Mardsen, 1994; Lee & Marsden, 1994; Ménégaux et al., 1994; Moroo et al., 1994; Ghika et al., 1994; Miwa et al., 1996; Scott & Jankovic, 1996; Ghika-Schmid et al., 1997; Krauss et al., 1997; Smits-Engelsman & van Galen, 1997; Karsidag et al., 1998; Soler et al., 1998). Subthalamic infarcts can also be accompanied by an acute resting and action tremor (Chiray et al., 1923; Ferbert et al., 1990). Rarely lesions of caudate or striatum are reported (Andrews et al., 1990; Kim, 1992; Dethy et al., 1993), frontal, parietal strokes (Ferbert et al., 1990; Dove et al., 1994; Kim & Lee, 1994; Ghika et al., 1998) or cerebellar strokes are reported (Lovis et al., 1996). Most cases are children, or adults, with stroke, in whom tremor develops during the acute phase or within weeks (Quaglieri et al.,1977) or years (Burke et al., 1980) after the ischemic lesion. In some instances, a stroke can cure an essential or parkinsonian tremor (Kim et al., 1996) (Fig. 12.4).

Acute tremor

Delayed tremor

Tremor is exceptionally reported as an acute event in strokes. Benedikt’s syndrome (1889) associating a resting and action tremor of 3–4 Hz to a contralateral corticospinal deficit is rarely seen in small mesencephalic infarcts or hemorrhage (Chiray et al., 1923; Lunsford, 1988; Berkovic & Bladin, 1984; de Recondo et al., 1993; Mossuto-Agatiello et al., 1993; Nakamura et al., 1993; Defer et al., 1994; Lee & Marsden, 1994; Bhatia & Marsden, 1994; Lynch et al., 1994). Pontine strokes with tremor are exceptional (Shepherd et al., 1997). An acute resting tremor is reported in a patient with a lacunar infarction at the border between the thalamus and the internal capsule (Lee et al., 1993) or lateral or posterior thalamus (Holmes, 1904; Sigwald & Monnier, 1936; Lapresle & Haguenau, 1973; Burke et al., 1980; GraffRadford et al., 1985; Ohye et al., 1985; Bogousslavsky et al.,

Progressive tremor, chorea and dystonia 7 years after stroke has been reported by Burke et al. (1980) in a boy. Intention, action, and postural tremor were found in a boy with venous sinus thrombosis with bilateral thalamic involvement (Solomon et al., 1982). Delayed tremor years after a stroke in posterior thalamic nuclei are reported (Kim, 1992; Ferbert & Gerwig, 1993; D’Olhaberriague et al., 1995; Volkmann et al., 1998), but also in patients with lesions of the cerebellar outflow tracts in the brainstem (Chiray et al., 1923; Burke et al., 1980; Berkovic & Bladin, 1984; de Recondo et al., 1993; Mossuto-Agatiello et al., 1993; Nakamura et al., 1993; Defer et al., 1994; Lee & Marsden, 1994; Miwa et al., 1996; Scott & Jankovic, 1996). We found delayed tremor, with choreo-athetotic and ballistic features, months after a stroke involving three

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Fig. 12.4. Asterixis. Synopsis of reported lesions.

patients with posterior thalamic infarcts in the territory of the posterior choroidal artery (Kim, 1992; Moroo et al., 1994; Ghika et al., 1994; Ghika-Schmid et al., 1997), thalamogeniculate artery (Holmes, 1904; Sigwald & Monnier, 1936; Graff-Radford et al., 1985; Caplan et al., 1988; Bogousslavsky et al., 1988a,b; Ferbert & Gerwig, 1993; Scott & Jankovic, 1996; Ghika-Schmid et al., 1997; Karsidag et al., 1998) but exceptionally in the territory of the anterior choroidal artery (Bogousslavsky et al., 1988a,b) or in giant cell arteritis (Caselli et al., 1988), but also rarely in cortical frontal or parietal strokes (Ferbert et al., 1990; Dove et al., 1994; Kim & Lee., 1994; Ghika et al., 1998) or cerebellar infarcts (Louis et al., 1996).

Asterixis Bilateral asterixis is usually found in association with diffuse encephalopathy (metabolic, toxic, infectious). Clinically, asterixis is a failure to sustain muscle contraction in postures, and electrophysiological studies show a negative myoclonus (paroxysmal brief (less than 200 ms) loss of muscular activity in muscles of the upper, lower extremity, axial muscles or tongue. Unilateral asterixis has been reported with contralateral lesions involving any possible structure involved in motion (fronto-parietal cortex, basal ganglia, cerebellum, thalamus, brainstem, but not yet in the spinal cord)(Conn, 1960; Tarsy, 1977; Tarsy et al., 1977; Degos et al., 1979; Morrey et al., 1979; Aguglia et al., 1990), and exceptionally in ipsilateral brainstem lesion (Peterson & Peterson, 1987) (Fig. 12.5). Sensory, motor, ataxic, eye movement, or neuropsychological disturbances can be associated. Ischemic or hemorrhagic lesions have been found on CT, MRI or pathology, involving the parietal lobe (Leavitt & Tyler, 1964; Degos et al., 1979; Feldmeyer et al., 1984; Ghika et al., 1998), in the territory of the lenticulostriate artery from MCA (head of caudate, lenticular nuclei, internal capsule) (Massey et al., 1979; Yagnik & Dhopesh, 1981; Trejo et al., 1986; Mizutani et al., 1990).

Thalamic ischemic or hemorrhagic lesions (posterior cerebral artery territory) can cause acute unilateral asterixis (Young et al., 1976; Massey, 1979; Morrey et al., 1979; Donat, 1980; Yagnik & Dhopesh, 1981; Feldmeyer et al., 1984; Shuttleworth & Drake, 1987; Bogousslavky et al., 1988a,b; Mizutani et al., 1990; Trouillas et al., 1990; Milandre et al., 1993; Bhatia & Marsden, 1994; Still et al., 1994; Ghika-Schmid et al., 1997). The lesions involved the paramedian nuclei (Donat, 1980), the lateral nuclei (thalamogeniculate territory) (Mizutani et al.,1990), the anterior (polar artery territory) or posterior nuclei (Trouillas et al.,1990), the mesothalamic region (Tarsy et al., 1977; Bril et al., 1979; Lee & Marsden, 1994) or both thalami (Rondot et al., 1983). Bril et al., 1979 and Tarsy, 1977 reported patients with unilateral acute asterixis in association with midbrain infarct, but no topographic correlate was described. In the posterior fossa, cases with mesencephalic (Tarsy et al., 1977; Bril et al., 1979; Fingerote et al., 1990) pontine or bulbar strokes have been reported (Kudo et al.,1985; Peterson & Peterson, 1987; Aguglia et al., 1990; Tarao et al., 1994; Shepherd et al., 1997) or in the cerebellum (Pullicino et al., 1990). Multiple bilateral hemispheric and cerebellar lesions are also described (Tarsy, 1977; Shuttleworth & Drake, 1987.

Myoclonus Myoclonus is exceptionally seen in patients with strokes, outside of clonic seizures. Generalized myoclonus has never been reported. The anoxic action myoclonus of Lance & Adams (1963) has been reported in association with multiple lacunar lesions in the basal ganglia. Intention and action myoclonus was found in a patient with a thalamic angioma (Avanzani et al., 1977). Focal reflex myoclonus has been reported by Sutton & Meyer (1974) in a patient with a superficial sylvian stroke involving the frontoparietal lobes and later by others (Bartolomei et al., 1995). It was a hemimyoclonus, mixed rhythmic and arrhythmic, both at rest and increased on action and reflex stimuli, disappearing during sleep. Segmental myoclonus have been reported in association with basilar lesions (De Mattos et al., 1992; Ghika-Schmid et al., 1997), midbrain or pontine strokes (Shibasaki et al., 1988; Palmer et al., 1991), basal ganglia (Scott & Jankovic, 1996) or cerebellar infarcts (Sutton & Meyer, 1974) and spinal cord ischemia (Fujimoto et al., 1989; Polo & Jabbari, 1994). Palatal myoclonus is generally found in association with pontine or bulbar strokes (Koeppen et al., 1980; Westmoreland et al., 1983; Overlacq et al., 1987; Iwadate et al., 1988; Itoh & Sakata, 1989; Kalshnikova & Lavrova, 1989; Diehl & Wilmes, 1990; Dubinsky et al., 1991; Chang et al., 1993). Intractable

Abnormal movements

Fig. 12.5. Tremor. Synopsis of reported lesions.

hiccup has similar topography (Al Deeb et al., 1991). Myorrhythmia have also been found in thalamic strokes (Lee & Marsden, 1994).

Transient, paroxysmal, episodic, orthostatic dyskinesia, ‘limb shaking’ Paroxysmal, episodic or transient dyskinesia can be symptoms of transient cerebral ischemia in the territory of the internal carotid artery (ICA) or the vertebrobasilar system. Repetitive stereotyped, often complex involuntary limb movements have been reported in the literature as carotid TIA. The movements are described as rhythmic or arrhythmic, uncontrollable, transient, lasting a few seconds to minutes, and are elicited by sitting, standing or stress, rarely kinesigenic (Loiseau, 1969) or progressive (Solomon et al.,1982). Orthostatic ‘limb shaking’ spells have been described, with involuntary, uncontrollable shaking, coarse irregular wavering, flapping, circling, flailing-type lateral excursions, drawing up or trembling of the upper and/or lower extremity on one hemibody or bilaterally, sometimes with pseudojaskonian march, sometimes difficult to be distinguished from epileptic seizures (Fisher, 1962; Loiseau, 1969; Pessin et al., 1977; Margolin & Marsden, 1982; Ross Russell & Page, 1983; Baquis et al., 1985; Yanagihara et al., 1985; Gordon & Lendon, 1985; Stark, 1985; Prick & Korten, 1988; Lopez Arlandis et al., 1989; Michel et al., 1989; Tatemichi et al., 1990; Hess et al., 1991; Milandre et al., 1993). Flexion and pronation of the wrist, movements of the hand behind the neck, transient hemichoreo-athetoid, writhing, snake-like, gyratory or hemiballic movements lasting a few minutes have also been reported without neuroimaging by Margolin & Marsden (1982), in association with severe uni- or bilateral carotid stenosis, or basilar artery stenosis or occlusion (Stark, 1985; Prick & Korten, 1988), and in children with moya-moya disease (Suzuki & Kodama, 1983) and verteb-

robasilar thrombosis (Gordon & Lendon, 1985). Transient weakness and transient sensory, visual, or aphasic symptoms can coexist with these movements. Painful tonic spasms (Merchut & Brumlik, 1986) or transient abnormal movements in patients with thalamic infarcts (Milandre et al., 1993) can be of difficult differential diagnosis. EEG performed during the paroxysmal movements showed slow waves without paroxysms, and cerebral blood flow studies demonstrated transient hypoperfusion in contralateral fronto-parietal regions (Yanagihara et al., 1985; Baquis et al., 1985; Michel et al., 1989). Paroxysmal complex dyskinesias with elements of dystonia, ballism, chorea, jerks and stereotypies have been described in a postero-lateral thalamic infarct (Camac et al., 1990), another patient presented with a paroxysmal stimulus-sensitive complex dyskinesia (Nijssen & Tijssen, 1992).

Stereotypies Complex stereotypies have been found in a patient with an infarct in the territory of the lenticulostriate arteries on the right side (Maranganore et al., 1991), bilateral thalamocapsular infarcts (Combarros et al., 1990), parietal strokes (Ghika et al., 1998), and Wallesch et al. (1983) reported stereotypies of speech in patients with aphasic strokes.

Mirror movements Mirror movements have been described in strokes and recently studied (Nelles et al., 1998).

Hyperplexia Hyperplexia exacerbated by the occlusion of posterior thalamic arteries has been described (Farriello et al., 1983).

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Akathisia, maniform agitation, compulsive motor behaviours Akathisia per se has not been reported in association with stroke, except in one case of unilateral akathisia in a posterior thalamic infarct (Ghika et al., 1995). Cases of agitation or agitated confusional state have also been reported in association with various locations (Robinson et al., 1984; Starkstein et al., 1987, 1988, 1991; Pardo et al., 1993) especially subthalamic infarcts (Bogousslavsky et al., 1988a,b; Bhatia & Marsden, 1994; Trillet et al., 1995) but also caudate hemorrhagic and ischemic strokes (Cambier et al., 1979; Stein et al., 1984; Weisberg, 1984; Fernandez-Pardal et al., 1985; Pozzoli et al., 1987; Krishnan & Figiel, 1989; Mendez et al., 1989; Wang, 1991; Milhaud et al., 1994), mesencephalic and substantia nigra (Lauterbach & Barreira, 1989), thalamic (Lauterbach et al., 1994; Lauterbach, 1996), right hemispheric (Cummings & Mendez, 1984; Migliorelli et al., 1993) or multiple lacunar strokes (Danel et al., 1991, 1992; Fujikawa et al., 1996). Hypergraphia (Yamadori et al., 1986), graphomania (Williams et al., 1988), logorrhea (Trillet et al., 1995), compulsive grasping or manipulation (Castaigne et al., 1970; Mori & Yamadori, 1982; Lhermitte, 1983; Strub, 1989; Eslinger et al., 1991; Sandson et al., 1991) or obsessive-compulsive behaviours have been described in basal ganglia (Berthier et al., 1996; Laplane et al., 1989, Laplane, 1994; Tonkonogy & Barreira, 1989; Weilber et al., 1989), thalamic (Guard et al., 1986; Eslinger et al., 1991; Sandson et al., 1991), subthalamic (Trillet et al., 1990), temporo-parietal (Bogousslavsky et al., 1995) and cingulate (Paunovic, 1984) strokes.

Hyperkinesia contralateral to hemiplegia We reported a series of patients with hemiplegic strokes who presented various types of hyperkinetic motor behaviors contralateral to the motor deficits (Ghika et al., 1995), including compulsive grasp reaction reported in frontal strokes (Castaigne et al., 1970), but also generalized non goal-directed hypermotility and stereotypias.

the Dejerine–Roussy syndrome (1906). Very complex dyskinesia with dystonia, avoidance and withdrawal behaviors, hypertonia (poikilotonia), persistence of awkward postures (hemicatalepsy, levitation), akinesia, multiple apraxias, ataxia, and sensorimotor deficits is found in the parietal lobe motor syndrome (Critchley 1953; Ghika et al., 1998), but also in temporo-parietal (Ferbert et al., 1990), basal ganglia (Williams et al., 1988) and fronto-cingulate strokes (also see maniform agitation, compulsive motor behaviours and athymormic states above).

Modification of previous movement disorders by strokes Strategic strokes can be a treatment for essential tremor contralaterally to a thalamic (Gioino et al., 1966; Kim et al., 1996; Urushitani et al., 1997) or subthalamic lesion (Struck et al., 1990).

Conclusions In conclusion, acute hypo- or hyperkinetic syndromes can occur in patients with acute strokes at any level of the motor fronto-subcortical circuit of Alexander. The majority of them are hemichorea and hemiballism, but acute unilateral asterixis, dystonia, or less frequently myoclonus, tremor, stereotypy or complex motor behaviours including akinetic states, can be found. Most of them are transient and are not specific for any vascular topopraphy or anatomical structure, but the majority of them are caused by a lesion in the basal ganglia or thalamus. Exceptional complex recurring acute movement disorders like ‘limb shaking’ can be found in transient ischemic attacks and are important to recognize early. Delayed or recurring hyperkinetic syndromes can be found months or years after a stroke. Parkinsonism-like syndromes in association with diffuse small artery disease are common, usually not asymmetrical, and resistant to treatment.

Complex hyperkinesias

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Seizures and stroke Anne L. Abbott, Christopher F. Bladin and Geoffrey A. Donnan National Stroke Research Institute, Austin, Heidelberg, Victoria, Australia

Introduction Historical references for stroke as a cause of seizures date back to Greco-Roman times when Hippocrates in 400  described epilepsy as a disease of the brain due to natural rather than supernatural causes. Hippocrates described older persons with paralysis following seizures consistent with seizures occurring at the onset of stroke. However, it was not until 1864 that Hughling Jackson clearly documented stroke as a cause of epilepsy. Jackson noted that ‘it is not uncommon to find when a patient has recovered or is recovering from hemiplegia, the result of embolism of the middle cerebral artery, or of some branch of this vessel, that he is attacked by convulsions beginning in some part of the paralysed region’. (Taylor, 1958). Since these times it has become clear that stroke is an important cause of seizures and epilepsy, particularly in the older age group. There are, however, some important questions still to be answered.

Post stroke seizures – comparison of cerebral infarction with hemorrhage Timing and frequency of seizures Reports on the frequency of seizures at the onset of, and following, stroke vary quite widely because of differing stroke patient populations, sample sizes studied, followup periods, definitions used for stroke and seizures, use of investigations such as computerized tomography (CT) and types of statistical analysis. In most studies to date the follow-up period was less than a few weeks, so the documentation of later onset or recurring seizures is limited. Studies of early and late onset poststroke seizures where patients with prestroke seizures, were largely excluded and CT was used in the diagnosis of cerebral ischemia or hem-

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orrhage in 90% or more of patients, are summarized in Table 13.1. Early seizures are usually defined as those occurring within 2 weeks of stroke onset. They are reported in anywhere from 1.0–5.5% of patients with recent stroke, more commonly after intracerebral hemorrhage than infarction. When intracerebral hemorrhage alone has been studied, seizures have been reported in 5–25% of patients (Table 13.2). The Seizures After Stroke Study (Stroke Research Unit, University of Toronto) was a prospective, international multicentre study examining the frequency and outcome of seizures in consecutive stroke patients (SAS Study, Bladin et al., 1998). In this study there were 1897 eligible patients followed for a mean of 9 months with an overall frequency of seizures of 9%. Seizures were significantly more common after intracerebral hemorrhage (10.6%) compared to cerebral infarction (8.6%). Most often, seizures occur at the onset or within the first few days of stroke due to infarction or bleeding. The risk of new seizures then falls progressively and is then very low beyond 2 years (Gupta et al., 1988; Faught et al., 1989; Lanceman et al., 1993; Bladin et al., 1996). Most seizures associated with stroke are single (Gupta et al., 1988; Kilpatrick et al., 1990; Giroud et al., 1994). As mentioned earlier, the frequency of recurrent otherwise unprovoked seizures (epilepsy) after stroke has rarely been quantified because of limited patient follow-up in most studies. In the SAS Study, although the incidence of early seizures was common, epilepsy developed in 3% of the stroke population overall. Even though the risk of an individual developing epilepsy after stroke is small, because stroke is such a common affliction in the older population, especially beyond 60 years, it is the leading cause of epilepsy in this age group. Cerebrovascular disease (infarction or hemorrhage) accounts for 14% to 54% of diagnosed cases of epilepsy in

Seizures and stroke

183

Table 13.1. Frequency of early and late seizures following cerebral infarction or hemorrhage in CT scan confirmed cases

Study

Kilpatrick et al., 1990(1)a,b

Davlos et al., 1992(2)a,b

Lanceman et al., 1993(1)

Giroud et al., 1994(2)a

Lo et al., 1994(1)a

Arboix et al., 1997(2)a

Reith et al., 1997(3)

Bladin et al., 1998(4)

Total patients

1000

1000

219

1640

1200

1220

1195

1897

Number of infarcts haemorrhages

601 65

662 156

183 36

1213 129

696 384

1012 208

900 75

— —

Follow-up

7 months (mean, early seizures only)

not stated

11.5 month (mean)

none

none

not stated

not stated

9

Threshold; early vs. late seizures (days)

14

2

30

15

14

2

14

14

Early seizures (%) all patients infarction hemorrhage

4.4 6.5 15.4

5 5.4 8.3

5.4 3.8 14

5.4 7 16

2.5 2.3 2.8

2.4 2 4.3

4.2 3 8

— — 8

Late seizures (%) all patients infarction hemorrhage

— — —

— — —

4.5 3 11

— — —

— — —

— — —

— — —

— — —

Notes: 1⫽hospital stroke patients, 2⫽stroke registry/database, 3⫽hospital/community database, 4⫽multicentre hospital stroke patients. a includes patients with TIA and/or subarachnoid haemorrhage and/or unclassified stroke types. b includes underlying causes of hemorrhage such as arteriovenous malformation, coagulation disorders.

Table 13.2. Frequency of seizures after intracerebral haemorrhagea

Number of patients Follow-up duration (months) Total seizures (%) Threshold of early vs. late seizures (days) Early seizures (%) Late seizures (%) Frequency of total seizures according to hemorrhage location (%); • Lobar/cortical • Thalamic • Basal ganglia. • Massived

Berger et al., 1988b

Faught et al., 1989c

Sung & Chu, 1989b

Weisberg et al., 1991b

112 2 (median) 17 — 17 —

123 55 (mean) 25 30 19 6

1402 20-22 (mean) 5 14 3 2

222 12 15 3 12 3

26 — — —

54 0 17 5

32 2 2 —

30 4 3 —

Notes: all studies were CT supported, largely descriptive, with only two ( Berger et al. and Faught et al. ) having limited univariate analysis with delineation of risk factors for seizures. b study includes patients with underlying causes such as neoplasm, aneurysm, mycotic aneurysm, anticoagulant complication, arteriovenous malformations and angioma. c includes patients with seizures before cerebral haemorrhage. d massive haematoma defined as ⬎ 50ml/s. a

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Table 13.3. Etiology of epilepsy in the elderly Etiology (%) Author

Year

N

Stroke

Tumour

Trauma

Metabolic

Drug/Alcohol

Otherb

Unknown

Roberts et al.c Guptad Dam et al.c Luhdorf et al.d Sundaramc Forsgrena,d,e Sander et al.a,d Sung and Chuc Loiseau et al.a,d Cohen & Scheuerd Hauser et al.a,d Ettinger & Shinnarc

1982 1983 1985 1986a 1989 1990 1990 1990a 1990 1991 1992 1993

81 78 221 151 67 239 196 342 284 123 214 80

44 50 14 32 22 41 49 39 47 25 32 54

12 0 16 14 24 10 11 11 9 18 3 8

6 4 4 4 6 5 — 21 3 0 3 —

6 2 — 2 7 — — 7 18 0 0 16

0 — 25 10 — — — — 3 — — —

15 12 3 13 7 7 — 10 7 7 12 14

16 28 38 25 34 37 38 12 13 50 50 8

Notes: N =number of elderly patients (⭓60 years). a subjects are subsets of larger population studies. b includes CNS infection, dementia, degenerative diseases, mixed conditions. c hospital-based study. d community-based study. e includes only non-provoked seizures; occurring without an identifiable causative metabolic or acute structural abnormality.

older patients according to the most recent studies (Table 13.3). Although a cause for epilepsy is more frequently found in older compared to younger people, up to about a third of cases are idiopathic (Luhdorf et al., 1986a; Loiseau et al., 1990; Sander et al., 1990). In addition, epilepsy in the elderly is a common medical problem with a high age-specific incidence (Forsgren, 1990; Tallis et al., 1991; Hauser, 1992). Tallis et al. (1991) in a large primary care computerized database encompassing over 300 000 patients in the United Kingdom, noted a bimodal distribution in the annual incidence of new seizures according to age. There was a peak incidence of 100/100 000 at approximately 5 years of age and a progressive rise from an incidence of 76/100 000 at 60 years. The incidence continued to rise with each decade to a figure of 159/100 000 for those aged over 80 years. A similar trend in the age-specific incidence of epilepsy was seen in the community-based study in Rochester Minnesota by Hauser (1992).

Types of seizures Partial seizures predominate after cerebral infarction and haemorrhage (Faught et al., 1989; Sung & Chu, 1989; Sung

& Chu 1990b; Kilpatrick et al., 1990; Lo et al., 1994; Giroud et al., 1994; Bladin et al., 1998). Partial seizures are usually simple motor in type, sometimes secondarily generalizing. Tonic-clonic seizures are also common but it is probable that, in many, the focal onset is unwitnessed or not appreciated. Complex partial seizures occur relatively rarely after stroke. Status epilepticus has been reported in up to 13% of stroke patients with seizures (Sung & Chu 1990b; Kilpatrick et al., 1990; Lo et al., 1994; Bladin et al., 1998). Status epilepticus can be a presenting feature of cerebral infarction or hemorrhage, or occur later. Seizure activity is often focal motor involving the hemiparetic limbs or may be tonicclonic in nature (Berger et al., 1988; Faught et al., 1989; Sung & Chen, 1989; Kilpatrick et al., 1990). Lobar hemorrhages are more commonly associated with status epilepticus than other types of intracerebral hemorrhage (Sung & Chen, 1989). Cerebrovascular disease is a common cause of status epilepticus in older patients. In addition, the mortality of status epilepticus increases with advancing age beyond 60 years and duration of seizures (DeLorenzo et al., 1992), hence the importance of early treatment. Important causes of status epilepticus after stroke are anticonvulsant

Seizures and stroke

withdrawal and non-compliance (Lowenstein & Alldredge, 1993).

Risk factors for post-stroke seizures Stroke location The most consistent risk factor for seizures at the onset or following cerebral infarction or hemorrhage is cortical involvement in pathological (Richardson & Dodge, 1954) and clinical studies (Olsen et al., 1987; Berger et al., 1988; Faught et al., 1989; Kilpatrick et al., 1990; Davlos et al., 1992; Lanceman et al., 1993; Lo et al., 1994; Arboix et al., 1997; Bladin et al., 1998). The anterior hemispheres and carotid arterial territory are sites of brain infarction with a higher risk of seizures (Lo et al., 1994; So et al., 1996; Burn et al., 1997). In the SAS study (Bladin et al., 1998), cerebral infarcts producing seizures were typically in the frontoparietal lobe in the region of the motor strip and extending down to the insula. With respect to intracerebral hemorrhage, lobar hemorrhages carry a higher risk of seizures compared to those located subcortically (Table 13.2). Deep cerebral and brain stem infarcts and infratentorial hemorrhages have not commonly been associated with seizures (Kilpatrick et al., 1990).

Stroke type The greater risk of seizures following intracerebral hemorrhage compared to infarction has been noted. Seizure risk does not appear to increase with amount of ventricular or cisternal blood nor the presence of hydrocephalus or shift of intracranial structures (Berger et al., 1988; Bladin et al., 1996). Hemorrhagic infarction did not confer a higher risk of seizures in the SAS study (Bladin et al., 1998). Subcortical infarctions are less commonly associated with seizures than cortical. Seizures have been noted in up to 3% of patients following lacunar infarcts (Kilpatrick et al., 1990; Giroud et al., 1994; Arboix et al., 1997; Bladin et al., 1998). However, some have proposed that lacunar infarcts are a marker of more widespread vascular disease rather than being directly responsible for stroke-related seizures (Roberts et al., 1988). Seizures have been noted in 23% of patients with striatocapsular infarction (Giroud & Dumas, 1995). It is possible that CT underestimates the number of patients with cortical ischemia in this form of subcortical stroke. A more sensitive indicator may be single photon emission tomography (SPECT), positron emission tomography (PET) or magnetic resonance imaging (MRI) (Olsen et al., 1986; Perani et al., 1987; Reith et al., 1997). The mecha-

nisms by which over lying cortical tissue can be functionally deranged in subcortical infarction and therefore involved in seizure production is discussed elsewhere (Olsen et al., 1986; Donnan et al., 1991). Less than 2% of patients with transient ischemic attacks experience seizures (Kilpatrick et al., 1990; Giroud et al., 1994). Patients suffering subarachnoid hemorrhage have 8 to 17% risk of seizures (Giroud et al., 1994; Kilpatrick et al., 1990) and these usually occur early, or with rebleeding.

Stroke size Larger strokes, especially cerebral infarctions, have been associated with an increased risk of seizures (Davlos et al., 1992; Lanceman et al., 1993; Arboix et al., 1997; Bladin et al., 1998). However, patients with small lobar hemorrhages, because of their cortical location, experience seizures more often than patients with larger bleeds located elsewhere (Berger et al., 1988; Faught et al., 1989; Weisberg et al., 1991; Bladin et al., 1996).

Presumed stroke mechanism; embolic vs. thrombotic Some studies have reported a presumed embolic cause of stroke more often than thrombotic among patients with seizures after stroke (Richardson & Dodge, 1954; Mohr et al., 1978; Giroud et al., 1994). Others have not found this association (Black et al., 1983; Kilpatrick et al., 1990; Davlos et al., 1992; Bladin et al., 1998). One must consider the limitations of diagnosing a cause of stroke in individual patients because of non-specific clinical syndromes, limitations of investigations and identification of several coincident predisposing factors (Ramirez-Lassepas et al., 1987; Lodder et al., 1994; Madden et al., 1995).

Underlying pathology Patients with intracerebral hemorrhage due to an underlying cause such as blood dyscrasia, tumour, arteriovenous malformations or aneurysm are more likely to have early and recurrent seizures than patients with spontaneous or hypertensive bleeds (Kilpatrick et al., 1990; Weisberg et al., 1991; Davlos et al., 1992). Lobar hemorrhages occur in the subcortical white matter of the cerebral lobes and are more often associated with seizures than deeper hemorrhages because of frequent cortical involvement. In addition, lobar hemorrhages are more frequently associated with underling causes of bleeding apart from hypertension (Kase et al., 1982; Kilpatrick et al., 1990).

Clinical features Reported clinical predictors for seizures after ischemic stroke are stroke severity, acute agitated confusional state,

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altered consciousness and persisting paresis (Olsen et al., 1986; Arboix et al., 1997; Reith et al., 1997). In the SAS Study, patient age, sex, hemisphere affected and vascular risk factors did not influence seizures following stroke (Bladin et al., 1996).

ring that is epileptogenic. The temporal occurrence of poststroke seizures, clinical features and proposed pathogenesis shares similarities with brain trauma associated seizures (Jennett, 1979; Willmore, 1993).

Morbidity and mortality Risk factors for poststroke epilepsy The issue of epilepsy following stroke has been poorly studied, mainly because of lack of long-term patient follow-up. Most patients suffering seizures within the first few weeks of a stroke do not have recurrent seizures, but have a higher risk than the age-matched population. Those with late onset seizures are possibly at higher risk (up to three-fold) for epilepsy than those with early-onset seizures (Louis & McDowell, 1967; Lesser et al., 1985; Faught et al., 1989; Sung & Chu, 1989, 1990b; Hornig et al., 1990; Weisberg et al., 1991). Cortical lesions increase the risk of epilepsy after cerebral infarction or hemorrhage (Olsen et al., 1987). With respect to intracerebral hemorrhage, lobar hemorrhage (Sung & Chu, 1989) and an identified structural cause (Weisberg et al., 1991) increase the risk of epilepsy.

Pathogenesis Little is known about the mechanism of seizures associated with stroke. As discussed earlier, it appears that cortical involvement is important in both infarction and haemorrhage. Because of the different frequency of seizures associated with cerebral hemorrhage compared to infarction, seizure pathogenesis is likely to be different. Some authors have raised the possibility that extravasated red cells and particularly the iron they contain may be responsible for the development over time of a chronic epileptic focus (Chusid & Kopeloff, 1962, Willmore et al., 1978; Lesser et al., 1985). Because most patients who experience early seizures after cerebral infarction or hemorrhage do not suffer recurrences, the pathogenesis of the two phenomena is likely to be different (Lesser et al., 1985). Acutely, seizures may occur due to transient metabolic alterations that may be seizure inducing. The size of the ischemic penumbra, for instance, may be influential, although this hypothesis needs to be formally tested. Bladin et al. (1996) detected a threefold greater blood flow defect in stroke patients with seizures compared to those without using CT and SPECT technology possibly indicative of a larger ischaemic penumbra. As acute metabolic derangements are reversed, seizures cease. Epilepsy, on the other hand, may occur when the stroke results in later structural change or scar-

Some authors have noted higher in-hospital mortality for patients with early seizures following cerebral infarction or hemorrhage (Arboix et al., 1997) but not others (Black et al., 1983; Davlos et al., 1992; Kilpatrick et al., 1990; Reith et al., 1997). In the SAS Study seizures were identified as an independent risk factor for death following cerebral infarction but not cerebral hemorrhage (Bladin et al., 1998). Predictors of a poor prognosis after stroke are the size of the lesion, initial stroke severity and a reduced level of consciousness (Davlos et al., 1992, Reith et al., 1997). There has been a reported lower mortality and better functional outcome for lobar compared to deeper hemorrhages because of their superficial nature (Kase et al., 1982).

Differential diagnosis The differentiation of seizures, and particularly ischemic stroke, can be difficult for several reasons (Godfrey et al., 1982). First, seizures can mimic stroke because of postictal worsening of preseizure neurological deficits. Fine in 1967 described posthemiplegic epilepsy in stroke patients. According to Fine, ‘after each convulsive seizure the hemiplegia was greatly deepened and could well be diagnosed as a fresh cerebral thrombus . . . or embolus’. Exacerbation of pre-existing neurological deficits postseizure can last more than a week or several months (Bogousslavsky et al., 1992; Hankey, 1993). Such an exacerbation is more likely after a prolonged seizure and a longer partial seizure before generalization, indicating the importance of prompt seizure control. Critical in the diagnosis is the history of the seizure preceding the exacerbation, previous stereotyped episodes which have recovered, absence of evidence of a further cerebral insult with brain imaging and the response to anticonvulsants. Secondly, seizures and strokes can also mimic each other because both can present with confusion. Ictal or postictal confusion can be prolonged for days (Ellis & Lee, 1978). Seizures and strokes can both be misdiagnosed as other disorders, commonly other confusional states or syncope, which can only be diagnosed clinically (Norris, 1982). Norris found in his study of 821 consecutive patients admitted to an acute stroke unit, that the initial diagnosis of stroke proved incorrect in 108 (13%). Misdiagnosis was most often due to inadequate clinical assessment. Norris

Seizures and stroke

concluded that ‘although CT and other neurological investigations are useful aids in the diagnosis of stroke, they remain a supplement to, and not a substitute for, correct clinical evaluation’. In addition, there are reports suggesting that focal seizures may resemble TIAs. These have been termed ‘inhibitory seizures’ and were first described by Gordon Holmes in 1927. Subtle postictal neurological deficits following these could mimic an ischemic stroke (Lee & Lerner, 1990). These are uncommon and noted by transient, focal loss of neurological function sometimes with coincident EEG changes and response to anticonvulsants. Various etiologies have been reported, including cerebral ischemia.

Role of the EEG EEG changes after stroke are not specific, but when present tend to be focal (Gupta et al., 1988; Faught et al., 1989; Lo et al., 1994; Arboix et al., 1997). With cerebral ischemia most commonly there is slowing, loss of normal background activity and reduction in overall amplitude (Faught, 1993). Other findings include periodic lateralizing epileptiform discharges (PLEDS), sharp activity and frontal intermittent delta activity (FIRDA). These changes can resolve within months of cerebral infarction or persist for years. The presence of PLEDS, however, usually indicates recent infarction. PLEDS have been particularly associated with watershed ischemia (Chatrian et al., 1964), see Fig. 13.1. After intracerebral hemorrhage, slowing is commonly focal but can be diffuse in the presence of coma or multifocal in the presence of vasospasm. The EEG is not reliable in predicting type, timing or recurrence of seizures after stroke and should not be used as the sole basis for prophylactic anticonvulsant therapy (Holmes, 1980; Luhdorf et al., 1986b; Bladin et al., 1996, 1998). In addition, there are considerable logistic difficulties in obtaining an EEG in ill patients with acute stroke.

Management There is little information on the impact of anticonvulsant medication or surgical intervention with respect to the risk of seizures associated with stroke. Fortunately, most stroke patients experiencing seizures within the first few weeks of stroke will not have another. Conversely, because of a higher likelihood of recurrence, to commence anticonvulsants after a second seizure would be appropriate in most cases. Some (Kilpatrick et al., 1990) but not all (Louis & McDowell, 1967) authors have reported that early seizures after stroke are easily controlled. A first prolonged seizure

or status epilepticus needs urgent therapy. A trial of anticonvulsant withdrawal if a patient has been seizure free for more than 2 or 3 years and is healthy enough to survive a recurrent seizure is reasonable. One must weigh up the risks of anticonvulsant therapy in the individual patient, especially as many will be elderly and particularly susceptible to adverse drug reactions and drug interactions (Reynolds 1975; Patsalos & Duncan, 1993; Scheuer & Cohen, 1993; Rambeck et al., 1996; Spina et al., 1996). Equally, the elderly are particularly vulnerable to injuries sustained from seizures (Grisso et al., 1991). In recent years a number of new anticonvulsants have been introduced. These include lamotrigine, vigabatrin, topiramate, gabapentin and tiagabine (Dichter & Brodie, 1996; Sander, 1996). As yet, these have not been evaluated specifically in the therapy of epilepsy related to cerebrovascular disease. However, they have the theoretical advantage of fewer adverse reactions and have demonstrated efficacy in other clinical situations.

Seizures preceding stroke Barolin (1982) coined the term ‘vascular precursor epilepsy’ for seizures preceding stroke. He described 69 cases in their neurology unit. Of these patients, 36 and 33, respectively, had focal and generalized seizures. Most of the patients with focal seizures experienced definite stroke of the relevant hemisphere within a year. He felt that such focal seizures were just as important a sign of impending stroke as transient ischemic attacks and an opportunity for prophylactic therapy. Cocito et al. (1982) reported that seizures (especially focal) may be the sole manifestation of subtotal or total internal carotid occlusion, and recommended a cerebrovascular assessment and risk factor management for patients with otherwise unexplained seizures. The basis for seizures preceding stroke symptoms for months or many years may be otherwise silent cerebrovascular infarction. Dodge et al. (1954) described three cases of focal epilepsy due to otherwise silent cortical infarction subsequently demonstrated at autopsy. Asymptomatic cerebral infarction detected on CT scan of patients presenting with their first or recurrent stroke are not uncommon and become more so with increasing age over 50 years (Jorgensen et al., 1994). Most of such infarcts are small and subcortical. It has been proposed that these infarcts are easier to see than small cortical ones that can be difficult to distinguish from atrophy. Hence, small subcortical infarcts may be a marker for vascular disease elsewhere and not directly responsible for seizures.

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Fp2-F8

7 nuV

F8-T4

7 uV

T4-T6

7 uV

T6-O2

7 uV

Fp1-F7

7 uV

F7-T3

7 uV

T3-T5

7 uV

T5-O1

7 uV

PG-PG

A.L. Abbott, C.F. Bladin and G.A. Donnan

– – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – –

Fig. 13.1. Sample of an EEG showing PLEDS (periodic lateralizing epileptiform discharges) in the left temporal electrodes in a patient with cerebral ischemia. PLEDS is sometimes seen with focal cerebral pathology, especially watershed infarction demonstrated in the computerized tomogram (CT scan). In this case the infarction is bilateral and extensive, particularly in the left cerebral hemisphere.

Seizures and stroke

Further evidence for the epileptogenic potential for silent cerebral infarcts came from a study by Shinton et al. (1987) who showed an increased frequency of preceding epilepsy in first stroke patients compared to age, sex and race matched controls. In addition, patients with late onset unexplained epilepsy may have a higher prevalence of silent ischemic lesions on CT brain compared to age and sex matched controls (Roberts et al., 1988). The mechanism of silent ischemia and associated seizures may relate to internal carotid artery stenosis or occlusion and associated embolism, or hypoperfusion (Cocito et al., 1982). Regardless of the mechanism, unexplained seizures in an older population should be considered a marker for possible underlying cerebrovascular disease and appropriate investigations instigated.

Conclusions Seizures following stroke are common and occur in about 9% of patients overall, especially in the first few weeks. Seizures are more common after cerebral hemorrhage than infarction. The risk of epilepsy following stroke for the individual is low, about 3%, yet still higher than the age-matched population. Because stroke is common in older age groups, poststroke seizures and epilepsy are important community health issues. While little is known about the pathogenesis of seizures and epilepsy after stroke, it is clear that cortical location is a risk factor after both cerebral infarction and hemorrhage. Lesion size is such a predictor only after cerebral infarction. Underlying structural lesions increase the risk of seizures and epilepsy after intracerebral hemorrhage. A better understanding of the role of anticonvulsant therapy in the management and prophylaxis of poststroke seizures and epilepsy is required to provide guidelines for management. Currently, there is little clinical experience with the newer anticonvulsants in this setting, but an extrapolation of available data from studies in epilepsy would suggest that they are likely to be of use in the future.

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Shinton, R.A., Zezulka, A.V., Gill, J.S. & Beevers, D.G. (1987). The frequency of epilepsy preceding stroke. Lancet, i, 11–12. So, E.L., Annegers, J.F., Hauser, W.A. et al. (1996). Population based study of seizure disorders after cerebral infarction. Neurology, 46, 350–5. Spina, E., Pisani, F. & Perucca, E. (1996). Clinically significant pharnacokinetic drug interactions with carbamazepine. Clinical Pharmacokinetics, 31, 198–214. Sundaram, M.B.M.(1989). Etiology and pattern of seizures in the elderly. Neuroepidemiology, 8, 234–8. Sung, C.Y. & Chu, N.S. (1989). Epileptic seizures in intracerebral haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry, 52, 1273–6. Sung, C.Y. & Chu, N. (1990a). Epileptic seizures in elderly people: aetiology and seizure type. Age and Aging, 19, 25–30.

Sung, C.Y. & Chu, N.S. (1990b). Epileptic seizures in thrombotic stroke. Journal of Neurology, 237, 166–70. Tallis, R., Gillian, H., Craig, I. & Dean, A. (1991). How common are epileptic seizures in old age? Age and Aging, 20, 442–8. Taylor, J. (ed.) (1958). Selected Writings of John Hughlings Jackson; edited for the quarantors of Brain. Vol 1. Epilepsy and Epileptiform Convulsions. New York: Basic Books Inc. Weisberg, L.A., Shamsnia, M. & Elliott, D. (1991). Seizures caused by nontraumatic parenchymal brain haemorrhages. Neurology, 41, 1197–9. Willmore, L.J., Sypert, G.W. & Munson, J.B. (1978). Recurrent seizures induced by cortical iron injection: a model for post-traumatic epilepsy. Annals of Neurology, 4, 329–36. Willmore, L.J. (1993) Post-traumatic seizures. Neurologic Clinics, 1, 823–33.

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Disturbances of consciousness and sleep–wake functions Claudio Bassetti Neurology Department, University Hospital, Bern, Switzerland

Introduction Quantitative and qualitative alterations of consciousness are frequently observed in stroke patients, rarely in the absence of major sensorimotor deficits (‘inobvious stroke’; Dunne et al. 1986). Disorders of wakefulness and delirium (acute confusional state), often in combination, are the most common disorders of consciousness in patients with acute stroke. In prospective studies, decreased levels of wakefulness – ranging from somnolence (hypersomnia) to coma – can be observed in 15–25% of patients (Bassetti, 2000; Bogousslavsky et al., 1988b; Melo et al., 1992), and acute confusional states are seen in up to 48% of patients (Gustafson et al., 1991). Less often, stroke causes coma-like states (akinetic mutism, locked-in syndrome), vegetative state, or other sleep–wake disturbances. Analysis of disturbances of consciousness and sleep–wake functions in stroke patients is of clinical interest. First, the presence of an altered consciousness may suggest topography or etiology of stroke. A severe impairment of wakefulness favours the presence of large hemispheric or (bilateral) brainstem strokes, whereas an acute confusional state is suggestive of a supratentorial stroke. In addition, a decreased level of consciousness is relatively common in patients with intracerebral hemorrhage (Bogousslavsky et al., 1988a), cardioembolic stroke (Kittner et al.,1990), and intracranial dissections (Bassetti et al., 1994a), being conversely rare in those with lacunar strokes. Secondly, patients with altered consciousness require different monitoring and therapeutical strategies. Early detection and prompt surgical treatment of patients with decreased levels of consciousness due to cerebellar stroke and large hemispheric stroke was shown, for example, to improve prognosis (Hornig et al., 1994; Mathew et al., 1995; Schwab et al., 1998). Thirdly, level of consciousness (as estimated, for example, by the Glasgow

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Coma Score) is among the best predictors of outcome in ischemic as well as hemorrhagic stroke (Broderick et al., 1993; Bushnell et al., 1999; Hénon et al., 1995; Lampl et al., 1995; Steiner et al., 1997; Tuhrim et al.,1988). The shortterm case fatality goes from 80% in comatose, to 60% in stuporous, and 40% in somnolent patients (Asplund & Britton, 1989; Melo et al., 1992). Finally, recent observations have shown that the prevalence of sleep disturbances is high not only in patients with brainstem strokes but also in hemispheric stroke patients (Bassetti et al.,1996a; Bassetti et al., 1997a,b; Markand & Dyken, 1976). Studies of sleep disorders in stroke patients not only could provide new insights into the mechanisms of sleep–wake regulation, but also may suggest new approaches to treatment (e.g. control of sleep apnea), and improve stroke outcome.

Physiology of consciousness and sleep–wake functions Consciousness can be defined as the ability to relate both to self and to environment (Cobb, 1957). From a pragmatic viewpoint, consciousness has been differentiated into its partial aspects of wakefulness (arousal, alertness, vigilance) and awareness. Awareness involves both a subjective experience (‘consciousness as such’) and the sum of higher cognitive and emotional functions (contents of consciousness).

Wakefulness (arousal systems) Wakefulness corresponds to the cortical ‘tone’ necessary to run the cognitive apparatus and depends on the integration of the ARAS (ascending reticular activating system) with the descending (cortico-reticular) pathways that modulate its function. The ARAS is viewed today as a functional system

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Fig. 14.1. The ascending reticular activating system (ARAS) in the upper pons and midbrain projecting diffusely to the cortex through synaptic relays in the midline (intralaminar, IL) and dorsomedial thalamic nuclei (thalamic route), and in the basal forebrain (BF, extrathalamic route). BG, basal ganglia, DM, dorsomedial nucleus of the thalamus (Drawing by C. Langenegger, AUM, University Hospital, Bern, Switzerland.)

in the upper brainstem and paramedian diencephalon (Fig. 14.1), which is organized in morphologically and biochemically distinct subgroups of neurons (Berlucchi, 1997; Jouvet, 1996; McCormick & Bal, 1997; Moruzzi & Magoun, 1949; Steriade, 1996). These bilateral, mainly adrenergic, cholinergic, and dopaminergic neuronal networks project diffusely to the cortex through synaptic relays in the midline (intralaminar) and dorsomedial thalamic nuclei (thalamic route) and in the basal forebrain (extrathalamic route) leading to a non-specific activation of the hemispheres (‘tonic arousal’) necessary for the awake or aroused state (Jones, 1994). Descending projecting neurons from the posterior hypothalamus (subthalamus) to brainstem, medulla, and spinal cord are necessary for the motor expression of this activated state (Chammas et al., 1999). Single reticulo-cortical as well as cortico-reticular neuronal systems, such as Nauta’s forebrain–midbrain circuit modulate the activity of the ARAS and, while regulating the level of cortical activation, subserve the capacity to focus and sustain attention to specific tasks and stimuli (‘phasic arousal’) (Contreras et al., 1996; Villablanca & Salinas-

Zeballos, 1972). An adequate tonic and phasic arousal of associative cortical regions is a requisite for a normal state of consciousness.

Awareness Awareness requires sufficient arousal and attention, and corresponds to the experience (‘consciousness as such’) and the sum of higher cognitive and emotional functions (contents of consciousness). Directing and maintaining attention to a specific task depends upon the function of the prefrontal cortex of the right hemisphere and its descending connection to the thalamus. These pathways allow selective gating of external inputs and consequently the choice between environmentally driven and internally driven behaviour. The ‘aroused and attentive’ brain is finally enabled by multiple partially segregated corticosubcortical circuits to perform such higher cognitive functions as memory, thinking and language. Awareness has been suggested to arise from the simultaneous activation (‘binding’) of these brain areas over a few milliseconds, a

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synchronization which, in turn, may depend on intrinsic oscillatory properties of thalamo-cortico-thalamic networks (Bogen, 1997; Munk et al., 1996; Paré & Llinas, 1995).

Sleep–wake cycle Modulation of the state of wakefulness and the appearance of a normal sleep–wake cycle depend on a complex reciprocal interaction between the wakefulness-maintaining systems of the ARAS (and its inputs) and sleep-promoting systems localized in the brainstem, anterior hypothalamus and basal preoptic area (Jones, 1994; Steriade, 1992). Sleep onset is accompanied by a decreased activity of the ARAS and an increased firing rate of ‘sleep neurons’ in basal forebrain and anterior hypothalamus. As a result, the transfer of sensory information at the level of the thalamic relay nuclei is diminished and thalamocortical neurons become hyperpolarized. Sleep spindles and slow wave sleep (1–4 Hz delta rhythms), the electrophysiological hallmarks of NREM sleep, arise from the interaction of increasingly hyperpolarized thalamocortical neurons with neuronal oscillators in the reticular thalamic nucleus (pacemaker of sleep spindles) and cerebral cortex (pacemaker of ⬍1 Hz rhythms) (Amzica & Steriade, 1998). The generators of the different REM sleep phenomena (EEG activation, muscle atonia, rapid eye movements) are located in the mediolateral tegmentum of the ponto-mesencephalic junction (Siegel, 1994). There is increasing support for the hypothesis that mental, motor (behavioural), autonomic, and EEG arousal may depend upon the action of different ascending and descending neuronal systems (Chammas et al., 1999; Holstege, 1992; Koella,1986). This diversity may explain how different focal brain lesions may lead to such ‘dissociated states’ as normal mental wakefulness with insufficient motor arousal (akinetic mutism) (Cairns et al., 1941), hyperkinesia with mutism (Inbody & Jankovic, 1986), behavioral coma with normal EEG (alpha-coma EEG) (Loeb & Poggio, 1953), alert state with severely disturbed EEG (Cravioto et al., 1960), intrusion of REM motor atonia (cataplexy) or dreaming (peduncular hallucinosis) in the awake state (Lhermitte, 1922).

Disturbances of consciousness and sleep–wake functions Disorders of wakefulness In clinical practice, wakefulness and awareness are often affected together but the profile of involvement of arousal,

and of cognitive, motor, and vegetative functions may differ depending on the topography, nature, and time course of the underlying lesion. Disorders of wakefulness can be differentiated clinically depending on the intensity of stimulation needed to arouse the patient in: (i) hypervigilance (hyperalertness, hyperarousal), (ii) normal arousal, (iii) hypersomnia (drowsiness, somnolence, sleepiness) (iv) sopor (stupor), and (v) coma. In patients with large cortico-subcortical hemispheric strokes, disorders of wakefulness are the first symptom of developing brain edema due to vertical (transtentorial herniation) or horizontal (midline shift of the pineal gland) displacement of the brain with disruption of the upper brainstem (McNealy & Plum, 1962; Plum & Posner, 1980; Ropper, 1986; Ropper & King, 1984). Disturbances of wakefulness are accompanied by the clinical features of ‘uncal’ and ‘central’ syndromes (Plum & Posner, 1980), which typically precedes a critical rise in the intracranial pressure (Franck, 1995; Schwab et al., 1996). Pupil enlargement contralateral to hemiparesis is characteristic of ‘uncal syndrome’ (herniation of the medial temporal lobe into the space between the edge of the tentorium and the midbrain). The other pupil may subsequently present a diminished light reaction and a reduction or increase in size (Ropper, 1990). The ‘central syndrome’ (downward displacement of the upper brainstem through the tentorium) is characterized by initially bilaterally small and reactive pupils, which later may be in midposition and become areactive (Plum & Posner, 1980). In both syndromes decreased wakefulness and pupillary abnormalities are accompanied by paratonia and Babinski‘s sign contralateral to hemiparesis and periodic (Cheyne–Stokes) breathing (Broderick et al., 1993; Ropper & Shafran, 1984). In deep (subcortical) hemispheric strokes sparing the thalamus dearousal is usually mild and transient, probably because of the widespread distribution of ARAS projections at this level. The occasional observation of significant hypersomnia following anterior caudate and other deep hemispheric stroke suggests that subcortical centres may play a more important role in sleep–wake functions than usually considered (Braun et al., 1997; Villablanca et al., 1976). The rare occurrence of hypersomnia following corticosubcortical hemispheric strokes without mass effect supports the hypothesis of a role of the cerebral cortex in sleep–wake functions (Bassetti, 2000;Villablanca & Marcus, 1972). A few positron emission tomography studies suggested that hypersomnia may be related in these patients to a reduced metabolism of the contralateral hemisphere (‘transhemispheric diaschisis’) (Lenzi et al., 1982).

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In patients with brainstem stroke, disorders of wakefulness are due to direct disruption of the ARAS (Cairns, 1952; Plum & Posner, 1980). The most severe and persisting disturbances of wakefulness are seen in patients with thalamic, subthalamic, midbrain and upper pontine strokes, where fibres of the ARAS are bundled and can be severely affected by a single lesion. Mental arousal seems to be affected more by medial lesions, whereas involvement of lateral portions of the ARAS may impair preferentially motor arousal (Castaigne & Escourolle, 1967; Passouant et al., 1967). In paramedian thalamic lesions (even without subthalamic extension) the initial clinical picture may be similar to disturbance of consciousness of midbrain origin but recovery is usually better, probably because of the existence of an extrathalamic route of cerebral activation (Jones, 1994). The core of the lesion in these patients involves the dorsomedial nucleus (particularly its magnocellular part) and intralaminar (midline) nuclei (Bassetti et al., 1996b; Castaigne et al., 1981). Patients with lower pontine and medullary strokes have usually no, or only a limited, effect on arousal (Bassetti et al., 1997c; Toyoda et al., 1996). Insomnia, sleep deprivation, seizures, drugs, and systemic complications (fever, infections, metabolic disturbances) may contribute to decreased arousal in all patients with stroke. Genetic factors may play a role in determining the variable clinical effects of similar brain lesions in different patients (Bassetti, 2000).

Hypersomnia (drowsiness, somnolence, sleepiness) Hypersomnia can be defined on clinical grounds as an exaggerated sleep propensity with excessive daytime sleepiness, increased daytime napping or prolonged nighttime sleep. Patients are drowsy or appear asleep, show little interest in the environment, may be difficult to arouse or to stay awake once awakened. Verbal stimuli are usually sufficient to elicit speech and appropriate motor behaviour. Hypersomnia can appear after an initial period of sopor or coma, less commonly of hypervigilance with insomnia. Hypersomnia is often associated with inattention, decreased motor activity, reduced speech production, and flattening of mood. As a direct effect of brain damage poststroke hypersomnia may arise from decreased wakefulness (somnolence, ‘passive’ hypersomnia, or dearousal), enhanced sleep mechanisms (sleepiness or ‘active hypersomnia’), or both (Davison & Demuth, 1946a,b; Passouant et al., 1967). Both somnolence and sleepiness are characterized by a reduced latency to sleep. The somnolent patient usually presents – in addition to a disturbed state of consciousness – other neurological or neuropsychological deficits.

Conversely, the sleepy patient has usually – once aroused – a normal neurological examination. In clinical practice, somnolence and sleepiness may, however, be difficult to separate, evolve to each other or even coexist. ‘Passive’ hypersomnia is due to damage of the ARAS (see above). ‘Active’ hypersomnia with increased production of sleep can be induced in the cat by small, bilateral lesions of the periaqueductal gray and reticular formation at the ponto-mesencephalic junction (Petitjean et al., 1975; Sastre et al., 1996). In patients with poststroke hypersomnia, an increased sleep production has been documented by EEG criteria in only a few patients with thalamic, mesencephalic and pontine stroke (Arpa et al., 1995; Bassetti et al., 1996b; Bastuji et al., 1994). In large cortico-subcortical hemispheric strokes hypersomnia is accompanied by an ipsilateral (to the lesion) gaze palsy or preference and head deviation, contralateral severe sensori-motor hemisyndrome, visual field deficits, and variable neuropsychological deficits (Hacke et al., 1996). Hypersomnia, which is usually only transient, can be seen also in the absence of significant brain edema (see also above) in anterior more than posterior strokes, and in left more than right hemispheric strokes (Albert et al., 1976; Glosser et al., 1999). In a prospective study of 47 patients, Albert et al. found for example an impairment of arousal in 57% of patients with left hemispheric strokes and in only 25% of those with similarly extensive right hemispheric lesions (Albert et al., 1976). This as well as other similar observations supports the hypothesis of a left hemispheric dominance for wakefulness (Ahern, 1995; Glosser et al., 1999). In patients with frontal (particularly cingulate) stroke akinetic mutism may be misinterpreted as hypersomnia (Buge et al., 1975).

Castaigne and Escourolle reported a 66-year-old patient with bilateral anterior cerebral artery stroke and severe hypersomnia persisting over a few months (Castaigne & Escourolle, 1967). We recently observed a 40-year-old patient with left cortico-subcortical, partial middle-cerebral artery stroke in whom profound hypersomnia was present for the first 4–5 days after stroke despite the absence of both mass effect on brain-MRI and medical complications (Fig. 14.2).

Hypersomnia can occasionally complicate also deep (subcortical) hemispheric strokes involving uni- or bilaterally the caudate nucleus, putamen, globus pallidum, or capsula interna. In such cases apathy, athymormia, and

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Fig. 14.2. Brain MRI (axial T2-images) of a 40-year-old woman with left cortico-subcortical middle-cerebral artery stroke. During the first 4–5 days after stroke the patient appears asleep during 12–13 hours per day, is depressed, and has crying spells. Hypersomnia (somnolence) resolves within 1 week (see also text). (Courtesy of Professor G. Schroth, Division of Neuroradiology, University Hospital, Bern, Switzerland.)

akinetic mutism (see below) are also commonly seen. Caplan et al. reported, for example, abulia in 10 of 18 patients with acute caudate stroke, occasionally alternating with periods of confused hyperactivity with restlessness, insomnia and hallucinations (Caplan et al.,1990).

In a 68-year-old woman with left paraventricular striatocapsular stroke and mild sensorimotor deficits, a profound inversion of sleep–wake cycle were first noted. Two weeks later daytime hypersomnia had almost recovered, while nighttime insomnia with estimated 2–3 hours of sleep per night was still present. Sleep–wake functions finally normalized 4 weeks after stroke onset.

Unilateral and particularly bilateral (‘en ailes de papillon’) paramedian thalamic strokes in the territory of the anterior thalamic–subthalamic (or thalamoperforating) arteries present typically with the triad hypersomnia, supranuclear vertical gaze defects and confabulatory (Korsakow-like) amnesia (the so-called ‘paramedian dien-

cephalic syndrome’ (Meissner et al., 1987)). Hypersomnia, which was found in a review of the literature in 15 of 40 cases of paramedian thalamic stroke, appears typically after an initial short-lasting coma, less commonly after an agitated delirium (Gentilini et al., 1987). In patients with bilateral thalamic strokes, hypersomnolent behaviour may be present for ⬎20 hours per day and mimic physiologic sleep with normal postures, regular quiet breathing and rapid arousability (Bassetti et al., 1996a). In patients with a unilatreal stroke extending to the midbrain, however, hypersomnia may persists for weeks or even months (Bassetti et al., 1996a; Freund, 1913). Hypersomnia may correspond in other patients to a preparatory behaviour for sleep rather then ‘true sleep’ (Catsman-Berrevoets & Harskamp, 1988). During this socalled ‘pre-sleep behaviour’, the patients yawn, stretch, close their eyes, curl up and assume a normal sleeping posture while complaining of a constant urge to sleep. When stimulated or given explicit tasks to perform, these patients are, however, able to control their behaviour. In patients with unilateral paramedian thalamic stroke, hypersomnia is usally mild and transient. Additional symptoms of paramedian thalamic strokes include dysarthria, gait instability, skew deviation, Horner’s syndrome, hypogeusia, hyposmia, incontinence. Breathing is usually unaffected. Some patients also present a ‘frontal lobe syndrome’ with anosognosia, hyperphagia (and weight gain), hypersexuality, ‘utilization behaviour’, and altered mood (Bassetti et al., 1996a; Eslinger et al., 1991; Gentilini et al., 1987; Guberman & Stuss, 1983). Flat or depressed mood is frequently observed. Less commonly, patients present with insomnia, hallucinatory confusional state, logorrhea, euphoria with childish behavior, and motor restlessness with compulsive-like activity (Bogousslavsky et al., 1988a; Feinberg & Rapcsack, 1989; Fukatsu et al., 1997; Walther, 1945). Hypersomnia after thalamic stroke can persist for several months or years or evolve to apathy and dementia (Castaigne et al., 1966; Gentilini et al., 1987; Schuster, 1937).

A 60-year-old patient with bilateral paramedian thalamic stroke presented with abrupt coma followed by sleep behaviour over 19 hours per day, complete vertical gaze palsy, ‘frontal’ behaviour, moderate amnesia, hyperphagia and hypersexuality (Fig. 14.3). One week after stroke onset the patient is ‘asleep’ by actigraphic criteria over 80% of the time. At 8 months the patient still sleeps 12 hours per day. Methylphenidate (20 mg per day) and mazindol (4 mg per day) do not improve hypersomnia. Because of attentional and mnestic deficits,

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of a frequent common arterial supply through the socalled thalamo-perforating pedicle of Foix and Hillemand, upper mesencephalic strokes can extend to paramedian thalamic structures and give rise to a variety of possible clinical pictures. Isolated mesencephalic or thalamo-mesencephalic strokes are less common than strokes involving simultaneously midbrain, superior cerebellum and occipital cortex – (so-called top of the basilar syndrome (see also ‘Stuper and coma’, p. 198; Caplan, 1980). The severity of hypersomnia is variable and even in a single patient fluctuations between coma, hypersomnia and akinetic mutism are observed (Brage et al., 1961). Mesencephalic hypersomnia is characteristically associated with hypnagogic hallucinations (so-called peduncular hallucinations, see also ‘Hallucinations and altered dreaming, p. 202). III nerve palsy, a vertical gaze impairment and (less commonly), contralateral sensory and – occasionally – motor deficits (tremor, hemiparesis or ataxia).

Fig. 14.3. Brain MRI (coronal T2-images) of a 60-year-old man with bilateral paramedian thalamic stroke of cardiac origin presenting with initial coma evolving to severe hypersomnia (sleep-like behaviour over 19 hours per day) with severe upgaze palsy and amnesia. At 8 months the patient still reports sleeping 12 hours per day (see also text). (Courtesy of Professor G. Schroth, Division of Neuroradiology, University Hospital, Bern, Switzerland.)

the patient has to retire from work. Two years after stroke onset, hypersomnia has clinically improved to 9–11 hours sleep per day (Bassetti et al., 1996a).

Hypersomnia is also very characteristic of tegmental mesencephalic strokes due either to occlusion of the posterior thalamic–subthalamic (superior mesencephalic) arteries or to occlusion of the inferior mesencephalic arteries. The presence of a bilateral lesion is usually required but mild and transient hypersomnia is occasionally observed also in unilateral lesions (Claude & Loyez, 1912). Because

Façon et al. (1958) described a 78-year-old patient with bilateral tegmental mesencephalic infarct due to basilar thrombosis presenting with a bilateral III nerve palsy including ptosis, bilateral Babinski’s sign, hallucinations and severe hypersomnia. The latter was accompanied by an inversion of the sleep–wake cycle with nocturnal agitation and it persisted unchanged until his death 3 years later. A 54-year-old patient with right paramedian tegmental mesencephalic stroke of cardiac origin (coronarography) presented with peduncular hallucinosis, transient hypersomnia, skew deviation, amnesia, and vertical-oneand-a-half syndrome (Fig. 14.4). The patient reported the vision over several minutes of a group of dwarf-like figures, accompanied by tigers, and headed by a small girl in bright-orange dress.

Upper tegmental pontine stroke is suggested by the association of hypersomnia with ipsilateral IV nerve palsy, nystagmus, internuclear ophthalmoplegia, irregular breathing, and contralateral (or bilateral) sensory and motor deficits. Compared to thalamic and midbrain lesions, rostral pontine strokes lead more commonly to coma (see below) than to hypersomnia or akinetic mutism

Van Bogaert (1926) reported a 47-year-old patient with right tegmental ponto-mesencephalic stroke presenting with right IV and VII nerve palsy, facial myoclonus, right hemiparesis, severe, imperative (narcolepsy-like)

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Fig. 14.4. Brain MRI (axial T2-images) of a 54-year-old man with right paramedian tegmental mesencephalic stroke of cardiac origin presenting with transient hypersomnia, peduncular hallucinosis, skew deviation, amnesia, and vertical one-and-ahalf syndrome (see also text). (Courtesy of Dr A. Uske, Division of Neuroradiology, University Hospital, Lausanne, Switzerland.)

hypersomnia, and increased dreaming persisting until death five months later. Arpa recently reported a 44-year-old man with a right lateral-tegmental pontine hematoma and severe hypersomnia, in whom long-term EEG-monitoring showed, during the first 3 months after stroke, increased amounts of sleep ranging from 11 to 15 hours per day (Arpa et al.,1995).

In lower tegmental pontine and medullary strokes, a mild hypersomnia is occasionally observed (Bassetti et al., 1997a,b; Davison & Demuth, 1946a,b; Rousseaux et al., 1993).

Stupor (sopor) and coma Stupor and coma correspond to more advanced stages of impaired arousal. In stupor patients usually appear to be asleep and awaken only when stimulated with a loud voice

or vigorous shaking. They may be agitated or combative at such times but they do not communicate in a meaningful way apart from monosyllabic sounds, groans, and simple behaviors. They return to a sleep-like state as soon as stimulation ceases. Coma refers to a sleep-like state of unarousability in which consciousness is completely absent. Comatose patients keep their eyes closed even after painful stimuli, are not capable of any comprehensible verbal response, do not obey commands, and do not localize painful stimuli, although they may make posturing and reflexive responses. The percentage of patients in coma ranges from 5–18% in ischemic stroke to 31–55% in intracerebral hemorrhage (ICH) (Melo et al.,1992). In patients with hemispheric strokes, stupor and coma develop progressively over time with the clinical features of ‘central’ or (less commonly) ‘uncal’ syndromes (Plum & Posner, 1980; Ropper & Shafran, 1984), see also above). Stupor and coma are associated with a horizontal pineal displacement of greater than 4–8 mm which is usually maximal 4–5 days after stroke onset (Franck, 1995; Pullicino et al., 1999; Ropper, 1986). In patients with intracerebral hemorrhages, disturbances of wakefulness can have an abrupt onset, particularly in patients with basal ganglia hematomas. In hematomas ⬎55 cm3 coma was found in 14 of 17 patients (Kase & Caplan, 1994). In brainstem strokes coma may appear abruptly as a consequence of bilateral thalamic, midbrain or upper pons lesions (Cairns, 1952). Sudden disturbances of wakefulness, with delirium, hemi-tetraparesis, ataxia, gaze palsy, pupillary abormalities, and cortical blindness are typical features of the ‘top of basilar’ syndrome related to embolism of the rostral part of the basilar artery (Caplan, 1980; Mehler,1988, 1989). In most cases, some spontaneous fragmentation of the embolus occurs leaving multiple infarcts involving the paramedian thalamus (80% of cases), occipital lobes (46%), cerebellum (44%), midbrain (29%), and pons (18%) (Schwarz et al., 1997). As a consequence of spontaneous recanalization, over 40% of patients with ‘top of the basilar syndrome’ have a good outcome with no or only minor deficits (Schwarz et al., 1997). Sudden coma as well as coma of progressive onset are typical features also of basilar artery occlusion. Coma was found at hospital admission, for example, in 26 out of 85 consecutive patients with angiographic proven basilar artery occlusion (Ferbert et al., 1990). In these patients, particularly when the pathogenesis is local atherothrombosis, mortality exceeds 80%. After thrombolytic treatment, survival may be achieved in up to 50% of patients (Brandt et al., 1996; Ferbert et al., 1990; Kubik & Adams, 1946). Disturbances of wakefulness reaching from somnolence to coma, occa-

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sionally associated with hyperthermia, increased sweating and tachycardia, are seen also in patients with isolated ventro-tegmental infarcts of the pons or pontine hemorrhage (Bassetti et al., 1996b; Wijdicks & St. Louis, 1997). Finally, in patients with cerebellar infarcts and hemorrhages, coma can appear within a wide range of time (minutes up to 10 days), typically between day 3 and 4, after onset of symptoms due to compression of the brainstem, from upward or downward herniation (Cuneo et al., 1979; Hornig et al., 1994). Coma is rarely a permanent state, probably because of redundancy of activating systems, and most patients either die or regain identifiable sleep–wake cycles after a few days or weeks. Mortality of stroke patients in stupor and coma, particularly when requiring mechanical ventilation, is as high as 80% (Bushnell et al., 1999; Melo et al., 1992; Wijdicks & Scott, 1996). Coma persisting over more than a few days or weeks is rare and usually associated with bilateral pontine and mesencephalic strokes (Chase et al., 1968; Ingvar & Sourander, 1970; Obrador et al., 1975).

Hypervigilance (hyperarousal) Although decreased arousal is most often encountered in organic brain disorders, the opposite occasionally is observed. Hypervigilance may be caused by an increase in activity of systems maintaining wakefulness or by impairment of sleep promoting mechanisms as can occur with lesions of the anterior hypothalamus, thalamus or brainstem. Hypervigilance, insomnia (see ‘Insomnia’), inversion of sleep–wake cycle and delirium often coexist in the same patient (Girard et al., 1962; Van Bogaert, 1926).

Syncope Syncope is defined as a short and transient loss of consciousness with loss of postural control. Syncope is rarely caused by TIA or stroke (Davidson et al., 1991; Kapoor, 1983). Among a series of 551 patients with acute cerebrovascular disorders, syncope was observed in 6% of those who had suffered stroke and in less than 1% of those with TIAs (Bousser et al., 1981), more often in the carotid than in the vertebrobasilar territory. About half of all cases were attributed to seizures, and the rest to brainstem ischemia (with impairment of the ARAS) or to bihemispheric dysfunction related to diaschisis.

Coma-like conditions Patients in coma after stroke usually have a simultaneous involvement of ARAS and motor pathways. However, due to the anatomic segregation of the two systems in the ventral and tegmental portions of the brainstem respec-

tively, there is no close correlation between impairment of consciousness and motor dysfunction (Cairns, 1952). Occasionally, even a dissociated involvement of the two systems is possible with, at the one extreme patients with preserved ARAS but tetraplegia (locked-in syndrome and its variants) and, at the other extreme, patients with preserved motor control but disrupted ARAS (akinetic mutism).

Akinetic mutism The term akinetic mutism was coined by Cairns to describe a patient with an epidermoid cyst of the third ventricle, who was mute and immobile, but followed with her eyes the observer as well as moving objects and who could be brought by repetitive stimulation to ‘whisper few monosyllables’ and ‘slow feeble voluntary movements’, in the absence of ‘gross alterations of sensory–motor mechanisms operating at a more peripheral level’ (Cairns et al., 1941). Akinetic mutism (a.m.) represents an extreme form of abulia (abulia major) due to disruption of reticulothalamo-frontal and extrathalamic reticulo-frontal afferents. Two forms of a.m. have been identified. The first variety of a.m. has been described in patients with bilateral occlusion of the anterior cerebral arteries (Fig. 14.5) and hemorrhages (with vasospasm) from anterior communicating aneurysms. In a literature review of patients with bilateral infarctions in the territory of the anterior cerebral artery, a.m. was found in seven of eight cases (Minagar & David, 1999). Damage to the cingulate gyri seems to be crucial but alone not sufficient for the appearance of a.m. (Buge et al., 1975; Plum & Posner, 1980). Additional features of this ‘fronto-diencephalic’ variety of a.m. are urinary incontinence, normal wakefulness, grasping and bifrontal or generalized EEG-slowing, with lack of desynchronization following external stimuli. The second variety of a.m. has been observed in paramedian thalamic and thalamomesencephalic strokes and is characterized by the association of akinetic mutism with disturbances of vertical eye movements and hypersomnia (Lhermitte et al., 1963; Segarra, 1970). Occasionally, the discrepancy between hetero- and autoactivation can be extreme, with normal (or almost normal) behaviour of the patients under the influence of exogenous stimulation. This particular form of abulia or a.m. has been observed in bilateral deep lesions of the frontal white matter or of the basal ganglia (especially of the globus pallidum) and has been called athymormia (loss of psychic self-activation or ‘pure psychic akinesia’) (Bogousslavsky et al., 1991; Laplane, 1990; Laplane et al., 1984). Finally, a lesser degree of abulia (abulia minor) has been described also in bilateral caudate

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1979; Patterson & Grabois, 1986). Recovery is possible not only in incomplete LiS but also in patients with complete LiS and persistence of tetraparesis for months (McCusker et al., 1982; Yang et al., 1989). Bilateral, simultaneous deep hemispheric strokes (usually involving the capsula interna) can cause a clinical picture similar to akinetic mutism and LiS, for which different terms have been used in the literature (Chia, 1984; De Smet et al., 1990; Ferbert & Thron, 1992; Nicolai & Lazzarino, 1993). Because of the direct disruption of cortico-spinal and cortico-bulbar pathways and because of the normality of horizontal eye movements it should rather be called anarthric tetraparesis.

Disorders of awareness* *Most related clinical syndromes are presented in other chapters of this book (in particular ‘Agitation and delirium’ by A. Yamadori)

The spectrum of disorders of awareness is wide and includes relatively isolated dysfunctions of such specific functions as memory or language, or more diffuse disturbances of mental activities as occur with delirium, dementia or the vegetative state.

Delirium (acute confusional state) Fig. 14.5. Brain CT of a 24-year-old woman with bilateral strokes in the territory of the Heubner’s arteries due to spontaneous intracranial dissection of the anterior system presenting with akinetic mutism. (With permission from Bassetti et al., 1994a,b.)

stroke, thalamic infarcts in the territory of the polar artery and infratentorial stroke (Fisher, 1983).

Locked-in syndrome The term locked-in syndrome (LiS) was coined in 1966 by Plum and Posner for a condition first described by Alexander Dumas with the figure of the Count of Villefort in his book ‘Le comte de Monte-Cristo’ (Plum & Posner, 1980). The criteria of classical LiS are paralysis of all cranial nerves except vertical eye movements, tetraplegia and preserved consciousness. A differentiation between transient and chronic form as well as between incomplete, classical and total locked-in syndrome (LiS) has been proposed (Bassetti et al., 1994a,b; Bauer et al., 1979). LiS is classically due to bilateral pontine infarction (Fig. 14.6), related to basilar thrombosis, bilateral occlusion of paramedian arteries and vertebral artery dissection (Fisher, 1977; RaeGrant et al., 1989). Occasionally, LiS can be due to bilateral midbrain stroke (Karp & Hurtig, 1974; Meienberg et al.,

Delirium is characterized by reduced ability to maintain attention; disturbance of immediate memory; and disorganized, slowed, and impoverished thinking (Lipowski, 1990; Taylor & Lewis, 1993). Disorientation, altered shortterm and long-term memory, illusions, and hallucinations are frequently but not invariably present. Although delirium usually is accompanied by decreased arousal and psychomotor slowing, occasionally it may be characterized by hypervigilance and enhanced psychomotor activity. Occasionally, there is a ‘dreamy’ or ‘twilight’ state associated with partial loss of contact with the outer world. The severity of delirium typically waxes and wanes, occasionally from minute to minute, and may be interrupted by relatively lucid moments. Exacerbation of delirium in the night hours is typical and is called ‘sundowning’. Associated nighttime insomnia (Fisher, 1983), and daytime hypersomnia are common (Bassetti et al., 1996a). Stroke of any topography may lead to delirium (Bassetti & Regli, 1994; Fisher, 1983; Gustafson et al., 1991), although tegmental mesencephalic (Mehler, 1989), and paramedian thalamic (Bogousslavsky et al., 1988a), basal ganglia (Bhatia & Marsden, 1994; Caplan et al., 1990), right frontotemporal (Mori & Yamadori, 1987), and occipital strokes (Devinski et al., 1988) have been more commonly implicated with this disturbance of consciousness.

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Other disorders of sleep Due to the widespread anatomo-physiological organization of wakefulness, NREM sleep and REM sleep, other disorders of sleep–wake functions – in addition to the already mentioned hypersomnia – can be found in patients with both supra- as well as infratentorial stroke ranging from severe insomnia and other clinically relevant disturbances to subclinical polysomnographic findings.

Insomnia

Fig. 14.6. Brain MRI (sagittal T1-images) of a 36-year-old man with bilateral ventral pontine infarction due to basilar thrombosis presenting with a ‘locked-in syndrome’. (With permission from Bassetti et al., 1994a,b.)

Vegetative state This syndrome is defined as an awake-but-unaware condition with preservation of vital vegetative functions and absence of all cognitive functions (Jennett & Plum, 1972; The Multi-Society Task Force, 1994a,b). Spontaneous eye opening, yawns, chewing, grimacing, and other reflex motor actions occur along with spontaneous respiration. The lack of awareness and cognition is apparent in the inability of such patients to respond in a learned manner to external stimuli and the absence of sustained, reproducible, purposeful, or voluntary responses to stimulation. The reduction in cognitive and metabolic activity is usually associated with extensive damage to cortex and subcortical structures with relative sparing of brainstem structures; preserved brainstem function accounts for the persistence of autonomic functions and sleep–wake cycle. Less commonly, PVS can follow more or less selective damage of paramedian thalamic structures, emphasizing the key role of these structures in cognitive processes (Kinney et al., 1994). The vegetative syndrome has no topographic specificity and can follow different types of brain injury (head trauma, diffuse cerebral hypoxia, stroke or diffuse encephalopathies) (Jennett & Plum, 1972). In non-traumatic cases, persistence for over 1 month carries a very poor prognosis, provided that the diagnosis is accurate (Childs et al., 1993).

Insomnia is a frequent, usually non-specific, and often multifactorial complication of acute stroke. Insomnia may predispose to such quantitative and qualitative disturbances of consciousness as delirium and hypersomnia (see above), and may slow poststroke functional recovery. Recurrent arousals, sleep discontinuity and sleep deprivation can result from pre-existing disorders (e.g. congestive heart failure, chronic pulmonary disease). Seizures, sleepdisordered breathing (see ‘Sleep disordered breathing’, p. 202); drugs, infections and fever, inactivity, environmental disturbances (e.g. noise, medical controls and tests, light) and emotional stress are other stroke-related factors predisposing to insomnia. Insomnia as a direct consequence of brain damage (agrypnia) is less common in stroke patients but may occur, often in association with inversion of the sleep–wake cycle and depressive symptoms (Garrel et al., 1966; Girard et al., 1962; Rondot et al., 1986; Van Bogaert, 1926). The occasional observation of patients with rapid transition from insomnia to hypersomnia emphasizes the dual influence of such brain areas as thalamus, basal forebrain and ponto-mesencephalic junction in sleep–wake regulation (Bogousslavsky et al., 1988a; Fisher, 1983; Hösli, 1962; Jones, 1994).

Van Bogaert reported a patient with thalamohypothalamic stroke, who presented an almost complete insomnia over more than 2 months (Van Bogaert, 1926) . Freemon reported a patient with a ‘locked-in’ syndrome following brainstem infarction of the basis pontis bilaterally, left pontine tegmentum and pontine and mesencephalic raphae nuclei who presented with severe polygraphically confirmed insomnia, which was almost complete for at least 1 month (Freemon et al., 1974). Stroke patients occasionally have an inversion of the sleep–wake rhythm, which is usually characterized by insomnia with agitation during the night and by hypersomnolence during the day.

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Sleep disordered breathing* *see also chapter on ‘Respiratory dysfunction’ by F. Vingeroets

The presence of breathing disturbances in stroke patients has been linked in several studies with a poorer outcome (Dyken et al., 1996; Good et al., 1996; North & Jennett, 1974; Rout et al., 1971). Breathing disturbances are more common during sleep than during wakefulness (Bassetti et al., 1997b; Lee et al., 1974; North & Jennett, 1974). Several studies have shown that sleep disordered breathing (SDB) can be found in over 50% of patients with acute TIA or stroke (Bassetti & Aldrich, 1999; Bassetti et al., 1996a; Dyken et al., 1996). Specific types of poststroke breathing disorders have limited topographic specificity (Bassetti et al., 1997a; Lee et al., 1974, 1976). Supratentorial stroke is, however, often associated with Cheyne–Stokes breathing, whereas central hyperventilation, central apnea, apneustic breathing, and ataxic breathing usually indicate the presence of infratentorial stroke. Finally, OSA is found in both supra- and infratentorial strokes.

Obstructive sleep apnea (OSA) This is the most common type of SDB in patients with acute cerebrovascular disorders. Although patients at risk for cerebrovascular disease frequently have OSA before they experience a stroke, in some patients OSA appears to have been aggravated (e.g. by sleep disruption, Cheyne–Stokes breathing) or even caused ‘de novo’ (e.g. medullary infarction, severe pharyngeal palsy) by acute brain ischemia. OSA can influence the course of cerebrovascular diseases in different ways. Chronically, recurrent nocturnal respiratory events and hypoxemia (Fig. 14.7) may lead to hypertension, heart disease, increased platelet aggregation, decreased fibrinolysis, and increased atherogenesis (Bassetti & Aldrich, 1999). Acutely, hypopneas and apneas may lead to brady- and tachyarrhythmias, hypotension, decreased cardiac output, increased intracranial pressure, decreased cerebral blood flow, and eventually brain ischemia (Bonsignore et al., 1994; Diomedi et al., 1998; Fischer et al., 1992; Leslie et al., 1999; Netzer et al., 1998).

Cheyne-Stokes breathing (CSB) This is well known in bihemispheric stroke, heart failure, somnolence, and brain edema with increased intracranial pressure (Brown & Plum, 1961; Heyman et al., 1958). Recent studies have shown, however, that CSB is also frequent in awake patients without cardiac disease who have had a unilateral hemispheric or infratentorial stroke (Bassetti et al., 1997a,b; Hudgel et al., 1993; Nachtmann et al., 1995). Finally, CSB and OSA may occur in the same

patient and exacerbate each other (Nachtmann et al., 1995; North & Jennett, 1974). Strokes in the frontal cortex, basal ganglia or capsula interna may cause respiratory apraxia, with impairment of voluntary modulation of breathing amplitude and frequency, leaving patients unable to take a deep breath or hold the breath (Plum, 1970). Volitional breathing can be impaired also by brainstem strokes involving corticobulbar and corticospinal pathways at pontine and medullary levels (Munschauer et al., 1991; Plum, 1970). Sustained respiratory rates above 25–30/minute in the absence of hypoxemia (neurogenic hyperventilation) were originally described in six comatose patients with ventro-tegmental pontine strokes (Plum & Swanson, 1959), but were subsequently attributed to stimulation of lung and chest wall afferent reflexes due to pulmonary congestion (Plum & Posner, 1980). Inspiratory breath holding (apneustic breathing), originally described in two patients with bilateral ventro-tegmental infratrigeminal pontine stroke (Plum & Alvord, 1964), is rare and usually secondary to basilar artery occlusion. Erratic variations in breathing frequency and amplitude (ataxic or Biot’s breathing), and failure of automatic breathing (central sleep apnea or Ondine’s curse), usually imply a lateral, often bilateral medullary stroke (Bogousslavsky et al., 1990; Levin & Margolis, 1977). Damage to the medullary reticular formation and nucleus ambiguus may be sufficient to cause a loss of automatic breathing, while a lesion that also includes the nucleus tractus solitarius is necessary to cause failure of both automatic and voluntary respiration (Bogousslavsky et al., 1990).

Hallucinations and altered dreaming Patients with tegmental mesencephalic strokes (Fig. 14.4) and, less commonly, with paramedian thalamic strokes, may experience vivid dream-like hallucinations that are complex, colourful, full of motion, and typically occur in the evening and at sleep onset, Lhermitte’s peduncular hallucinosis (Feinberg & Rapcsack, 1989; Garrel et al., 1966; Howlett et al., 1994; Lhermitte, 1922; Van Bogaert, 1924). The original patient described by Lhermitte had, in addition to the complex visual hallucinations, an inversion of the sleep–wake cycle with nocturnal insomnia and daytime hypersomnia (Lhermitte, 1922). Peduncular hallucinosis may represent a release of REM sleep mentation (Mahowald & Schenck, 1992), can be associated with insomnia and usually resolves spontaneously.

Disturbances of consciousness and sleep–wake functions 203

Fig. 14.7. Polysomnographic study of a 51-year-old man performed 2 days after a severe middle cerebral artery stroke. There is a severe sleep-disordered breathing (apnea–hypopnea index ⫽ 48) consisting of mainly mixed and obstructive apneas with severe oxygen desaturations (minimal SaO2 ⫽ 33%). The figure shows an apneic event during light NREM sleep of a duration of almost 90 seconds with accompanying SaO2-desaturation to 54.5%.

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Similar hallucinatory phenomena can be seen also in patients with delirium and right temporal and occipital stroke (Milandre et al., 1994; Mori & Yamadori, 1987). The Charles Bonnet syndrome generally involves less complex visual hallucinations that also occur in the setting of diminished arousal (Lepore, 1990; Teunisse et al., 1996). These hallucinations represent ‘release phenomena’ of strokes that involve visual loss and may be limited to a hemianopic field (Martin et al., 1992; Vaphiades et al., 1996). Cessation or reduction of dreaming occurs in the Charcot–Wilbrand syndrome and is occasionally limited to alteration of the visual component of the dream (as in the original patient described by Charcot) (Charcot, 1883; Gloning & Sternbach, 1953; Grünstein, 1924; Solms, 1997; Wilbrand, 1887). This syndrome can occur in patients with parieto-occipital, occipital or deep frontal strokes and the lesions are often bilateral (Bischof et al., 1998; Murri et al., 1984; Solms, 1997). Patients frequently, but not invariably, show deficient revisualization (referred to as visual irreminiscence), topographical amnesia, and prosopagnosia (Murri et al., 1985). A 73-year-old woman with a bilateral medial occipital lobe and left posteroventral thalamic infarction presented with left homonymous hemianopsia, right quadrantanopsia, achromatopsia, mild left hemiparesis, and bilateral crural ataxia. Detailed neuropsychological examination revealed only reading difficulties related to visual field deficits. The patient reported frequent dreaming (several times/week) before stroke. After stroke the patient denied any dream experience for the first 3 months after stroke. On polysomnography REM sleep characteristics were normal and even after four awakenings from REM sleep the patient denied any dream experience (Bischof et al., 1998). The syndrome of dream-reality confusion and recurrent nightmares may occur as a consequence of focal seizures secondary to stroke, particularly in the course of rightsided temporal lesions (Boller et al., 1975; Solms, 1997). Increased frequency or vividness of dreaming may occur after thalamic and occipital stroke (Gloning & Sternbach, 1953; Grünstein, 1924).

Sleep EEG changes Sleep EEG changes have been reported more often in brainstem strokes but are common also in hemispheric stroke. Changes in sleep architecture are due to brain damage but also other such non-cerebral factors as sys-

temic complications of stroke (e.g. fever, infections, breathing disturbances, depression/anxiety), drug treatment, and environmental causes.

Brainstem strokes These can cause selective loss of REM-sleep or a decrease of all, REM- and NREM-sleep as well as total sleep time (Autret et al., 1988; Freemon et al., 1974; Markand & Dyken, 1976; Tamura et al., 1983). In paramedian thalamic strokes reduction of sleep spindles and NREM-sleep stage 2 correlates with clinical severity of hypersomnia (Bassetti et al., 1996c).

Hemispheric strokes These can be accompanied by a decrease of sleep spindles, NREM-sleep and REM-sleep, which have been correlated with stroke extension and clinical outcome (Bassetti & Aldrich, 1999; Giubilei et al., 1992; Hachinski et al., 1978; Körner et al., 1986).

Others Occasionally, brainstem strokes can disrupt specific components of REM-sleep. REM-sleep behaviour disorder, with potentially injurious ‘acting out’ of dreams due to loss of REM-sleep atonia, has been reported in patients with small (lacunar) strokes in the dorsal ponto-mesencephalic tegmentum (Culebras & Moore, 1989). A reduction of physiologic sleep myoclonus during NREM-sleep was described in the hemiplegic limbs of a stroke patient (Dagnino et al., 1969). Periodic leg movements in sleep can increase or decrease after unilateral hemispheric stroke and may persist after spinal stroke (Dyken & Rodnitzky, 1992; Yokota et al., 1991). Whereas circadian hypersomnia is common following stroke (see above), paroxysmal hypersomnia (narcolepsy) is extremely rare. The best-documented case has been observed in an HLA-DR2-negative patient with multiple pons lesion following respiratory arrest (Rivera et al., 1986). A Kleine–Levine-like syndrome characterized by hypersomnia and megaphagia has been reported once in association with brain infarction in an elderly hypertensive woman with multiple lacunar strokes (Drake, 1987).

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15

Aphasia and stroke Andrew Kertesz St Joseph’s Health Centre, London, Ontario, Canada

Introduction The regular recurrence of aphasic syndromes, especially with strokes, has formed the basis of the cortical localizationist models and has provided clinicians a solid foundation for diagnosis and prognosis. Approximately 25% of stroke patients have significant aphasia (Leske, 1981), making this a common neurological and rehabilitation issue. Broca (1861) established the importance of the left hemisphere in language. Meynert (1867/1868) is credited with the motor sensory dichotomy of cortical function and also with recognizing the accompanying anteroposterior anatomical distinction. Wernicke (1874), subsequently, extended the description of aphasic syndromes including comprehension deficit, on the basis of this motor–sensory dichotomy. Upon these foundations, a number of aphasic syndromes have been described subsequently. The taxonomy of these syndromes has been much debated, but in Table 15.1 the most commonly accepted classification and terminology are summarized. The issue of specialized language cortex, functionally unique and anatomically localizable, similar to the primary motor or visual cortex, has become an important question for research. The existence of such a language cortex is supported by the large number of persisting aphasic patients and the anatomical and physiological evidence for networks for language output and comprehension. The characteristics of such networks can be summarized as: (i) a function is represented at multiple sites, therefore lesions from multiple sites can produce a similar deficit, (ii) each area may belong to several overlapping networks, therefore a lesion in a single area often produces multiple deficits, and (iii) severe and lasting deficit of function occurs when all or most structural components of a network are involved.

Broca’s aphasia, expressive aphasia, motor aphasias Articulated language This is an example of complex cognitive function subserved by a neural network. Speech output is an easily available, clinically and scientifically much studied function. It is elaborated differently whether it is in response to questions (responsive speech), spontaneous (internally generated) expression of ideas, descriptive speech, or repetition. Spoken language incorporates many subfunctions, which have been categorized by linguists as articulation, fluency, prosody, phonological processing, lexical retrieval, syntax, and pragmatics, etc. Nevertheless, all or most of the functional components tend to be involved to some extent in the clinical syndrome of Broca’s aphasia which can be reliably defined by standardized test scores (Kertesz, 1979) or by careful clinical description. Many identifiable, even dissociable central processes, such as agrammatism or dysprosody contribute to the syndrome, but these do not have nearly as reliable localization as the syndrome as a whole. Articulation and language output are affected in other syndromes as well and these will be discussed further.

Broca’s aphasia This is defined as effortful speech output with hesitations, pauses, word-finding difficulty, phonemic errors (verbal apraxia) consisting of substitutions, deletions, transpositions and anticipations, occasional semantic errors, and agrammatism, but relatively preserved comprehension (Goodglass & Kaplan, 1972).

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Table 15.1. Major aphasic stroke syndromes

Broca’s aphasia – expressive aphasia Pure motor aphasia – aphemia Transcortical motor aphasia Global aphasia Wernicke’s aphasia – sensory aphasia Pure word deafness – cortical deafness Transcortical sensory aphasia Anomic aphasia Conduction aphasia Isolation or mixed transcortical aphasia

Output

Comprehension

Repetition

Naming

Other feature

– – – – ⫹ ⫹ ⫹ ⫹ ⫹ –

⫹ ⫹ ⫹ – – – – ⫹ ⫹ –

– – ⫹ – – – ⫹ ⫹ – ⫹

– ⫾ ⫾ – – – ⫾ – ⫹ –

agrammatic better writing not paraphasic mute or stereotypy paraphasic better reading semantic jargon only naming deficit mainly repetition deficit only repetition spared

Agrammatism This is characterized by short utterances, omission of small grammatical words such as article, preposition, auxiliary verbs, and inflexions. Nouns or single words substantive utterances predominate and the verb is often deleted. Speech becomes telegraphic suggesting to some that it represents an ‘economy of effort’ (Pick, 1913). Agrammatism has different manifestations in different languages (Goodglass, 1997). Lesions producing Broca’s aphasia have been described from Broca’s area, which is the ‘foot’ of the inferior frontal convolution or F3, although they often extend beyond this to involve the rolandic operculum, anterior insula, subcortical (capsulostriatal) area, and periventricular or centrum semiovale lesion (Moutier, 1908; Henschen, 1922; Kertesz et al., 1979; Levine & Sweet, 1983). Involvement of only Broca’s area is usually followed by good recovery (Mohr, 1976). The variation in lesion size and location is related to the extent of anterior middle cerebral artery occlusion. The overlap of acute aphasic lesions, based on our study, is summarized in Fig. 15.1 (Kertesz et al., 1979). Broca’s aphasia which persists is associated with large lesions including not only Broca’s area (posterior third of F3 and the frontal operculum), but also the inferior parietal and often the subcortical regions (Kertesz, 1988; Kertesz et al., 1979; Mohr, 1976). Persistent non-fluency has been associated with lesions extending to the rolandic cortical region and underlying white matter in previous studies (Lecours & Lhermitte, 1976; Levine & Sweet, 1983). The involvement of the central white matter was also important for the fluency deficit in the head-injured population of Russell and Espir (1961) and Ludlow et al. (1986), and in stroke (Naeser et al., 1989). The centrum semiovale or periventricular white matter, which is involved in persistent

cases of global or Broca’s aphasia, often includes the pyramidal tract, thalamocortical somatosensory projections, striatocortical connections, callosal radiations, the subcallosal fasciculus (Muratoff, 1893), thalamocortical projections from the dorsomedial and ventrolateral nuclei (Yakovlev & Locke, 1961), and the occipitofrontal fasciculus (Dejerine & Dejerine-Klumpke, 1895). The overlap of lesions with persisting aphasic syndromes is summarized in Fig. 15.2. Lesion location was evaluated in Broca’s aphasics, who were divided at the median for poor and good recovery. The structures with significant involvement (more than 50%) were the inferior frontal gyrus, especially the pars opercularis and triangularis, and the insula in both groups. The difference between the persisting cases of Broca’s aphasics and those who show good recovery was most prominent in the involvement of the precentral, postcentral, and supramarginal gyri in cases of poor recovery. The subcortical regions showed significant differences in the involvement of the putamen and the caudate, which was twice as frequent in the persistent cases (Kertesz, 1988). Outcome measures had a high negative correlation with lesion size throughout. Naming was an interesting exception, indicating possibly a ceiling effect combined with the relative persistence of even moderate naming deficit. All of these patients were treated with a variable amount of language therapy; many of them for the duration of the study. Some of them participated in a formal study of language therapy (Shewan & Kertesz, 1984). There are several patterns by which a vascular lesion could produce Broca’s aphasia. The most common pattern involves the frontal opercular and central cortex, and the anterior insula, with or without significant subcortical involvement. These patients often recover quite well, with the exception of those who had cortical, central, insular, and

Aphasia and stroke

Fig. 15.1. The overlap of lesions in acute aphasic syndromes. (Reprinted with permission from Kertesz et al., 1979.)

subcortical involvement. There is, however, a certain amount of variability in how the components of the network are affected producing different degrees of recovery.

Global aphasia This is defined by the loss of speech output, as well as comprehension, usually associated with destruction of both the anterior and posterior language areas (Kertesz & Phipps, 1977). Large middle cerebral artery stroke, occasionally hemorrhage, is the usual etiology. However, in patients who are initially global, Wernicke’s area may be spared. These patients tend to recover towards Broca’s aphasia. Even ‘Broca’s area’ cortex may not be destroyed, although it is usually disconnected from the rest of the language cortex by white matter involvement (Naeser et al., 1989). Occasionally, mostly white matter lesions can produce persistent global aphasia. There are also case reports of patients with initial global aphasia without hemiplegia, who recover dramatically when they have posterior–frontal and posterior temporal regions but sparing of the central structures (Van Horn & Hawes, 1982; Ferro, 1983). The classification of severely non-fluent aphasics influences the results of localization and recovery studies. For instance, in the Boston Diagnostic Aphasia Examination (BDAE) (Goodglass & Kaplan, 1972), a large group of what others would classify as severe Broca’s aphasics may be labelled, at times, as ‘mixed anterior aphasics’. In the clas-

sification system of Aachen Aphasia Test (AAT) (Huber et al., 1983), many global aphasics would be reclassified as Broca’s aphasics in other clinics. Some of these problems in taxonomy have been systematically studied in the comparison of aphasia batteries and how their scoring systems affect classification (Ferro & Kertesz, 1987). Global and Broca’s aphasias, as defined by our taxonomy and methods of measurements, have similar spontaneous language characteristics. In our previous taxonomic studies (Kertesz & Phipps, 1977), these were the two closest groups in the nearest neighbour-network analysis. The major difference between the two groups is in the extent of comprehension deficit. Since comprehension often recovers well, there are a great number of patients who change from global to Broca’s aphasia during recovery (Syndromenwandeln) (Leischner, 1976).

Pure motor aphasia Also called cortical motor aphasia aphemia, or verbal apraxia, this has been associated with Broca’s area anterior subcortical, inferior rolandic, and insular cortical lesions. Verbal apraxia is frequently used by speech pathologists to denote hesitation, stuttering, dysprosody, ritual consonant substitution, deletions, repetition, transposition and anticipation (Darley et al., 1975) that can occur as part of non-fluent or Broca’s aphasia, or occasionally alone. All forms of speech output are affected, including repetition, in contrast with transcortical motor aphasia.

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Fig. 15.2. The overlap of persisting aphasic lesions. (Reprinted with permission from Kertesz et al., 1979.)

Transcortical motor aphasia This is characterized by poor spontaneous speech but good repetition and comprehension. There is a variable naming deficit and the writing output is also poor. The localization of lesions is characteristically in the mesial frontal region or the supplementary speech area in the dominant hemisphere (Goldstein, 1948; Kornyey, 1975; Rubens, 1975; Chusid et al., 1954; Arseni & Botez, 1961). These are often caused by an anterior cerebral artery stroke. The importance of the supplementary motor areas on the left was recognized by Penfield and Roberts (1959), who renamed it the ‘supplementary speech area’ because of the frequent speech arrest which was found during stimulation of this region. Cytoarchitecturally, the supplementary motor cortex appears to represent a paralimbic extension of the limbic cortex (Sanides, 1970). This suggests a link between the limbic system and initiation of the motor mechanisms of speech. The lack of speech initiation is often considered a part of a general hypokinetic syndrome associated with frontal lobe lesions. The term ‘adynamic aphasia’ has also been used to describe this behaviour since Arnold Pick and Kleist. Recovery is usually excellent and these patients are only seen in acute units as a rule. A similar, but progressive nonfluent aphasia is recognized increasingly as part of clinical Pick’s disease (Kertesz et al., 1994), but the temporal characteristic of this syndrome is the opposite from stroke-induced aphasia.

The onset is insidious and deterioration instead of improvement takes place with time.

Wernicke’s aphasia, sensory aphasia Language comprehension This is a complex process involving analysis of acoustic and phonological properties of input, as well as a recognition of syntactic and lexical elements (Liebermann et al., 1967). This rapid parallel processing of input and matching it to linguistic precepts is an analytical left hemisphere function. The most likely candidate to perform this is the auditory association cortex, localized to the superior temporal gyrus region and the planum temporale located behind Heschl’s gyrus.

Wernicke’s aphasia This is characterized by fluent, paraphasic speech with impaired comprehension, repetition, and naming. Syntax and morphology are relatively preserved, but the substantive words are often substituted by semantic or phonological paraphasias. At times, a large number of paraphasias, almost all nouns, distort the speech output to the extent it sounds like jargon. At times this is produced under pressure in great quantities and the patients are not aware of

Aphasia and stroke

their disability (anosognosia for language impairment). Reading and writing are similarly affected. The taxonomic boundaries of Wernicke’s aphasia can be defined with language scores, although this may be considered arbitrary (Kertesz, 1982).

‘Pure word deafness’ This is used when the patient complains of not understanding speech, but hearing, reading, and speech output remain undisturbed. One type is called word form deafness (Kohn & Friedman, 1986). These patients often ‘mishear’ phonologically similar words, and they cannot tell words from non-words (lexical decision). The other type is ‘word meaning deafness’ where patients can perform lexical decision tasks but cannot access semantics (Franklin et al., 1994). Auditory agnosia for non-verbal sounds and amusia is often associated, although these symptoms may be seen with right-sided lesions without the verbal component. In cortical deafness, which is the result of bilateral temporal lesions, the patient appears clinically deaf with preserved primary hearing, but impaired central auditory processes (Kertesz, 1983).

Neologistic jargon Neologistic jargon output is distinctive and occurs in severe Wernicke’s aphasia, associated with lesions of both the superior temporal and inferior parietal regions (Kertesz & Benson, 1970). The superior posterior temporal branch of the middle cerebral artery is usually involved. Wernicke’s aphasia with semantic jargon is correlated with lesions which are somewhat smaller, inferior and more temporal than those with neologisms or phonemic paraphasia (Kertesz, 1983). Other CT studies indicated that patients with semantic substitutions have lesions posterior to those with phonemic paraphasia (Cappa et al., 1981). Wernicke postulated that the auditory association area plays a monitoring role in language output (presaging modern concepts of feedback and parallel processing), and its damage results in paraphasic, faulty speech.

Conduction aphasia This is distinguished by poor repetition with relatively fluent, but paraphasic, speech and good comprehension. The term was originated by Wernicke (1874) on the basis of the theory that conduction of sensory impulses to motor patterns is impaired. However, it was Lichtheim (1885) who specified the disturbance of repetition as a feature of conduction aphasia. Others have observed the close asso-

ciation of conduction aphasia and claimed it is part of a spectrum. Goldstein (1948) considered it ‘central aphasia’ and many others subsequently accepted it as a separate form. Some conduction aphasics struggle a great deal to approximate target phonemes (conduites d’approche) and some investigators consider conduction aphasia a form of expressive aphasia such as Luria, who called these patients ‘afferent motor aphasics’. The patients are aware of their mistakes and their efforts are considered corrective. The repetition deficit in conduction aphasia has been viewed as a disturbance in short-term verbal memory (Warrington & Shallice, 1969) or as an ordering deficiency (Tzortis & Albert, 1974). The more fluent varieties can be distinguished on taxonomic studies (Kertesz & Phipps, 1977) and their lesions are also more posterior. More recently some patients have been renamed ‘deep dysphasia’ as they had difficulty accessing meaning through phonology, lexicalized nonwords and produced semantic paraphasias (Katz & Goodglass, 1990).

Transcortical sensory aphasia This is characterized by fluent, semantic jargon, poor comprehension and good repetition. These patients usually have far more posterior lesions, usually in the watershed area between the middle cerebral and posterior cerebral circulation (Kertesz et al., 1982), although at times thalamic lesions are described with ‘transcortical sensory’ features. Recovery is usually rapid unless the syndrome evolves from a more severe lesion initially producing Wernicke’s aphasia.

Isolation syndrome, or mixed transcortical aphasia This has features of both motor and sensory transcortical aphasia, and tends to have a poor prognosis with nonfluency persisting and not all comprehension returning, depending on the etiology. It is called isolation syndrome because the lesions tend to surround the middle cerebral artery territory, often in watershed areas, isolating the language areas (Goldstein, 1948). It occurs relatively uncommonly and the recovery patterns have not been described extensively. In our experience, persisting cases occur with strokes and with post-traumatic lesions.

Anomic aphasia This is the mildest form of aphasic syndrome, characterized by fluent output, good comprehension, and only naming and word finding difficulty. Word finding or word access, the retrieval of lexical items (often tested by

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naming), is a fundamental process in language, and anomia is a feature of most aphasic syndromes. Various types of anomia however have been distinguished, and certain differences in brain damage associated with these types have been described (Benson, 1979). Anterior and central lesions are more likely to produce lexical retrieval deficit without a loss of semantic representation. Posterior temporoparietal lesions often produce naming difficulty which is associated with some comprehension deficit for the same lexical item or a loss of meaning of words, even though they may be used in a correct grammatical sentence. Head (1926) called these cases ‘semantic aphasia’. The study of lexical access and semantic processing is a major scientific and clinical topic. Recent advances in this field include the study of modality-specific fields (verbal vs. visual) and the category specificity of recognition and retrieval of lexical items. Lexical retrieval is thought to be dependent on a widely distributed cortical network (Berndt & Mitchum, 1997). Lesion studies and functional activation have suggested the role of left temporoparietal and temporo-occipital cortex and functional activation and have added the frontal lobe as having a role in semantic processing (Petersen et al., 1990). Considering the complex nature of semantic association, narrowly restricted localization of this function is not likely. This is already evidenced from the wide distribution of lesions resulting in anomia or anomic aphasia. Patients who only have anomic aphasia de novo usually recover well. Mild word finding and naming difficulty are very common in acute stroke. They can be seen transiently with subcortical, anterior cortical and posterior cortical lesions. Rapid recovery is the rule even before these patients are transferred to rehabilitation.

Subcortical stroke aphasias The role of subcortical structures in language is not fully understood. Marie (1906; 1926) proposed a role of subcortical structures in language early on, some of these have been recently duplicated. Motor impairments often dominate the deficit in lesions of the basal ganglia. This is ranging from dysarthria and hypophonia (which has been known to occur commonly after thalamotomies) to severe global aphasia. Anomic aphasia is often observed, presenting as a disturbance of word retrieval and rather hesitant speech (Mazzocchi & Vignolo,1979; Alexander & Loverme, 1980). The often preserved repetition is called a ‘transcortical feature’ (Selby, 1967; Cappa & Vignolo, 1979). Bell (1968) considered the deficit to be similar to the aphasias of the frontal regions. Lesions in the putamen and the anterior internal capsule produces slow, anomic, dysarthric

speech and with posterior extension comprehension is also impaired with paraphasic speech and jargon (Barat et al., 1981; Naeser et al., 1982; Damasio et al., 1982). Isolated lesions of the caudate or putamen are rare, but both have been described as causing transient speech deficits (Hier et al., 1977). Damasio et al. (1982) found that infarcts in the anterior limb of the internal capsule and in the striatum caused aphasia, while non-aphasics had more lateral or caudal lesions. Naeser et al. (1982) divided nine patients with capsuloputaminal lesions into three syndromes related to lesion site. Patients with lesions extending into anterior–superior paraventricular white matter had good comprehension and grammatical, but slow, dysarthric speech. Posterior extension across the temporal isthmus resulted in fluent speech with poor comprehension. Patients with both anterior-superior and posterior extension had global aphasia. Alexander et al. (1987) presented a more detailed model. Only minor language disorders were seen with lesions confined to striatum and internal capsule, and it was postulated that subcortical aphasia is due to disruption of intra-hemispheric white matter pathways. Thalamic lesions produce fluctuating jargon aphasia alternating with relatively non-fluent speech (Mohr et al., 1975). Although subcortical lesions are often said to produce atypical syndromes (Damasio et al., 1982) when an attempt is made to compare the scores of patients with subcortical lesions with equivalent sized cortical lesions, the differences are not significant (Kertesz, 1984; Basso et al., 1987; Kirk & Kertesz, 1994). Distant cortical hypometabolism or diaschisis are considered possible reasons for the deficit, in addition to whatever intrinsic coordinating or processing may take place in the basal ganglia (Metter et al., 1981; Perani et al., 1987; Baron et al., 1986).

Alexia and agraphia Disturbance of reading and writing may occur in isolation with distinct cortical localization, but also in various combinations with aphasia. Written language functions are also subserved by networks and therefore more than one lesion site will account for the same syndrome. Dejerine (1892) made the classical distinction between pure alexia with left occipital lesions which usually involve the splenium or its radiation, and alexia with agraphia which are associated with parietal, at times specifically angular gyrus, lesions on the left side. Dejerine’s description of the lesion in pure alexia was the prime model for the disconnection theories postulating the existence of white matter lesions disconnecting various cortical language processors (Geschwind, 1965). The recent linguistic distinction of

Aphasia and stroke

deep and surface dyslexia (deep and surface refers to linguistic, not anatomical structures), based on error analysis of the reading of non-words and orthographically irregular words, are partially correlated with anatomical differences (Ellis, 1984). Deep dyslexia seems related to large perisylvian infarcts and corresponds to what other authors describe as aphasic alexia (or the third alexia) (Benson, 1979). Surface dyslexia or reading without comprehension is seen with temporal damage mainly (Bub & Kertesz, 1982). Other varieties of lesions disconnecting primary visual input from the angular gyrus were termed ‘preangular’ or ‘subangular’ alexias by Greenblatt (1983). Agraphia is associated with parietal lobe lesions on the dominant side but agraphia is common with any lesion producing aphasia, although dissociations have also been observed (Bub & Kertesz, 1982). Frontal lobe lesions can produce agraphia, although the existence of Exner’s centre in the second frontal convolution in front of the hand area of the precentral gyrus has not been generally supported. Recent studies showed a considerable amount of agraphia with purely subcortical lesions, which is somewhat different from agraphia due to cortical lesions because it seems mostly the graphomotor aspects rather than grammatical and semantic aspects are involved (Kertesz, 1984). This type of agraphia used to be designated as apraxic agraphia. Ideographic (Kanji) and syllabic (Kana) writing in Japanese have been reported to be dissociated with different lesion localization, suggesting different neuronal processing. Kanji processing is semantic and context dependent. Kana, on the other hand, can be read aloud without semantic processing. Iwata (1984) suggested semantic processing takes place through inferior occipitotemporal connections, because lesions in this area interfere with Kanji selectively (Kawahata et al., 1988; Kawamura et al., 1987). Dorsal connections through the angular gyrus are involved in Kana (or phonological) processing, similar to Indo-European languages. Pure agraphia for Kanji has also been reported with subcortical damage under-cutting the left inferior temporal gyrus (Mochizuki & Ohtomo, 1988).

Recovery of aphasic stroke syndromes Clinicians have recognized aphasic stroke syndromes are not stable and recovery takes place to a considerable extent. Wernicke (1886) postulated much of the recovery from aphasic symptoms is affected by right hemisphere compensation. Von Monakow (1914) stated, ‘the temporary nature is one of the most important characteristics of aphasia’. He based his diaschisis theory on observations

with aphasics and on the analogy of spinal shock, well established by physiologists. Diaschisis means acute brain damage deprives the surrounding, functionally connected areas of a trophic influence causing a severe deficit initially. As the surrounding areas recover by acquiring reinervation from somewhere else or become active after adapting to the state of partial denervation, in either way, recovery takes place. There are certain structural limitations of recovery, allowing compensation to take place only in certain areas, such as the adjacent cortex, contralateral homologous cortex or hierarchically connected structure, such as the subcortical ganglia (Lashley, 1938; Bucy, 1934). The principle of contralateral homologous cortical substitution was based on large left hemisphere lesions with relatively good recovery where there was very little left hemisphere remaining to take over. More recently, CAT scan studies made the same point (Cummings et al., 1979; Landis et al., 1980). In addition, in some patients who became aphasic with a single left hemisphere stroke but recovered, a second, right hemisphere stroke produced a language deficit again (Nielsen, 1946; Levine & Mohr, 1979; Cambier et al., 1983). These cases, however, may have represented bilateral language organization to begin with, rather than a commonly operating mechanism of functional transfer to the contralateral hemispheres. The idea of compensation through right hemisphere function, even after partial left hemisphere damage, was also supported by studies of effects of sodium amytal given to aphasics who had recovered (Kinsbourne, 1971; Czopf, 1972). These studies indicated that, even though the aphasic disturbance occurred from a left hemisphere lesion, it was the right hemispheric injection which increased the language disturbance, implying the right hemisphere compensated for the previous deficit produced by the left-sided lesion. The variation in recovery, which cannot entirely be explained by the extent and location of lesions, has been postulated to relate to differences in language laterality, handedness, age, and gender. Subirana’s (1969), Gloning et al’s (1969), and Geschwind’s (1974) suggestion that left handers and right handers, with a family history of left handedness, recover better from aphasia because of more bilateral language distribution, is based on anecdotal evidence. Recent studies of anatomical asymmetry on CT scans, inspired by the demonstration of commonly larger planum temporale on the left by Geschwind and Levitsky (1968), have correlated better outcome with atypical or less asymmetry (Pieniadz et al., 1983). This is also based on the idea that this pattern may be associated with more right hemisphere language. We have studied the factor of anatomical asymmetry on CT, as measured by occipital width,

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frontal width, and protuberance (petalia) and could not confirm atypical asymmetry played a role in recovery in any of the aphasic groups (Kertesz, 1988). It could be that anatomical asymmetries relate more to handedness variables rather than language distribution, as suggested by some of our studies in normals (Kertesz et al., 1992); therefore, we are not seeing an effect on language recovery. It has been suggested woman have more bilaterally distributed language (McGlone, 1980). However, when we looked at sex differences in recovery, we found none and no evidence to support better right hemisphere substitution by women (Kertesz, 1988). We did not find a sex difference in the anterior–posterior distribution of language impairment either (Kertesz & Benke, 1989). Cerebral blood flow (CBF) and positron emission tomography (PET) studies of cerebral metabolism provide methodologies which add functional information to structural or lesion studies of recovery. Recent studies of CBF with xenon 133 have also revealed a right-hemisphere hypometabolism in aphasic strokes, the extent of which has correlated with recovery to a modest degree (Knopman et al., 1984). PET studies of cerebral metabolism have shown a great deal of hypometabolism surrounding, but also remote from, cerebral infarcts thus suggesting not only surrounding areas but also homologous areas in the contralateral hemisphere play a role in compensation (Metter et al., 1981). However, one CBF study showed no significant change, while clinical recovery occurred in severe aphasics (Demeurisse et al., 1983). Patients who improved more, showed more blood flow in the left hemisphere. This appears to be the consequence of the size of the lesion, which correlates with the CBF changes. Another CBF study showed better than 60% hemispheric flow in patients with good recovery (Nagata et al., 1986). More recent studies of PET activation suggested right hemisphere, as well as ipsilateral, compensation (Weiller et al., 1992).

Functional activation of language More recent functional activation confirms the importance of the posterior temporal area in auditory perception of language, and the central and premotor cortex in articulation, in addition to some newly emphasized components to the language network, such as the mesial frontal and lateral frontal areas in word retrieval and semantic association (Petersen et al., 1990). The anterior cingulate gyrus appeared part of an anterior attentional system indicated by its activation while monitoring lists of words for semantic category (Petersen et al., 1990). Some of the con-

tinuing work with PET and O15 and recent efforts on magnetic resonance functional activation promises to shed further light on these issues (Weiller et al., 1992; Binder & Rao, 1994; Chertkow & Murtha, 1997). Functional activation is complementary to the clinical study of aphasic stroke syndromes.

Conclusions The size and location of lesions, time-from-onset, etiology and initial severity, are complex, interdependent factors in clinical symptomatology and the recovery of language loss. Other biological factors, such as age, education, handedness, and sex play a less significant role when an adult stroke population is followed. Lesion size is undoubtedly a significant factor in the extent of recovery and can be easily determined by CT or MRI scanning. An exception to the negative correlation between language recovery and lesion size is comprehension. In some patients, even with large lesions, the amount of comprehension recovery is considerable; while patients with small lesions demonstrate a relatively small degree of recovery. One of the unresolved issues remains whether ipsilateral connected adjacent, or distant, even contralateral, cortex plays a major role in compensation. The answer is probably both, but our studies of lesion location and recovery in Broca’s and Wernicke’s aphasia suggest ipsilateral connected structures play the major role in restoration of function after damage. These are structures which are likely to be used normally in the language network, although for somewhat different functions at different times. The functional participation by these structures implies neuroplasticity rather than a built-in redundancy when recovery from damage occurs. The cytoarchitectonic similarity and anatomical contiguity make adjacent structures prime candidates for substitution. The language network of the left hemisphere is capable of a considerable degree of compensation, producing various clinical patterns of deficit, but its complete destruction results in permanent loss in the majority of individuals. Functional activation and cortical stimulation provides convergent evidence of such networks, as well as bilateral activation and integration in language function. The addition of cognitive neuropsychology and functional neuroimaging to the clinical knowledge of aphasic syndromes has deepened our understanding of language organization in the brain. In clinical practice, the value of clinical symptoms and aphasic syndromes in predicting localization of stroke lesions and prognosis remains undiminished.

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Agitation and delirium John C.M. Brust1 and Louis R. Caplan2 1 2

Department of Neurology, Harlem Hospital Center, New York, USA Beth Israel Deaconess Medical Center, Boston, USA

Introduction, definition of terms, and frequency of the problem The fundamental feature of delirium is disordered attention. Delirious patients cannot focus and sustain attention on one stimulus among multiple stimuli, and cannot shift attention at will. Table 16.1 lists diagnostic criteria for delirium from the American Psychiatric Association. If delirious patients are attentive enough to allow testing, abnormalities of thinking, perception, and memory will usually be found. The abnormalities may include disorientation to time and place, impaired immediate, recent, and remote memory, dysnomia, agraphia, and visual-spatial dysfunction. Much of the difficulty with perceptual function and speech output relates to the inability to sustain attention to the task at hand. Illusions, hallucinations, and delusions may also be prominent. Sleep–wake patterns are usually abnormal with reduced wakefulness during the day and reduced, often fragmented sleep at night. Autonomic hyperactivity produces flushing, mydriasis, sweating, tachycardia, and labile blood pressures. Delirious patients may quickly shift from hyperactivity to reduced activity. During the day lethargy and even catatonic behaviour may predominate, shifting at night to agitation, shouting, and aggressive behaviour. The terms delirium, confused, agitation, and confusional state are used variously by different neurologists and psychiatrists. The criteria cited in Table 16.1 incorporate several very different elements including acuteness of onset, altered thought and concentration, level of consciousness, and cause. Confusion is defined by Adams et al. (1997) as: denoting the patient’s incapacity to think with customary speed, clarity, and coherence. Its most conspicuous attributes are an

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inner sense of bewilderment, impaired attention and concentration, an inability to properly register immediate events and to recall them later, and a dimunition of all mental activity including the normally constant inner ideation . . . Reduced perceptiveness with visual and auditory illusions and even hallucinations and paranoid delusions are variable features.

Confusion in their terminology is an essential component of delirium. Adams et al. (1997) use the term delirium to denote a special type of confusional state. ‘Delirium is marked by a prominent disorder of perception, terrifying hallucinations and vivid dreams, a kaleidoscopic array of strange and absurd fantasies and delusions, inability to sleep, a tendency to convulse, and intense emotional reactions.’ Lipowski (1990) defined the acute confusional state as: an organic mental syndrome featuring global cognitive impairment, attentional abnormalities, a reduced level of consciousness, increased or decreased psychomotor activity, and a disordered wake–sleep cycle.

Some authors, including Victor et al. (1997) reserve the term delirium to describe an overactive state of heightened alertness that includes agitation, frenzied excitement and trembling, while other physicians and authors, including many psychiatrists, include both hypoactive and hyperactive behavior with confusion within the spectrum of delirium. Many simply reserve the term delirium to describe behavioural and cognitive states that closely resemble the most familiar form of delirium – delirium tremens that develops in alcoholics during withdrawal. Delirium and confusional state are thus terms that are used variably and these terms are difficult to apply practically. The word confused is used in common parlance to mean mixed up. Confusion refers to altered thinking ability. It is not a technical term. Since the terms delirium

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Table 16.1. Diagnostic criteria for delirium (American Psychiatric Association (1987) A. Reduced ability to maintain attention to external stimuli (e.g. questions must be repeated because attention wanders) and to appropriately shift attention to new external stimli (e.g. perseverates with the answer to a previous question) B. Disorganized thinking as indicated by rambling, irrelevant, or incoherent speech C. At least two of the following: 1. reduced level of consciousness (e.g. difficulty in keeping awake during examination) C. 2. perceptual disturbances (misinterpretations, illusions, or hallucinations) C. 3. disturbances of sleep–wake cycle, with insomnia or sleepiness during the day C. 4. increased or decreased psychomotor activity C. 5. disorientation to time, place, or person C. 6. memory impairment (e.g. inability to learn new material, such as the names of several unrelated objects after 5 min, or to remember past events, such as the current episode of illness) D. Clinical features developing over a short period of time (usually hours to days) and tending to fluctuate over the course of a day E. Either 1 or 2 below C. 1. evidence from the history, physical examination, or laboratory tests of a specific organic factor (or factors) judged to be etiologically related to the disturbance C. 2. in the absence of such evidence, an etiologic organic factor can be presumed if the disturbance cannot be accounted for by any nonorganic mental disorder (e.g. manic episode accounting for agitation and sleep C. 2. disturbance)

and confusional state are used so variously and include so many disparate features, their use sometimes only serves to confuse physicians. Preferable is to describe in simple direct English: (i) the acuteness or chronicity of the disorder, (ii) the level and amount of activity, (iii) the nature of the altered thinking, and (iv) the cause. It is well understood and appreciated that individuals who are sleepy or stuporous cannot pay attention or concentrate normally and cannot think as clearly as those who are wide awake and alert. For that reason, we believe it serves little purpose to apply the term delirium to individuals who have decreased alertness. In this chapter we will limit the discussion to hyperactive behavioural states in which thinking and concentration are abnormal. In our opinion it is best to consider etiology as a separate

issue and not to incorporate it into the definition of the clinical state. Diffuse brain dysfunction characterized by altered level of consciousness, poor ability to concentrate, and altered cognitive functions when caused by potentially reversible biochemical and physiological changes is usually referred to as encephalopathy. When the behavioral abnormality relates to endogenous usually biochemical abnormalities in various internal organs, the term metabolic encephalopathy is used, while dysfunction due to exogenous factors such as drugs and toxic substance exposure is usually called toxic encephalopathy. Since this book is concerned mostly with the neuroanatomy and neurophysiology of various neurological stroke-related symptoms and signs, we will emphasize hyperactive states with accompanying confusion associated with focal strokes and will not discuss the encephalopathies herein. Delirium is common. Agitation or delirium occur at one time or another in one-third to one-half of hospitalized elderly patients and after surgery in 10–15% of general surgery patients ages 65 and older (Lipowski, 1983). Delirium is associated with a variety of medical illnesses including pneumonia, urinary tract infection, sepsis, meningitis, dehydration, electrolyte imbalance, congestive heart failure, uremia, liver failure, head injury, and postictal states. It is often associated with drugs such as anticholinergic agents, cocaine, amphetamines, hallucinogens, etc., and may occur after withdrawal from benzodiazepines, alcohol, or barbiturates. The presence of delirium carries a poor prognosis, especially in the elderly. In one study, onethird of 4000 patients admitted to a hospital with delirium died within 1 month (Bedford, 1959). Increased mortality and morbidity are likely due to the seriousness of the underlying disease and the difficulty in caring adequately for very agitated patients who often cannot co-operate with treatments.

Neuroanatomical substrate of hyperactivity and agitation Delirium may occur after an acute stroke. Often unappreciated, however, is that delirium may be the predominant or even the only readily observable neurological abnormality and yet may indicate focal brain damage rather than a general toxic or metabolic abnormality. In a retrospective study of 661 stroke patients admitted to a hospital in Perth, Australia, 19 (3%) patients presented with ‘delirium, an organic delusional state, the acute onset of dementia, or mania, mimicking psychiatric illness’; computed tomography (CT) or autopsy showed focal lesions in all of these

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patients (Dunne et al., 1986). Among nine patients with ‘acute delirium’ all had right cerebral hemisphere infarcts (perisylvian in 3, temporal 2, frontal 1, parietal 1, frontotemporal 1, and temporoparietal 1). A prospective study of 145 consecutive stroke patients found delirium, either at admission or within 1 week of admission, in 69 patients (48%) (Gustafson et al., 1991). In this study, delirium affected 56 of 113 (50%) patients with brain infarcts, 6 of 21 (29%) patients with TIAs, and 7 of 8 (88%) patients who had brain hemorrhages. Delirium was more common in patients with left-sided brain lesions (38/65, 58%) than in patients with right-sided lesions (18/47, 38%). Independent predictors of the likelihood of delirium were: severe weakness, previous episodes of delirium, old age, and treatment with anticholinergic drugs. Delirium was also associated with complications of stroke such as myocardial infarction, pulmonary embolism, deep vein thrombosis, urinary retention, and urinary tract infection. In a later report, the same authors found that delirium correlated with elevated blood levels of cortisol, both before and after receiving dexamethasone (Gustafson et al., 1993). In a study that addressed the association of delirium and structural lesions, 36 of 60 hospitalized patients with ‘acute confusional state’ had focal brain lesions (Mullally et al., 1982a). Nineteen of these patients had ‘minor or absent elementary signs’. In that and other reports, confusion and delirium were associated with infarction involving the territories of the anterior, middle, or posterior cerebral arteries (de Reuck et al., 1982). Miller Fisher (1983) reviewed his experience with two behavioural states that seemed to be polar opposites: abulia and agitated behaviour. Abulic patients had decreased activity. They were often apathetic and lacked initiative and exploratory behaviour. They were slow to respond and their responses were brief and unsustained. In contrast were patients who were hyperactive and agitated. These individuals were often restless, excited and hyperalert, and had an increased amount of speech (logorrhea) and activity (Fisher, 1983). The brain lesions in patients with abulia, when localizable, were located in the upper mesencephalic tegmentum, substantia nigra, medial thalami, striatum, and frontal lobes. Many of the lesions involved or interupted projecting fibres to the frontal lobes. In contrast, when hyperactive agitated patients had focal brain lesions, the location was most often in the posterior portions of the cerebral hemispheres in the temporal, occipital and inferior parietal lobes. Many of the agitated patients had infarcts or inflammatory lesions that involved limbic cortex.

Posterior circulation territory strokes Top-of-the basilar artery embolism and posterior cerebral artery territory (PCA) strokes Embolism to the rostral basilar artery causes infarction in the paramedian midbrain and thalamus and/or in the temporo-occipital lobe territory of the posterior cerebral arteries (PCAs) (Caplan, 1980). Agitation lasted 2 months and was followed by ‘severe dementia’ in a middle-aged woman who had bilateral infarction of the hippocampal formation and the fusiform and lingual gyri (Glees & Griffith, 1952). Horenstein et al. (1962) reported nine patients who had hyperactive agitated behaviour and sudden onset visual loss. They described the behaviour of their patients as ‘restlessness, agitation, forced crying out, and extreme distractability’. These patients were very talkative and their conversations tended to flow freely from one topic to another without any external interference. All had infarcts in the unilateral or bilateral territory supplied by the PCAs. The infarcts most often involved the fusiform and lingual gyri (Horenstein et al., 1962). Later, Medina et al. (1974) described the clinical and pathological findings in a 78-year-old man who had the sudden onset of an agitated, excited state. This man was described as previously quiet and stable, despite a prior stroke that caused a transient left hemiparesis and left hemisensory loss, and a persistent left hemianopia. His niece found him suddenly agitated. He cursed and became violent, striking her. On admission to the hospital he was extremely agitated, perspired profusely and screamed, tried to bite individuals, and spat. He was also blind and had poor memory. This man remained agitated and shouted most responses to queries until his death about five months after his stroke. Necropsy showed an old infarct in the territory of the inferior division of the right middle cerebral artery involving the superior temporal gyrus and the inferior parietal lobe. The left PCA territory was also infarcted including the entire lingual gyrus and portions of the adjacent fusiform, parahippocampal, and calcarine gyri (Medina et al., 1974). The left hippocampus, the mamillary bodies, and portions of the left thalamus were also involved including the pulvinar. Reviewing nine of their own patients and 49 patients gleened from other reports, Symonds and MacKenzie (1957) noted ‘confusion at the onset’ in half of patients who had acute infarct with visual loss in the bilateral territories of the PCAs. One of the patients reviewed by Symonds and MacKenzie (1957) had paranoid behaviour associated with bilateral PCA territory infarction. Other patients had either hallucinations, or denial of blindness, but none was

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described as frankly delirious (Symonds & MacKenzie (1957). Caplan (1980, 1996, 2000) reviewed reports of patients who developed an agitated delirious state caused by embolism to the rostral basilar artery and its PCA branches. Necropsy and neuroimaging of these patients showed bilateral infarcts invariably involving occipital and temporal lobe cortex below the calcarine sulcus including the lingual and fusiform gyri. Bilateral visual field defects and memory loss usually accompanied the agitated, hyperactive state. Some patients had visual defects that predominantly affected the superior quadrants. Some also had infarcts in the rostral brainstem and superior cerebellar artery territory of the cerebellum; however, no patient with an isolated rostral brainstem infarct had an agitated hyperactive state. The patients with bilateral rostral brainstem tegmental infarcts were, in contrast, sleepy and had reduced activity. Infarction of the PCA territory on the lower bank of the calcarine sulcus was always present in delirious patients with posterior circulation brain embolism (Caplan 1980, 1996, 2000). A hyperactive agitated state also occasionally develops after vertebral artery angiography (Caplan, 1996). During or after dye contrast angiography, these patients become hyperactive and restless, have markedly reduced vision, and poor memory. The agitation, confusion, and other neurological signs usually remit within several hours. In most patients angiography is normal and the patients have received a large amout of iodinated contrast material. This syndrome is most probably caused by a reaction to the contrast material in the bilateral territories of the PCAs. Other reports describe patients with unilateral lesions in the territory of one PCA. Devinsky et al. (1988) reported the clinical and imaging abnormalities in four patients with left PCA territory infarcts who had an agitated confusional state, and reviewed prior reports of confusional states in patients with unilateral PCA terrritory infarcts. All four patients had lesions of the left occipital and posteromedial temporal lobes. Three had infarcts in the distribution of the left PCA that were most likely explained by cardiogenic embolism. One patient most likely had dural sinus and cortical venous thrombosis with left posteromedial temporal lobe and occipital lobe infarction. Three of the patients had agitated states sometimes alternating with lethargy. One had the sudden onset of ‘confusion, agitated disorientation, and aggressive behavior’, shouting curses and threats and throwing objects at the wall. He was ‘distractable and shifted the focus of his attention to virtually any novel stimulus’ (Devinsky et al., 1988). Another agitated patient had speech described as ‘fluent but tangen-

tial with difficulty finding words’. In some patients the agitated confusional state was transient. Devinsky and colleagues reviewed prior reports of patients with unilateral PCA territory infarction who had acute confusional states. Eighteen of the 19 patients (95%) described in ten different reports had left PCA territory infarcts while only one had a right PCA territory infarct. Fisher (1983) also commented that, when an agitated delirium developed in patients with unilateral PCA territory infarct the lesion was usually in the dominant left cerebral hemisphere.

Thalamic strokes Graff-Radford et al. (1984) described altered cognitive functioning in five patients with unilateral thalamic infarcts involving in four patients, the dorsomedial, anterior, ventrolateral, ventral anterior, and midline nuclei, and in one, the central median and the parafascicular, dorsomedial, and ventral posterior nuclei. Each had abnormalities of memory, visual-spatial perception, intellect, and personality. Patients with left-sided lesions had transcortical aphasia. One patient had delusions but none was frankly delirious. Santamaria et al. (1984) described five patients with anteromedial small thalamic hemorrhages who showed ‘lack of initiative and spontaneous movements, loss of insight, placidity, and impaired attention, orientation, and anterograde memory’. One also showed prominent ‘agitation, loquacity, easy laughing, and social disinhibition’. Four were incontinent. All five patients had minimal focal neurological signs. Bogousslavsky et al. (1988) reported a woman with ‘a disinhibition syndrome affecting speech (with logorrhea, delirium, jokes, laughs, inappropriate comments, extraordinary confabulations)’. This patient had an infarct in the right thalamus involving the dorsomedial nucleus, the intralaminar nuclei, and the medial portion of the ventral lateral nucleus. In contrast to her disinhibited speech, there was little motor or behavioural spontaneity (Bogousslavsky et al., 1988). In this patient, single photon emission computed tomography (SPECT) showed hypoperfusion of the overlying cerebral cortex especially frontally. The authors posited that the patient’s findings might have represented a disconnection of the dorsomedial thalamic nucleus from the frontal lobe and limbic system (Bogousslavsky et al., 1988).

Brainstem strokes Arseni and Danaila (1977) described hyperactive behaviour and increased amount of speech in relation to pontine brainstem disease. A patient with a basilar artery aneurysm and a clinical deficit localizable to the pons and upper

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brainstem showed logorrhea and hyperactivity. Speech flowed without stimulation from one idea and topic to another without interuption. They emphasized that logorrhea and hyperactivity did not always occur together. Among their 13 patients, six had both logorrhea and hyperactivity while one patient had logorrhea without hyperactivity and six other patients were hyperkinetic but mute. A patient reported by Pessin et al. (1989) had a dolichoectatic basilar artery and an infarct in the territory of a penetrating pontine artery branch and suddenly became loquacious and had persistent logorrhea after she developed a hemiparesis caused by her pontine infarct. Logorrhea and hyperactivity are frequent components of agitation and delirium. None of the reported patients with brainstem lesions was frankly delirious.

Infarcts in the territory of the middle cerebral arteries (MCA) Boudin et al. (1963) described ten patients who had the sudden onset of confusion with agitated behaviour. Two of the patients died and necropsy showed right temporal lobe infarcts. In the other patients clinical and EEG abnormalities suggested that the vascular lesions involved the right temporal lobe. Juillet and colleagues (1964) reported four patients who had visual abnormalities and confusion often with agitation. In two of these patients the clinical and EEG abnormalities suggested right temporal lobe infarction. Mesulam et al. (1976) reported three patients who had acute confusion with agitation related to infarction in the territory of the right MCA. The abnormal behaviour in these patients began abruptly, with extreme distractability, incoherent streams of thought, restlessness, agitation, and hyperactive behaviour. In one patient an early generation CT scan showed a lesion in the inferior right frontal lobe, although this patient had no motor or sensory signs. In the other two patients a radionuclide scan showed lesions in the right temporal and inferior parietal lobes. Angiography in one patient showed an occlusion of the right angular artery branch of the MCA but was normal in the patient with the CT-documented frontal lobe infarct. These patients all had emboli to the right MCA. Although the authors posited that right parietal lobe infarction was the likely explanation for the agitated state, the localization of the ischemic lesions in their patients was imprecise. Guard et al. (1979) reported ten patients with right temporal lobe lesions who had inattention, disorientation, agitation, and impaired cognitive functioning. Four had visual hallucinations, and one was initially thought to have a manic-depressive illness. Only 6/10 had left-sided neuro-

logical signs. Mullally et al. (1982b) reported three patients with left hemiparesis secondary to MCA territory infarction who had ‘failure to maintain a coherent stream of thought or action with inattention and distractabiltiy’. A year later, left hemiparesis had cleared, but all three patients remained ‘confused’. Levine and Finkelstein (1982) described ‘delayed psychosis’ in eight right-handed patients with acute right temporo-parietal lesions. Four had embolic infarcts, three had subcortical hemorrhages, and one had a contusion. Mental symptoms began abruptly 1 month to 11 years after the initial brain damage and lasted days to months, recurring in two patients. All patients had formed auditory and visual hallucinations; insight into the reality of the hallucinations varied, as did coexisting abnormalities of orientation, memory, cognition, and affect. Each patient had paranoid delusions and agitation, and some had fluctuating inattentiveness, perseveration, incoherent thinking, screaming, or aggressive violent behaviour. Focal signs were slight. No patient had prior psychiatric illness or drug abuse. Seven of the eight patients had seizures, often focal. The psychotic symptoms did not resemble the seizure manifestations and were too long-lasting to be postictal. Seizures and mental symptoms were considered parallel rather than causal manifestations of ‘an unstable pathophysiological state’ (Levine & Finkelstein, 1982). Price and Mesulam (1985) reported five right-handed patients with inattention, agitation, hallucinations, and paranoid delusions following probable infarction of the right parietal, frontal, or temporal lobes. Schmidley and Messing (1984) reviewed the clinical and imaging findings in 46 patients who had infarction in the territory of the right MCA. Two patients presented with agitation and confusion. Each had left hemianopia and minor left limb motor signs. CT scans in one of these patients were normal, and in another, showed an enhancing right temporal–parietal infarct. Angiography in the agitated patient who had a normal CT showed delayed filling of the temporal and inferior parietal branches of the inferior division of the right MCA. The other 44 patients had more severe motor and sensory signs indicating that their infarcts were more anterior, deeper, or both. A clinico-pathological conference in Paris concerned a 68-year-old man who had the sudden onset of abnormal behaviour. (Awada et al.,1984). He was agitated, could not attend to tasks, and spoke incessantly and incoherently. There was left hemianopia but no motor, sensory, or reflex abnormalities. CT showed an infarct that involved the right inferior parietal and temporal lobes in the territory of the inferior division of the right MCA. In another report, Dunne et al. (1986) considered seizures the most likely

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cause of intermittent altered behaviour that appeared weeks to months after left lobar cerebral hemorrhages (temporal, frontal, occipito-parietal) in three patients. Two patients had delusions and hallucinations and one had a ‘manic delirium’. Caplan et al. (1986) searched the Stroke Data Bank registry and their own patient files for patients with acute strokes that involved the inferior division of the right MCA. All ten patients reported had left visual field abnormalities. Motor abnormaliites were slight and transient. Three had severe agitated delirium at onset. One patient moaned continuously and repeatedly removed all treatment lines, tubes, and catheters despite four-limb restraints. He became less restless after 12 hours, but continued to call out random names and spoke incoherently, and his conversation incessantly flitted from one topic to another. His wife said that he had told her that people entered his room through the windows and so he often hid under the covers to avoid them. Four other patients were restless and had difficulty concentrating for neurologic testing. The restless agitated patients had abnormal drawing and copying. The anatomical localization of infarcts was plotted in the five agitated, restless patients vs. the five other patients who were not agitated. Figs. 16.1 and 16.2 show this reconstruction. The agitated patients all had right temporal lobe infarcts. The authors concluded that infarction of the right temporal lobe was the likely explanation for the agitation that sometimes accompanies right MCA territory infarcts. Mori and Yamadori (1987) studied 41 patients with right MCA territory infarcts, among whom 25 had acute confusion and six had acute agitated delirium characterized by extreme agitation, irritability, vivid hallucinations, delusions, insomnia, and signs of autonomic nervous system overactivity. The six patients with agitation had infarcts in the distribution of the inferior division of the right MCA, involving the territories of middle and posterior temporal artery branches in five of the six patients. Mori and Yamadori (1987) attributed confusion to right frontal and basal ganglionic dysfunction and agitated delirium to temporal lobe infarction. They posited a limbic–sensory disconnection as the mechanism of the agitated state. Agitation, anger, and paranoia are sometimes noted in patients with Wernicke’s aphasia, who most often have embolic occlusions of the inferior branch of the left MCA causing temporal lobe infarction. Patients with aphasia, who are irascible and show anger, usually have Wernicke type aphasia (Fisher, 1970). These behavioural changes are most likely explained by dysfunction of structures that lie medial to the convexal temporal lobe infarcts that cause the aphasia. The reports cited provide conclusive data that infarcts

involving the right temporal lobe in the territories of temporal artery branches of the right MCA are an important cause of an agitated hyperactive state associated with logorrhea. Possibly relevant is that logorrhea is also a feature in patients with left temporal lobe infarcts and Wernicke’s aphasia and excessive loquaciousness may be a characteristic of temporal lobe dysfunction involving either hemisphere and may be present without aphasia.

Anterior cerebral artery territory, frontal and caudate strokes Medial frontal lobe lesions Infarction in the territory of the anterior cerebral arteries (ACAs), especially when bilateral, can cause a variety of behavioural abnormalities, most often abulia (decreased spontaneous behavior and speech with apparent emotional apathy). (Fisher, 1983; Brust, 1998). The relative contribution to abulia, or less often to agitation and delirium, of damage to the cingulate gyrus, supplementary motor area, orbitofrontal cortex and other limbic structures is uncertain. Hyland (1933) reported a patient who had thrombosis of an azygous type ACA and developed a left hemiparesis accompanied by hypersexuality and incessant talking. Amyes and Nielsen (1955) reported eight patients who had lesions involving the cingulate gyri; seven lesions were vascular and one patient had multiple sclerosis. Three of these patients had agitation, hyperactivity, and psychosis. One patient with an aneurysm and bilateral paramedian frontal and orbitofrontal infarcts had severe agitation that alternated with abulia. Agitation and screaming also alternated with akinetic mutism in a patient with bilateral ACA territory infarcts reported by Faris (1969). Starkstein et al. (1988) reported 12 patients with maniclike behaviour after brain lesions clustered in and near limbic areas with strong frontal lobe projections. After reviewing reports of similar patients, the authors posited that dysfunction of the orbito-frontal region might underlie the production of the somatic and mood abnormalities found in patients with mania. Starkstein et al. (1990) later described a second group of eight patients with mania after brain injuries. All were elated and had pressured speech and grandiose delusions. Seven were hyperactive and had insomnia and flights of ideas; five were irritable and six were hypersexual. All of the lesions involved the right cerebral hemisphere. One patient had an infarct involving the head of the caudate, medial temporal gyrus, and basotemporal and dorsolateral

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Fig. 16.1 and 16.2. Five CT scans from patients without agitation (Fig. 16.1) and 5 CT scans from patients with agitation (Fig. 16.2) were analysed. In patients without agitation (Fig. 16.1) the lesions tended to extend mostly into the inferior parietal lobe, sparing the temporal lobe. In agitated patients (Fig. 16.2) the lesions tended to extend into the temporal lobe. Solid black shading indicates involvement of the

frontal regions. Another had an infarct involving the head of the caudate, amygdala, hippocampus, and basotemporal cortex. Another patient developed an infarct after embolization of a right basotemporal vascular malformation. One had a right temporal lobe hemorrhage. Another had bilateral orbitofrontal contusions. Brain scans in three patients showed subcortical lesions including: a contusion that involved the white matter of the anterior frontal lobe, an infarct of the ventromedial caudate head and adjacent anterior limb of the internal capsule, and a larger infarct of the caudate nucleus and anterior limb. PET scans in the three patients with subcortical lesions showed abnormal metabolism in the right lateral basotemporal regions. Bakchine et al. (1989) reported a manic-like state in a patient with bilateral orbitofrontal and right temporoparietal lobe contusions. This patient had a reduced amount of spontaneous behavior when left alone but became manic when stimulated. She had reduced sleep time and frequent outbursts of anger. When spoken to, she became

logorrheic and constantly switched conversation from one topic to another. She was easily distracted and often told jokes with a sexual content. Agitation, hypersexuality, aggressiveness, and anger are often noted in patients with brain injuries that involve the orbitofrontal regions, although additional basotemporal contusions often cannot be excluded by the neuroimaging tests performed. Lesions of the orbitofrontal cortex do cause distractability, overactivity and motor disinhibition. A so-called ‘inhibitory control of interference’ is lost in patients with orbito-frontal lesions (Stuss et al., 1982). The patients seem unable to ignore even trivial stimuli and cannot maintain attention to tasks and ideas if there are any alternative external stimuli.

Caudate nucleus infarcts and hemorrhages Stein et al. (1984), describing patients with caudate nucleus hemorrhages, noted restlessness, agitation,

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area in 80% of patients, diagonal striped shading indicates involvement in 60% of patients, and cross-hatched shading indicates involvement in 40% of patients. (From Caplan et al. (1986) with permission.)

memory dysfunction and confusion. These hemorrhages often dissected into the anterior horn of the lateral ventricle causing blood to spill into the subarachnoid space. Restlessness, irritability, and agitation are well-recognized features in patients with subarachnoid hemorrhages and meningitis but the mechanism is unknown. Meningeal irritation and increased intracranial pressure are possible factors. Mendez et al. (1989) reported neurobehavioural abnormalities in 12 patients with caudate nucleus infarcts, 11 unilateral and one bilateral. Five patients had ‘affective symptoms with psychotic features’. One of these was extremely anxious and had difficulty sleeping and had feelings of panic. She was suspicious and paranoid and heard voices that commented on ‘activities in the atmosphere’. During examination she was very restless and ‘fidgety’. Patients with agitation and psychotic features had lesions that involved mostly the ventromedial portion of the caudate nucleus. Three other patients were disinhibited,

inappropriate and impulsive. One such patient was unkempt, distractable, loquacious, unconcerned, and sexually disinhibited. These three patients had larger lesions that included most of the head of the caudate nucleus and spread to adjacent structures. Mendez et al. (1989) pointed to the similarities of the behavioural and cognitive abnormalities found in their patients with those associated with Huntington’s chorea, another disorder known to involve the caudate nucleus. They pointed out that the ventromedial caudate (the ‘limbic striatum’; Nauta,1986; Nauta & Domesick, 1984) was topographically connected to orbitofrontal cortex. Caplan et al. (1990) reported 18 patients with caudate infarcts, which often extended into the adjacent anterior limb of the internal capsule and the anterior portion of the putamen. The cause was most likely occlusion of lenticulostriate arterial branches of the proximal MCA or recurrent artery of Heubner branches of the ACA. Transient or persistent restlessness and hyperactivity were present in

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seven patients, three of whom had left caudate infarcts and four had right-sided lesions. In these patients apathy and abulia often alternated with hyperactivity. Two patients with right-sided infarcts had severe hyperactivity, talked and moved incessantly, and often called out loudly. Reviewing the anatomical connections of the caudate nucleus (Alexander et al., 1986; Nauta, 1986; Nauta & Domesick, 1984) the authors noted that lateral orbitofrontal cortex (Brodman area 10) projects to the ventromedial portion of the caudate nucleus and that this portion of the caudate also receives input from temporal lobe visual and auditory association cortex. The anterior cingulate cortex (Brodman area 24), the hippocampi, the amygdala, and enterorhinal and perirhinal cortex project to the ventral striatum (nucleus accumbens, septal nuclei, olfactory tubercle, and ventromedial caudate nucleus). The caudate nuclei also have reciprocal connections with the internal segment of the globus pallidus, the rostromedial substantia nigra and the ventral anterior and dorsomedial thalamic nuclei (Caplan et al., 1990; Alexander et al. 1986; Nauta, 1986; Nauta & Domesick, 1984). To our knowledge, however, an agitated state has not been described in patients with lesions limited to the globus pallidus or putamen.

Concluding remarks Hyperactive agitated states can develop after focal brain lesions. Some but not all patients have additional features including logorrhea, press of ideas with rapid flitting from one idea to another, distractability, insomnia, shouting, aggressive sometimes violent behaviour, disinhibition, hypersexuality, hallucinations, delusions, and paranoia. The full syndrome is most apparent in patients with right temporal lobe infarcts that include the hippocampus, amygdala, entorhinal and perirhinal cortex and their underlying white matter. Patients with bilateral lesions involving the fusiform and lingual gyri have a similar agitated delirium, as do some patients with predominantly left fusiform and lingual gyri infarcts. Lesions of the ventromedial caudate nucleus and its underlying white matter can also produce a similar syndrome perhaps more often when the lesions are on the right. Less often, orbitofrontal lesions produce similar findings. Common to these lesions is involvement of structures that relate closely to the limbic cortex of the temporal lobes and the orbitofrontal regions. The right baso-temporal lobe and its connections with the right ventral limbic striatum and the left lingual and fusiform gyri are preferred sites for lesions that cause an overactive, restless, talkative

state. Occasional brainstem lesions also can produce logorrhea and hyperactivity but usually without an accompanying confusional state.

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Mendez, M.F., Adams, N.L. & Lewandowski, K.S. (1989). Neurobehavioral changes associated with caudate lesions. Neurology, 39, 349–54. Medina, J.L., Rubino, F.A. & Ross, E. (1974). Agitated delirium caused by infarctions of the hippocampal formation and fusiform and lingual gyri: a case report. Neurology, 24, 1181–3. Mesulam, M., Waxman, S., Geschwind, N. & Sabin, T. (1976). Acute confusional states with right middle cerebral artery infarctions. Journal of Neurology, Neurosurgery and Psychiatry, 39, 84–9. Mori, E. & Yamadori, A. (1987). Acute confusional state and agitated delirium. Occurrence after infarction in the right middle cerebral artery territory. Archives of Neurology, 44, 1139–43. Mullally, W., Huff, K., Ronthal, M. & Geschwind, N. (1982a). Frequency of acute confusional states with lesions of the right hemisphere. Annals of Neurology, 12, 113 (Abstract). Mullally, W., Huff, K., Ronthal, M. & Geschwind, N. (1982b). Chronic confusional state with right middle cerebral artery occlusion Neurology, 32, A96 (Abstract). Nauta, H.J.W. (1986). The relationship of the basal ganglia to the limbic system. In Handbook of Clinical Neurology: Vol 5, Extrapyramidal Disorders, ed. P.J. Vinken, G.W. Bruyn & H.L. Klawans, pp. 19–31. Amsterdam: Elsevier Science. Nauta, W.J.H. & Domesick, V.B. (1984). Afferent and efferent relationships of the basal ganglia. In Functions of the Basal Ganglia. Ciba Foundation Symposium 107, pp. 3–29. London: Pitman. Pessin, M.S., Chimowitz, M.I., Levine, S.R. et al. (1989). Stroke in patients with fusiform vertebrobasilar aneurysms. Neurology, 39, 16–21. Price, B.H. & Mesulam, M. (1985) Psychiatric manifestations of right hemisphere infarctions. Journal of Nervous and Mental Disease, 173, 610–14. Santamaria, J., Blesa, R. & Tolosa, E. (1984). Confusional syndrome in thalamic stroke. Neurology, 34, 1618. Schmidley, J. & Messing, R. (1984). Agitated confusional states in patients with right hemispheral infarctions. Stroke, 15, 883–5. Starkstein, S.E., Boston, J.D. & Robinson, R.G. (1988). Mechanisms of mania after brain injury: 12 case reports and review of the literature. Journal of Nervous and Mental Disease, 176, 87–100. Starkstein, S.E., Mayberg, H.S., Berthier, M.L. et al. (1990). Mania after brain injury: neuroradiological and metabolic findings. Annals of Neurology, 27, 652–9. Stein, R.W., Kase, C.S., Hier, D.B. et al. (1984). Caudate hemorrhage. Neurology, 34, 1549–54. Stuss, D.T., Kaplan, E.F., Benson, D.F., Weir, W.S., Chiulli, S. & Sarazin, F.F. (1982). Evidence for the involvement of the orbitofrontal cortex in memory function – an interference effect. Journal of Comparative Physiology, 96, 913–25. Symonds, C. & Mackenzie, I. (1957). Bilateral loss of vision from cerebral infarction. Brain, 80, 415–55.

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Frontal lobe stroke syndromes Paul J. Eslinger1 and Raymond K. Reichwein2 1

Department of Medicine and 2Behavioral Science Penn State University College of Medicine, PA, USA

Introduction Stroke is one of the most common neurological problems faced by neurologists and internists. Frontal lobe strokes produce wide variations of symptoms and outcome, which can be challenging even to experienced clinicians. Presentations range from profound akinesia and mutism to subtle changes in emotional processing and personality. Because of its large size, its dependence on both anterior and middle cerebral arteries, and its mediation of many processes underlying human adaptation, the frontal lobe is a particularly important cerebral region to understand. This chapter addresses both organizational and clinical aspects of the frontal lobe, particularly those signs, symptoms and cerebrovascular lesion patterns that clinicians are likely to encounter. Stroke management has changed dramatically over the past few years, particularly with the FDA approval of intravenous t-PA. The new acute stroke motto is ‘stroke is a brain attack and time is brain’. There are multiple acute stroke therapies, including intravenous/intra-arterial thrombolysis and various neuroprotective agents on the horizon, and these therapies may have a significant impact on subsequent stroke outcomes. There are currently no studies that specifically address functional outcomes after acute stroke with frontal lobe involvement. As frontal stroke syndromes can be quite devastating to the patient and family, we hope future studies will better address these syndromes and whether hyperacute stroke interventions alter their outcome.

Anatomical and organizational features of the frontal lobe Perhaps the most fundamental feature of the frontal lobe is its division into primary motor, premotor and prefrontal

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cortical areas. This is based on cytoarchitecture as well as functional distinctions, and is evident on lateral and mesial surfaces of the frontal lobe. In developing a comprehensive clinical-anatomical classification model for the frontal lobe, we and others have identified four major regions: lateral, mesial and ventral frontal cortices and the deep white matter. Table 17.1 provides a summary of these regions with reference to prominent anatomical landmarks, cytoarchitectonic characteristics (according to the schema of Brodmann, 1909), and their functional affiliation with diverse brain systems. Historical descriptions have emphasized important roles for the frontal lobe in motor strength, certain reflexes, autonomic processing, olfaction, personality and social–emotional behaviour (e.g. Harlow, 1848, 1868; Moniz, 1936; Freeman & Watts, 1942; Sachs & Brendler, 1946; Brickner, 1936; Hebb & Penfield, 1940; for historical review, see also Benton, 1991). Recent formulations have emphasized additional processes often subsumed under the rubrics of executive functions and self-regulation of cognition, emotion and behaviour (e.g. Tranel et al., 1994; Grafman, 1995; Damasio & Anderson, 1993; Eslinger, 1996). To accomplish such diverse and complex neural processes, the frontal lobes must be in a position to receive and evaluate ongoing information about the organism and the environment through afferent projections, as well as access prior experiences and expectancies in order to devise and pursue adaptive goals and actions. The latter also implies that the frontal lobes must be able to influence efferent systems such as cognitive, emotional, autonomic–visceral, endocrine and motor structures for implementation and modification of responses. The following summarizes several organizational aspects of these afferent–efferent systems: • Physiological frameworks in the frontal lobe are evident for both neocortical processing (e.g. temporary memory

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Table 17.1. Anatomical features of specialized frontal lobe regions

Regions Lateral frontal region Primary motor and premotor cortices Dorsolateral prefrontal cortex

Mesial frontal region Superior mesial

Inferior mesial Ventral frontal region Basal forebrain

Orbital

Deep white matter

Prominent anatomical landmarks

Brodmann’s cytoarchitectonic areas

Central sulcus/precentral gyrus Broca’s area (left) Frontal pole Frontal Gyri Inferior Middle Superior

4, 6 (lateral), 44, 45 8, 9, 10, 11, 43, 46, 47

Motor Premotor Prefrontal

Central sulcus/precentral gyrus Supplementary motor area Anterior cingulate gyrus Subcallosal gyrus Mesial gyrus rectus

4 (mesial), 6 (mesial) 24

Motor Premotor Limbic Paralimbic Prefrontal

Septal nuclei Precommissural fornix Nucleus accumbens Substantia innominata Diagonal band of Broca Gyrus rectus Olfactory tracts Orbital gyri Medial Middle Lateral Periventricular (rostral, lateral, inferior, superior to frontal horns)

representations, long-term knowledge storage, associative mechanisms for decision-making) and limbic system processing (e.g. learning and emotions). • Prefrontal cortex is interconnected with other cortical regions subserving visual, auditory, somatosensory and multimodal perceptual processing in temporal, parietal and occipital lobes. This is reflected in multiple projection pathways to and from prefrontal cortex, conveying details about environmental events and stimuli in relation to knowledge, language, spatial and other cognitive systems. • Prefrontal cortex is interconnected with limbic and paralimbic system structures including amygdala, hippocampus, dorsomedial nucleus of the thalamus, temoral polar cortex, insula and anterior cingulate gyrus. These struc-

25, 32, 14, 12

Neural systems

Limbic

10, 11, 13, 14, 47

Paralimbic Prefrontal

Frontal–striatal Frontal–thalamic Frontal–limbic Frontal–cortical pathways

tures are implicated in memory, emotion, and visceral–autonomic functions and have strong projections particularly to the orbital frontal region. Thus, there is convergence of cognitive, emotional and visceral–autonomic streams of processing in the frontal lobe. • Cortical and subcortical structures mediating somatic, visceral, autonomic and hormonal regulation are interconnected with prefrontal cortices, along with pathways to motor system structures of the basal ganglia, thalamus and primary motor cortex. Thus, multiple effector systems are influenced by the prefrontal cortex. • The frontal lobe is interconnected with key subcortical structures to form parallel networks that subserve adaptive behaviour. Damage to these subcortical structures (including portions of the basal ganglia and thalamus)

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can produce frontal-type impairments such as disinhibition, perseveration, loss of initiation, etc. (e.g. Cummings, 1993; Bogousslavsky, 1994). Hence, frontal–subcortical networks are an important extension to frontal lobe models. Recent examples of procedures that produce frontal lobe activation in functional brain imaging studies of normal volunteers include tasks of simple and complex finger movements (Rao et al., 1993), verbal associative fluency (Paulesu et al., 1997), memory retrieval (Tulving et al., 1994), deductive reasoning (Goel et al., 1998), interpretation of figurative aspects of language (Bottini et al., 1994), working memory (Ungerleider et al., 1998; McCarthy et al., 1994; Jonides et al., 1993), planning (Owen et al., 1996), and language/semantic processing (Binder, 1997; Spitzer et al., 1998).

as a general rule, the anterior cerebral artery supplies the mesial aspects of the frontal lobes and the middle cerebral artery supplies the lateral aspects. From available literature and clinical cases of frontal lobe stroke, it is possible to identify specialized regions which have distinctive clinical–behavioural characteristics. We classify these into seven general profiles, modelled after the anatomical regions described in Table 17.1. However, it must be realized that stroke may cause diverse combinations of these syndromes depending upon its size and location. Brief description of each syndrome follows (see Table 17.2 for summary of prominent impairments associated with damage to each region).

Lateral frontal syndromes Primary motor and premotor cortices

Clinical presentations and correlates of frontal lobe stroke Given the unique and complex characteristics of frontal lobe anatomy and organization, it is perhaps not surprising that diagnosis and management of frontal lobe stroke encompasses a broad range of signs and symptoms. These include motor, reflex, autonomic regulation, multiple cognitive domains, emotion, personality and social behaviour. The cognitive, emotional and behavioural domains of frontal lobe syndromes can be particularly challenging. It is often in a patient’s real-life management of temporary, changing circumstances, their planful achievement of long-term goals, and their handling of diverse social– emotional interactions that impairments related to prefrontal damage will be revealed most clearly and consistently. These deficiencies can include disorganization, loss of initiative, motivation and emotional expressions of face, voice and gesture, hypomania, depression, irritability, euphoria, disinhibition and impulsivity, perseveration, cognitive rigidity, obsessive behaviours, apathy, poor memory, loss of insight, empathy and social discourse processing. Some of these impairments seem almost opposite in nature (e.g. loss of initiative and disinhibition), yet these contrasts speak to an overarching principle of frontal lobe processing, namely the regulation of behaviour. Thus, frontal lobe stroke may cause release of complex behaviour–emotional processes, loss of such mechanisms or erratic regulation of such mechanisms. The frontal lobe is irrigated by branches of both the anterior and middle cerebral arteries. There are different nomenclatures describing such branches (see Damasio, 1983 for comparison and common vascular anatomy), but

Stroke involving the lateral primary motor and premotor cortices (area 4 and 6 lateral) typically involves rostral branches of the middle cerebral artery. These regions are involved in motor activation, planning and programmed execution of movement in coordination with sensory– perceptual systems. Weakness and loss of skilled movements of the contralateral face, oral masculature and upper extremity (apraxia) result from stroke in these areas. There is often more deficit in distal than proximal aspects of the contralateral extremity, with rigidity and abnormal muscle tone possible. Bilateral or contralateral motor impersistence can occur with right-sided stroke. An example is inability of the patient to maintain eye closure for 10 seconds. Input from the prefrontal cortex, basal ganglia and thalamus provides important information to these areas about perceptual processing and decision-making choices that activate and inhibit diverse motor responses. Involvement of the lateral premotor region (areas 6, 44, 45) can cause oral and limb apraxia, dysarthria and nonfluent aphasia with prominent disturbance in the initiation and fluency of speech. Smaller lesions have been associated with less severe speech and apraxic disturbances, often with good recovery (e.g. Damasio, 1992; Bogousslavsky, 1994). Larger lesions involving Broca’s area, underlying white matter of the frontal operculum and lower motor strip may lead to the severe syndrome of Broca’s aphasia with non-fluent, telegraphic speech, short verbal responses, paraphasic errors, repetition deficit, and impairments of reading, writing and naming. Oral apraxia is often present but functional levels of language comprehension may be preserved. Contralateral lower facial and distal upper extremity weakness may be present as well. Loss of emotional intonation of speech (aprosodia) can occur with left or right frontal opercular stroke.

Frontal lobe stroke syndromes

Table 17.2. Prominent impairments associated with damage to specific frontal lobe regions Region Lateral frontal region Primary motor and premotor cortices

Dorsolateral prefrontal cortices

Mesial frontal region Superior mesial cortices

Inferior mesial cortices

Ventral frontal region Basal forebrain

Orbital cortices

Deep white matter region

Clinical impairments

Hemiparesis Dysarthria Aprosodia Disorganized thinking and behaviour Perseveration Poor planning Impulsive responding Stimulus-boundedness Poor self-regulation Right left hemispatial neglect poor spatial cognition

Apraxia (oral and limb kinetic) Motor impersistence Non-fluent aphasia (left) Impaired working memory Cognitive rigidity Intentional disorders Inattention Lack of empathy Conjugate eye deviation Left transcortical motor aphasia

Akinesia/bradykinesia Apathy Apraxia Grasp reflex Intentional disorders Disinhibition Utilization behaviour Altered self-regulation

Mutism Loss of motivation Alien hand Altered self-regulation Callosal disconnection signs Lack of motivation Altered emotional processing

Amnesia Reduced motivation

Confabulations Delusions (e.g. Capgras syndrome, reduplicative paramnesia) Impulsive actions Reduced empathy Altered self-regulation

Personality change Poor social judgment Lack of goal-directed behaviour Environmental dependency Personality change Reduced emotions

Dorsolateral prefrontal cortices The dorsolateral prefrontal region contains the so-called ‘frontal eye fields’ and also mediates diverse cognitive operations often referred to as ‘executive functions’. The frontal eye fields (Brodmann’s area 8) regulate voluntary eye movements. Damage to this area results in conjugate eye deviation to the side of the lesion. This deviation is transient, usually resolving within several days. Executive functions are processes often invoked when conceptualizing goal-directed achievements that require planning, organization, timely responding, working memory, coordination of attentional abilities, implementing plans and intentions, problem-solving, and cognitive aspects of relating to and understanding others (empathy). Damage from stroke is devastating when it is bilateral (usually from two separate strokes), which fortunately is

Poor empathy Irritability

rare, and single left or right dorsolateral strokes are much more common (see Fig. 17.1 for an example). The ‘executive function’ capacities of these regions often respect general hemispheric biases. That is, left dorsolateral damage rostral or deep to Broca’s area can lead to transcortical motor aphasia and other less disabling impairments of verbal fluency, verbal working memory and verbal cognition. Transcortical motor aphasia is characterized as a non-fluent or semi-fluent aphasia causing difficulties particularly in the initiation and fluency of speech and to a lesser extent in comprehension, reading, writing and naming, but with preserved repetition. Poststroke depression is more common after damage to left prefrontal cortex and may interfere with recovery if not treated (Robinson, 1997). In contrast, right dorsolateral damage can disrupt visuospatial processing and cognitive organization,

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Fig. 17.1. CT scan demonstrating hemorrhagic infarct with edema and mass effect in the left dorsolateral frontal region. This patient presented with disorganization, difficulties in effective verbal communication, reduced problem-solving and mild right hemiparesis.

causing left hemispatial neglect, spatial planning and spatial working memory impairments, constructional apraxia and emotional indifference.

Mesial frontal syndromes Superior mesial frontal cortex Unilateral or bilateral stroke occurring in the territory of the anterior cerebral artery can damage extensive portions of the mesial frontal lobe. Stroke in the more distal, superior branches affects the mesial extension of the primary motor cortex (area 4), the premotor cortex (area 6: supplementary motor area) and the anterior cingulate gyrus. The posterior surface of the superior mesial frontal lobe contains the motor representation for the trunk and lower extremities. Effects of stroke can include lower extremity weakness and Babinski sign, with sensory loss occurring when the lesion extends to the postcentral gyrus (Bogousslavsky & Regli, 1990). Damage to the supplementary motor area and anterior cingulate gyrus leads to loss of behavioural initiation, ranging far beyond speech to many aspects of intentional, goal-directed behaviour such as dressing, preparing food, and completing other everyday tasks (see Fig. 17.2, for example of superior mesial frontal

stroke). Such damage disconnects the superior mesial frontal cortices from the basal ganglia, primary motor cortex, pons and limbic system. Clinically, such patients are described as akinetic and mute, the severity and duration depending upon the unilateral or bilateral extension of the lesion. This alteration of self-regulation extends to virtually all domains of behaviour, whether participating in social interactions, answering the telephone, initiating self-care or responding to other environmental stimulants. Brief responses may occur and be entirely appropriate, but there is a failure to maintain such responsiveness and to initiate spontaneous behaviour. Cases of bilateral superior mesial damage have a much more difficult course of recovery, with frequent lower extremity weakness, urinary urgency and incontinence and profound loss of motivation, emotional expression and emotional experience. Treatment with a dopamine agonist agent such as bromocriptine may hasten recovery (Eslinger et al., 1995). Patients with unilateral lesions recover more quickly and completely, with some greater involvement of speech and language behaviour (i.e. transcortical motor aphasia) after left-sided damage. Unilateral lesions may cause forced grasping/groping in the contralateral hand, abulia (i.e. diminution of spontaneous behaviour and reported emo-

Frontal lobe stroke syndromes

Fig. 17.2. T2 MRI scan showing right superior mesial frontal lobe ischemic stroke. Note the lesion location in the upper left image, disconnecting fibres crossing in the anterior corpus callosum.

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Fig. 17.3. T1 MRI scan in sagittal plane showing bilateral inferior mesial frontal lobe ischemic lesions from rupture and surgical repair of pericallosal artery and anterior communicating artery aneurysms. Reduced emotional expression, lack of motivation, personality change and decreased memory retrieval were residual consequences.

tional experience, often described as lowered motivation and personality change) as well as callosal-related abnormalities such as left upper extremity ideomotor apraxia, agraphia and tactile anomia.

Inferior mesial frontal cortex Inferior mesial frontal stroke can occur as isolated infarcts or as complications from rupture and surgical repair of anterior communicating proximal artery aneurysms (e.g. Bogousslavsky & Regli, 1990; Eslinger & Damasio, 1984). An example of infarction related to aneurysm rupture is shown in Fig. 17.3. Motivatonal, personality and memory changes are frequently observed but without the more profound akinesia, mutism and transcortical aphasia associated with damage to superior mesial frontal areas. There is reduced emotional expression in face and voice, and less emotional intensity with family members. This region has strong connections with the limbic system and autonomic effector structures, and has been implicated in bipolar disorder and primary familial depression (e.g. Drevets et al., 1997). Deficits in memory occur, particularly retrieval and efficiency of learning, but recognition memory and general orientation can be intact. Lapses in contextual memory and guidance of behaviour may lead to utilization behaviour and the environmental dependency syndrome such as

a patient reporting to a job not held in several years after encountering an old work uniform in the wardrobe (e.g. Lhermitte, 1983; Eslinger & Damasio, 1984).

Ventral frontal syndromes Basal Forebrain Almost all cases of basal forebrain damage arise from rupture and surgical repair of anterior communicating artery (ACoA) aneurysms, although rare cases have occurred of non-aneurysm stroke close to this region. There is a spectrum of cerebrovascular complications from ACoA aneurysms, and Fig. 17.4 shows one example. The basal forebrain encompasses several subcortical nuclear and pathway structures that are heavily interconnected with the amygdala, hippocampus and ventral striatum. Memory impairment, confabulations, delusions such as Capgras syndrome and reduplicative paramnesia and motivational changes can occur. Larger vascular lesions can extend to nearby medial and orbital frontal cortex as well as to basal ganglia, which complicates recovery and often leads to disability.

Orbital frontal cortex This region is most known for its association with prominent personality and social behaviour changes without

Frontal lobe stroke syndromes

Fig. 17.4. CT scan demonstrating extensive mesial orbital frontal ischemic lesion as a consequence of rupture and surgical repair of anterior communicating artery aneurysm.

primary neurologic signs or cognitive impairments. More recently, the orbital frontal cortex has been linked to emotional processing, empathy, contingency-based learning, and autonomic processing related to anticipation of the future consequences of one’s actions (e.g. Grafman et al., 1986; Rolls, 1999; Bechara et al., 1996; Eslinger, 1998). Stroke that is isolated to this cortical region is rare except as a complication of rupture and repair of anterior communicating artery aneurysms, when memory impairment will accompany personality and behavioural changes. Damage can lead to impulsive actions, disinhibition and poor social judgment despite lack of change in general intelligence, memory, perception, and language. Interpersonal behaviours and judgment are also affected by reductions in empathy that impair perception and appreciation of the situational and emotional experiences of others, most particularly family members.

Deep white-matter pathways Infarctions of the middle cerebral artery or the deep penetrating vessels of the anterior cerebral and anterior communicating arteries can affect the deep white-matter pathways of the frontal lobe. White-matter adjacent to the

frontal horns is a high traffic area for frontal–subcortical (e.g. frontal–striatal; frontal–thalamic; frontal–amygdala) and frontal–cortical (e.g. orbital–dorsolateral frontal; uncinate fasciculus) pathways that have behavioural, cognitive and emotional significance (e.g. Cummings, 1993). Disconnection of cortical areas by white matter lesion can lead to marked alterations in neural networks subserving complex emotional processes. For example, a 49-year-old man had a right middle cerebral artery territory infarct affecting the deep white matter of the frontal lobe with extension to the temporal lobe and insula. His cognitive and neurologic impairments (i.e. mild left-sided weakness, coldness of left upper extremity) were minimal and recovered quickly. However, his family reported marked disturbance of his emotional processing, with indifference to usual family dynamics and interactions, reduced sensitivity to their concerns and loss of emotional expression in face and voice. They interpreted this change as lack of interest and insensitivity, since he now spoke his mind without the grace, patience and humour he usually expressed. Treatment with Prozac and then low dose amitriptyline (50 mg qhs) led to improvement in emotional responsiveness and reduction of cold sensations in the left upper extremity. Despite this improvement, the patient

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continued to report few emotional experiences which did not concern him, and therapy was focused on addressing altered family dynamics.

of social comportment and empathic relationship with others. These subtle, and not so subtle, consequences of frontal lobe damage require long-term management by family and health providers.

Recovery and outcome Although few studies have systematically analysed the short- and long-term outcome of patients with frontal lobe stroke, it is clear that there is a substantial role for health providers in managing and supporting such recovery. Variables influencing recovery include the location and extent of the cerebral damage, associated cognitive, motor and emotional impairments, treatment services and supportive care. Since impairments can range from physical limitations to speech, cognitive, social and emotional changes, an interdisciplinary approach is often needed, encompassing neurological, neuropsychological and everyday functional abilities of patients. While hemiplegia, aphasia and memory impairments can often be recognized and addressed through current neurorehabilitation modalities, motivational, emotional, executive and interpersonal changes are more difficult to evaluate and remediate. Some pharmacologic interventions appear promising, such as dopamine agonists, low-dose stimulants and selective serotonin reuptake inhibitors for motivational, attentional and emotional impairments. In addition, environmental modifications, behaviour management and cognitive self-management training can be helpful approaches to long-term deficits that require in-home management by patients and family members (see Eslinger, 1996 for a summary of these approaches). More studies are needed to advance neurorehabilitation approaches.

Conclusions The sequelae of frontal lobe stroke can be evident and limited or enigmatic and life-changing for patients and their families. Early diagnosis with appreciation for both the obvious and subtle levels of poststroke impairment is a key step in fostering a multidisciplinary approach to patients’ recovery of function. Some frontal lobe syndromes may be particularly difficult for families, coworkers and others to understand since a patient’s general intelligence may appear normal. However, their lack of initiation, judgment and foresight may significantly limit their independence and productivity on a daily basis. Although depression is a recognizable emotional change after frontal lobe stroke, other changes may include a loss

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Moniz, E. (1936). Prefrontal leucotomy in the treatment of mental disorders. American Journal of Psychiatry, 93, 1379–85. Owen, A.M., Doyon, J., Petrides, M. & Evans, A.C. (1996). Planning and spatial working memory: a positron emission tomography study in humans. European Journal of Neuroscience, 8, 353–64. Paulesu, E., Goldaire, B., Scifo, P. et al. (1997). Functional heterogeneity of left inferior frontal cortex as revealed by fMRI. Neuroreport, 8, 2011–17. Rao, S.M., Binder, J.R., Bandettini, B.S. et al. (1993). Functional magnetic resonance imaging of complex human movements. Neurology, 43, 2311–18. Robinson, R.G. (1997). Neuropsychiatric consequences of stroke. Annual Review of Medicine, 48, 217–29. Rolls, E.T. (1999). The functions of the orbitofrontal cortex. Neurocase, 5, 301–12. Sachs, E. & Brendler, S.J. (1946). The orbital gyri. Brain, 72, 227–40. Spitzer, M., Kischka, U., Guckel, F. et al. (1998). Functional magnetic resonance imaging of category-specific cortical activation: evidence for semantic maps. Cognitive Brain Research, 6, 309–19. Tranel, D., Anderson, S.W. & Benton, A. (1994). Development of the concept of ‘executive function’ and its relationship to the frontal lobes. In Handbook of Neuropsychology, Vol. 9, ed. F. Boller & J. Grafman, pp. 125–48. Amsterdam: Elsevier Science BV. Tulving, E., Kapur, S., Craik, F.I.M. et al. (1994). Hemisphere encoding/retrieval asymmetry in episodic memory; positron emission tomography findings. Proceedings of the National Academy of Sciences, USA, 91, 2016–20. Ungerleider, L.G., Courtney, S.M. & Haxbry, J.V. (1998). A neural system for human visual working memory. Proceedings of the National Academy of Sciences, USA, 95, 883–90.

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Memory loss José M. Ferro and Isabel P. Martins University of Lisbon Faculty of Medicine, Portugal

Classification of memory

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Memory is the persistence of information in the central nervous system. It is not a unitary function, it comprises independent systems and processes that can dissociate from each other (Tulving, 1991). Three major cognitive processes are involved in memory: registration (or encoding, during which information is translated into a code to be stored), retention (or storage) and retrieval (when the information is searched and recalled). Memory can be impaired at any of these three steps, but it may be difficult to differentiate between them. A registration disorder should produce mainly an anterograde amnesia, since facts already stored should not be so much affected. However, it may also include a limited period of retrograde amnesia, involving recent memories still undergoing a process of consolidation (Squire et al., 1992). A retrieval or a storage impairment, on the contrary, will produce both a retrograde, and an anterograde, amnesia. While a storage disorder is irreversible, a retrieval impairment may recover and is identified by an improved performance in memory tests with cueing recall (vs. free recall) and in recognition tasks (when compared to recall tasks) (Ellis & Young, 1997). According to Tulving (1995), memory systems may be divided into five main categories: semantic, episodic, primary, procedural and perceptual representation systems. A major distinction is made between declarative (or explicit) and procedural (or implicit, non-declarative) memory (Table 18.1). Declarative memory is the type of memory one is aware of. It is directly acessible to conscious recollection and may be subdivided into semantic memory (our general knowledge of facts, concepts, and meanings) and episodic memory (consisting mainly in autobiographic events framed by a specific spatio-temporal context). In amnesia,

episodic memory (specially for recent episodes) is much more impaired than semantic memory. Both semantic and episodic memories are forms of longterm memory. They can be evaluated by the ability to learn new information, such as lists of unrelated words, pairs of words, stories, visual material, etc. The tests consist of recalling that information after a variable delay, during which another task is performed to prevent rehearsal. The subject is requested to reproduce the information either spontaneously (free recall), with some type of facilitation (cued recall), or by recognition. Autobiographic memory requires a safe source to check the information, someone that knows an individual’s life well. Primary memory, also called short-term, immediate and working memory, is a system that stores data for short periods of time, or holds several pieces of information ‘on line’, while some other type of mental task is being performed (mental arithmetic, reasoning, problem solving, complex sentence analysis, for example). This system is conceptualized as consisting of a central executive (an attentional control system) and two slave systems, one visual (the visuospatial sketch pad) and one verbal (the phonological loop) (Baddeley, 1999). It is usually evaluated by the serial recall of digits or words lists (or by the reproduction of visually presented material) immediately after its presentation. This type of memory is fully intact in human amnesia (Baddeley & Warrington, 1970; Cave & Squire, 1992). Procedural memory and perceptual representation systems are implicit forms of memory and underlie certain abilities like learning of motor and cognitive skills (skilled perceptuo-motor tasks and reading, for instance), simple conditioning and associative learning. They also include perceptual priming, which is a facilitation of perception, or identification, of a stimuli after a first encounter with it. These systems are relatively preserved in amnesics. They are difficult to study because there are no standardized

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Table 18.1. Major categories of human learning and memory System

Other terms

Subsystems

Retrieval

Evaluation tests

Procedural

Non-declarative

Implicit

Pursuit rotor Mazes Jigsaw puzzles

PRS

Priming

Implicit

Figure recognition Word-stem completion

Semantic

Generic Factual Knowledge Working Short-term Personal Autobiographical

Visuo-motor skills Cognitive skills Simple conditioning Simple associate learning Structural description Visual word form Auditory word form Spatial Relational

Implicit

Visual–spatial sketch pad Phonological loop

Explicit

Factual knowlegde Vocabulary Pairs, list of words Digit span Word span Personal history

Primary Episodic

Explicit

Note: Adapted from Tulving (1995). PRS = perceptual representation systems.

a

tests for those abilities. The most commonly used tasks consist of word stem completion (evaluating the effect of a previous exposure to a list of words on their use upon word completion), recognition of fragmented words, sentence puzzle solutions and perceptuo-motor tasks.

The functional anatomy of memory The anatomical structures underlying declarative memory are multiple. Episodic memory depends upon the ‘bottleneck structures’ where the information is processed before long-term storage. These structures can be divided into three major anatomical systems: the Papez circuit (hippocampal formation, parahippocampus, ento and perirhinal cortex, cingulate gyrus, fornix, nucleus anterior thalami, mammillothalamic tracts and mammillary bodies), the basolateral limbic circuit (comprising the dorso-medial thalamic nucleus, the subcallosal area and the amygdala), and the basal forebrain, which includes the septum, the diagonal band, and the nucleus basalis of Meynert. The basal forebrain is important for promoting the impact and memorability of novel and motivationally relevant events. The medial septal nucleus and the diagonal band provide the major cholinergic input of the hippocampus. The cerebral cortex receives dense cholinergic input from the nucleus of Meynert, through a medial and a lateral pathway (Selden et al., 1998). The retrieval of old episodic information also depends on other structures, namely the lateral temporo-polar and inferior prefrontal regions. On

the other hand, storage of episodic and semantic memories depends upon different areas of the associative cerebral cortex. Imaging activation studies (Cabeza & Nyberg, 1997) have shown that there are hemispheric asymmetries in those processes. While the left dorsolateral prefrontal region predominates in episodic memory encoding (possibly due to its semantic processing), the right prefrontal cortex (together with other regions) predominates in declarative memory retrieval. The specific role of the right frontal region consists of supporting or guiding the retrieval process rather than actually recovering stored information. This right/left difference has been conceptualized as an hemispheric encoding/retrieval asymmetry (HERA model) (Tulving, 1995; Desgranges et al., 1998). Working memory depends mostly upon the frontal (Brodman areas 6 and 44 for the phonological loop) and the parietal cortices. In what concerns implicit memory, its neural correlates are different from those of the explicit system. While the basal ganglia and the cerebellum play a role in learning motor skills and classical conditioning, PET studies have consistently shown an activation of the right posterior neocortex in perceptual priming (Markowitsh, 1995; Squire et al., 1992).

Arterial blood supply The arterial blood supply of anatomical structures involved in memory comes (Fig. 18.1) from different sources (Lazorthes, 1961; Krayenbühl & Yasargil, 1972;

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Fornix

NA

NA – anterior nuclei NDM – dorsomedial nuclei MTC – mammillothalamic tract

NDM Thalamus MTC

Basal forebrain

Mammillary body

HIPPOCAMPUS PARA HIPPOCAMPAL GYRUS

Posterior choroidal artery

Anterior cerebral artery

Anterior choroidal artery Posterior cerebral artery

Anterior communicating artery Posterior communicating artery

Fig. 18.1. Schematic representation of the anatomical structures involved in declarative memory and their blood supply.

Ghika et al., 1990). The anterior hippocampus and adjacent cortex are supplied by the anterior choroidal artery. Its posterior part, adjacent cortex and the parahippocampus gyrus belong to the territory of the anterior and posterior temporal arteries, which are branches of the posterior cerebral artery. The fornix is supplied by the anterior cerebral artery, the posterior communicating artery and by a branch from the posterior choroidal artery to the crura fornicis. The mammillary bodies are supplied by the posterior communicating and posterior cerebral arteries. The anterior nuclei of the thalamus and part of the mammillothalamic tract receive blood from the polar (tubero-thalamic) artery, which is a branch of the posterior communicating artery. The left and right polar arteries can have a common origin. The dorsomedial thalamus receives its blood supply from the thalamo-subthalamic (or thalamoperforating) arteries, that are branches of the P1 segment of the posterior cerebral artery. The left and right thalamoperforating arteries can also have a common origin. The basal forebrain has its blood supply from perforating branches of the anterior cerebral and anterior communicating arteries.

severe in 52%. It was the only neuropsychological abnormality in 6%. Patients with memory impairment were older and more likely to have left-sided lesions than those without. Memory deficits were not correlated with the intensity of depressive symptoms (Madureira et al, 1999). In some cases this memory impairment may be due to the cumulative effects of stroke and preclinical Alzheimer’s disease or to unrecognized pre-existing dementia (Hénon et al., 1997). In patients with vascular dementia, memory is less severely impaired in early stages than in Alzheimer’s disease. Vascular dementia patients have poorer verbal fluency, but better free recall, fewer intrusion errors and better recognition than Alzheimer’s disease (Pasquier & Leys, 1997) patients, indicating subcortical–frontal dysfunction as opposed to medial temporal in Alzheimer’s disease (Lafosse et al., 1997).

Specific vascular syndromes Medial temporal infarcts

Memory impairment following stroke Mild memory complaints are frequent in stroke survivors. Neuropsychological testing 3 months after stroke revealed impairment in memory tests in 20% of stroke survivors. This disturbance was mild in 38%, moderate in 10% and

About 25% of posterior cerebral artery (PCA) territory infarcts, present with severe memory defects (Brandt et al., 1995), in particular, when there is mesial temporal involvement. Hippocampal damage alone seems not to be sufficient to produce lasting amnesia. Additional damage to the ento- and perirhinal cortex, collateral isthmus or parahip-

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Fig. 18.2. Two cases of bilateral simultaneous mesial temporal infarcts producing permanent severe amnesia.

pocampal gyrus is deemed necessary (Von Cramon et al., 1988). Recent research indicates that damage to the hippocampus and its projections results in deficits in recall of episodic information, while damage to other regions, such as the rhinal cortex, disrupts recognition based on familiarity judgments (Aggleton & Saunders, 1997). The memory defect can follow unilateral or bilateral infarcts (Victor et al., 1961), but is more frequent after left-sided (Benson et al., 1974) or bilateral temporal damage. Left-sided infarcts usually cause predominantly verbal amnesia, often in combination with pure colour and object agnosia or anomia (Geschwind & Fusillo, 1966; Caplan & HedleyWhite, 1974), while right-sided ones can disturb visuospatial memory, as well as memory for faces or locations. Not infrequently, unilateral infarcts located on the left mesial temporal lobe can produce a global (verbal and visuospatial) memory defect (Ott & Saver, 1993). Visual amnesia, i.e. a modality-specific, visual learning defect was also reported after bilateral lesions (Ross, 1980). Medial temporal amnesia is a declarative memory defect, disturbing especially episodic memory. It produces mainly anterograde amnesia. The encoding and consolidation of new facts, events, names and concepts is defective, while retrieval of previously learned data is adequate. Working

and procedural memory are not affected. Most patients are aware of the defect. Confabulations are infrequent, unless there is coincidental medial thalamic damage, that hypothetically causes a fronto-cingular deafferentation (Servan et al., 1994). There are few studies on the recovery of memory defects after PCA infarcts. Recovery can be almost complete or fair, if the lesion is unilateral, but the prognosis is ominous when damage is bilateral (Fig. 18.2). Memory loss can then be very severe and permanent, leading to dependency in everyday life. Bilateral PCA infarcts are one of the mechanisms of ‘focal’ or ‘strategic infarct’ forms of vascular dementia (Román et al., 1993).

Thalamic infarcts and hemorrhages Anterior and dorsomedial thalamic infarcts (Graff-Radford et al., 1985; Bogousslavsky et al., 1988) (Fig. 18.3) and anterolateral, large medial and posteromedial hematomas (Kawahara et al., 1986) can disturb a wide range of neuropsychological functions (arousal, attention, motivation, initiative and executive functions), and produce severe memory deficits. Because blood supply to both anterior nuclei can derive from a single vessel, simultaneous bilateral infarcts can occur.The same applies to the dorsomedial

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Fig. 18.3. Polar (right) and medio dorsal (left) infarcts causing transient memory defects.

nuclei (Castaigne et al., 1981). When thalamic infarcts are bilateral, they also tend to be larger (in each hemisphere) than unilateral infarcts. Defects in verbal memory were also reported as a sequela of deep venous thrombosis with thalamic venous infarct (Haley et al., 1989; Peru & Fabbro, 1997; Rousseaux et al., 1998). After anterior (polar) infarcts, amnesia is found in combination with abulia, decreased expression of emotions, language disturbances or neglect (Bogousslavsky et al., 1986), but a case of pure amnesia has also been described (Clarke et al., 1994). After mediodorsal infarcts, memory defects are combined with drowsiness, abulia, flattened emotions and vertical gaze disturbances (Castaigne et al., 1966, 1981; Guberman & Stuss, 1983). Amnesia becomes specially apparent when vigilance improves. It is disputable which of the two locations, anterior or dorsomedial, produces the more severe and long-lasting amnesia. For some authors (Clarke et al., 1994), amnesia is more severe and stable after polar infarcts. This is due to damage to the mammillothalamic tract of the anterior nuclei and its projections to the posterior medial frontal lobe. After mediodorsal infarcts memory impairment is transient, unless the lesion extends rostrally enough to include the mammillothalamic tract, the ventral portion of the lamina

medullaris interna (Von Cramon et al., 1985) or the inferior thalamic peduncle, that includes axons of the ventroamydgalofugal pathway (Graff-Radford et al., 1990). In the experience of others (Caplan, 1996), memory defects are more severe and persistent after dorsomedial than after polar infarcts. The memory defect produced by thalamic lesions includes verbal (Mori et al., 1986) or both verbal and visual memory, for left-sided infarcts, and only visual memory, for right-sided lesions (Speedie & Heilman, 1983). However, both right (Rousseaux et al., 1991) and left (Von Cramon et al., 1985) unilateral thalamic lesions with global amnesia have been described. Unilateral amnesic stroke has been reported more often in association with left hemispheric lesions (Ott & Saver, 1993; Pepin & Auray-Pepin, 1993). Graff-Radford et al. (1990) attribute this dense amnesia to simultaneous damage to the mamillothalamic pathway and the inferior thalamic peduncle. In thalamic amnesia, the memory defect affects predominantly episodic declarative memory, i.e. the acquisition and recall of new facts and events. These patients have severe anterograde and moderate and partly reversible retrograde amnesia. As in other forms of diencephalic amnesia, there seems to be a dual pathology, affecting the

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encoding of new memories, as well as the retrieval of both new and old memories. There is no evidence of rapid decay or forgetting. Thalamic amnestic patients have preserved motor learning and implicit memory, with intact priming (Malamut et al., 1992). Some patients are aware of the defect but others are not. The memory defect is not secondary to the other behavioural abnormalities, as it can be demonstrated in single tasks requiring immediate recall. Performance of patients with dorsomedial infarcts in memory tasks is characterized by severe distractibility (Mennemeier et al., 1992). They can show a ‘scalloping’ effect, with alternating good–bad performance and the best performance on the first attempts, suggesting that motivation and attention influence performance (Stuss et al., 1988). After unilateral infarcts, memory disturbances usually show considerable recovery, but occasionally the defect persists. Sala et al. (1997) reported a case with persistent global amnesia caused by a unilateral right thalamic stroke, but displaying bilateral mesial frontal hypometabolism in PET. After tuberothalamic infarction, inactivity, depression and memory disturbances remain the dominant residual symptoms, often preventing return to work (Kotila et al., 1994). Patients with bilateral lesions have a more severe and long-lasting memory defect. Bilateral paramedian thalamic infarcts are another form of ‘strategic’ infarct vascular dementia (Román et al., 1993).

Strokes in other locations (caudate, capsular genu, retrosplenial cortex fornix) Caudate infarcts and hemorrhages can produce several cognitive and behavioural deficits (Caplan et al., 1990; Mendez et al., 1989). Formal neuropsychological testing reveals impaired problem-solving ability, decreased attentional capacity and moderate impairment on memory tasks due to difficulty in recall even with cues, but with normal recognition. However, in caudate lesions, abulia and ‘frontal-lobe like’ abnormalities predominate over memory troubles (Kumral et al., 1999). Confusion and memory loss can also result from infarction of the inferior genu of the internal capsule (Tatemichi et al., 1992). This syndrome features fluctuating alertness, inattention, memory loss, apathy, abulia, psychomotor retardation and severe memory loss. This strategic infarct location interrupts the inferior and anterior thalamic peduncles, and causes deactivation of the ipsilateral frontal cortex. The majority of these defects improve during follow-up, and the patients are left with minor residual cognitive and moderate memory troubles, that in

general do not interfere with previous lifestyle (Madureira & Ferro, 1999). Valenstein et al. (1987) reported a case of retrograde and anterograde amnesia, following hemorrhage from an arteriovenous malformation situated near the splenium of the corpus callosum, damaging the retrosplenial cortex and a pathway linking the subiculum to the anterior thalamus. Brion et al. (1969) described a Korsakoff syndrome (amnesia and confabulation) in association with a pathologically verified infarct of both columns of the fornix.

Intraventricular hemorrhage Many of the structures (fornix, medial thalamus, mammillary bodies, mammillothalamic tract) subserving episodic memory are situated in close anatomical relation to the third ventricle. It is therefore not suprising that memory is frequently disturbed after primary intraventricular hemorrhage. In this rare form of spontaneous intracerebral hemorrhage, intraventricular bleeding is confined to the ventricles and is not secondary to the rupture into the ventricles of a neighbouring intraparenchymatous hematoma. In the acute phase, non-comatose patients often display a general cognitive dysfunction with fluctuating attention, orientation and concentration, with slow improvement over weeks or months. Mild memory problems remain in about one-third of the survivors (MartíFábregas et al., 1999), formal neuropsychological testing revealing a learning defect more striking for novel words or associations (Darby et al., 1988).

Subarachnoid hemorrhage Despite progress in the management of subarachnoid haemorrhage (SAH), anterior communicating artery (ACoA) aneurysmal rupture is often complicated by a range of neuropsychological disturbances including amnesia, personality changes, confabulation, abulia and jocosity (Lindqvist & Norlen, 1966; Alexander & Freedman, 1984; Damásio et al., 1985; DeLuca & Diamond, 1995). Less often, memory troubles can follow posterior communicating artery aneurysmal rupture. These defects are specially prevalent in the acute/subacute stage. Although complete or considerable recovery occurs in the majority of the patients, some are left with permanent memory deficits. Amnesia is due to mediobasal frontal damage, secondary to ACoA aneurysmal rupture or the severing of ACoA perforators during surgery. The relevant structures involved include the anterior cingulate, the subcallosal area and basal forebrain, including the septal and Meynert nuclei and the diagonal band (Alexander & Freedman, 1984;

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Damásio et al., 1985). Hydrocephalus, intraventricular and subarachnoid bleeding do not play a relevant role in the pathogenesis of amnesia. Du Cros and Lhermitte (1984) found a link between resection of the gyrus rectus and the deterioration of mnestic capacities. Confabulations are attributed to dual frontal and basal forebrain damage (DeLuca & Cicerone, 1991). The amnestic syndrome of AcoA rupture is characterized by severe anterograde deficit, mild (weeks or months) retrograde loss and normal implicit memory (Bondi et al., 1993). Immediate recall is relatively intact while delayed recall is significantly compromised. Recognition is mildly impaired and later returns to normal. ACoA patients show impairment in their ability to tag episodic information with the appropriate spatiotemporal markers. Their memory defect is susceptible to proactive and retroactive interferences (Damásio et al., 1985; DeLuca, 1992; DeLuca & Diamond, 1995; Rousseaux et al., 1998a,b). In the acute/subacute stage patients are unaware of their memory defects, but awareness is retained in the chronic stage.

Reduplicative paramnesia Reduplicative paramnesia (Pick, 1903), also labelled disorientation for place or spatial delirium, is a bizarre disturbance where a patient believes he/she is in a different place from the actual one, even in the face of compelling counter evidence (Benson et al., 1976). While in the hospital ward, patients claim they are in another hospital they knew before, or even at home, that has been transformed in a hospital or in a section of the hospital. When faced with the evidence that the walls, furniture and people around are different from those at home, they reply with plausible answers like ‘Changes have been made without my permission’ or ‘These people are visiting me’. This delirious belief, or false conviction of familiarity, is in some patients associated with delirium, visuospatial defects and neglect, but is not fully explained by these disturbances. The majority of cases of reduplicative paramnesia have lesions involving the right hemisphere (Murai et al., 1997), with variable localization: parietal-occipital (Fisher, 1982), frontal (Kapur et al., 1988) or subcortical (De La Sayette et al., 1995).

Transient global amnesia Transient global amnesia (TGA) is a episodic dysfunction of the central nervous system during which there is a sudden loss of declarative memory for recent events

without other neuropsychological or neurological symptoms. The etiology of TGA is not yet clear: migrainous disorder, transient arterial hemodynamic disturbance or brief venous ischemia caused by Valsalva manoeuvre in prone individuals (Lewis, 1998). TGA is often precipitated by exertion, emotion or exposition to cold or warm temperatures (Melo et al., 1992). It usually lasts for some hours. During the episode patients display a very typical defect: profound anterograde amnesia, retrograde amnesia extending back for weeks or months, altered categorial fluency, preserved lexical–semantic and procedural memory and priming (Eustache et al., 1997). Metamemory is also spared, explaining patients’ anxious reaction, the characteristic repetitive questioning and adaptive behaviour to the defect. Patients with TGA are more likely to have hypertension and migraine than communitary controls but less likely to have diabetes, hyperlipidemia and also atrial fibrillation than TIA patients (Melo et al., 1992; Lauria et al., 1998). CT, routine MR, extracranial and transcranial Doppler are usually uninformative. During TGA, EEG and transcranial Doppler are also normal (Melo, 1995). Recent PET studies during TGA demonstrated patchy CBF-CMRO2 uncoupling compatible with a migraine-like phenomenon (Eustache et al., 1999). Strupp et al. (1998) were able to demonstrate left or bilateral hippocampal increased signal on diffusion-weighted MRI in seven of ten patients with TGA, interpreted as cellular edema. About 10% of the patients experience a second episode of TGA. The risk of stroke or dementia is not increased in TGA, and long-term antiplatelet treatment is not necessary. TGA should not be confused with amnestic TIAs or infarcts during which the memory loss is always accompanied by other neurological symptoms or an appropriate infarct is demonstrated by CT/MR. It should also be distinguished from post-traumatic amnesia and from ictal or postictal eplipeptic transient amnesic episodes, that are briefer (minutes), stereotyped and with multiple recurrences at short intervals (Hodges & Warlow, 1990; Melo et al., 1994).

Treatment There are, at present, no effective pharmacological treatments for amnesic disturbances of vascular cause. Whether some antidepressants would facilitate recovery, while diazepan and haloperidol would be detrimental, as suggested in animal studies (Goldstein, 1998), remains to be tested in clinical studies. Methylphenidate was reported to be of benefit in a single trial (Tiberti et al., 1998). Drugs with anticholinergic effects are better avoided. Cholinergic

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agents can conceivably be useful, but no trials have yet been completed in stroke patients. Several behavioural memory retraining programmes are available at memory clinics, but their long-term ecological efficacy remains to be proved.

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Neurobehavioural aspects of deep hemisphere stroke José M. Ferro University of Lisbon Faculty of Medicine, Portugal

Introduction The discussion of the role of subcortical structures in language and other higher nervous functions begins with the famous polemic opposing Dejerine (a corticalist) to Pierre Marie, who described several anatomico-clinical cases of subcortical strokes causing aphasia, and claimed that damage to an area including the insula and external capsule was crucial to the production of anarthria. However, during the next decades, few authors attributed any role to the thalamus or to other subcortical structures in relation to symbolic and cognitive behaviour. Since the widespread use of modern neuroimaging techniques, it has become evident that aphasia and other ‘cortical’ syndromes can result from lesions limited to subcortical structures. Both single-photon-emission computed tomography (SPECT) and positron-emission tomography (PET) have shown that subcortical strokes are accompanied by important abnormalities of cortical metabolism and perfusion. Magnetic resonance (MR) can demonstrate cortical lesions that were not apparent on CT. These facts raise the question as to whether neurobehavioural disturbances seen after subcortical strokes are due to subcortical damage per se or are related to functional cortical inactivation (diaschisis), to cortical hypoperfusion or to subtle concomitant cortical lesions.

Subcortical aphasia–striatocapsular aphasia Damasio et al. (1982) and Naeser et al. (1982) described the first patients with subcortical aphasia correlated with CT. Transcortical motor aphasia produced by small ischemic lesions of the basal ganglia, was first described by Wallesch et al. (1983). All of those authors stressed the difficulty of classifying subcortical aphasia in terms of the classic corti-

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cal aphasia syndromes (Table 19.1). Damasio et al. (1982) summarized the distinguishing features of subcortical aphasia: dysarthria independent of the degree of fluency, often accompanied by dysprosody, and rapid recovery, preceding that of motor disturbances. Subcortical infarcts producing aphasia involve the anterior limb of the internal capsule, the head of the caudate nucleus, and the anterosuperior part of the putamen. Lesions located in more posterior aspects of the internal capsule, corona radiata and striatum usually cause dysarthria only. Naeser et al. (1982) identified three capsuloputaminal aphasia syndromes, depending on the extension of the lesion into the white matter: (i) patients with anterosuperior extensions of white-matter lesion had a grammatical, slow, dysarthric speech and good comprehension, similar to what is seen in Broca’ s aphasia, except that they had more grammatical speech and longer phrase lengths; (ii) those with posterior white-matter extension to the auditory radiations and temporal isthmus showed a fluent type of speech; (iii) subjects with both anterosuperior and posterior extensions were global aphasics. Alexander et al. (1987), on the basis of a few positive cases, further detailed that classification, trying to design a neuroanatomic model for specific components of subcortical aphasia: small lesions of the striatum and lateral anterior limb of the internal capsule would cause aphasia or only mild word-finding deficits, whereas lesions extending beyond that territory would cause various speech and language disorders in predictable relationships to the extent of the lesion in the white-matter pathways. Auditory comprehension deficits would result from damage to the geniculotemporal pathway in the temporal isthmus and to the auditory callosal fibres in the posterior periventricular white-matter (PVWM). If the external, extreme capsules or the arcuate fasciculus were involved, repetition deficits and phonemic paraphasia would occur. Motor speech deficits could be due to ante-

Neurobehavioural aspects of deep hemisphere stroke

Table 19.1. Proposed distinctive features of subcortical aphasia Study

Features

Alexander and La Verme Hypophonia; mumbling (1980) Difficulty in initiating, and reduced spontaneous speech Fluent unhesitant responses ‘Extended’ jargon Relative preservation of repetition and praxis Similar to transcortical aphasia Damasio et al. Atypical (1982) Dysarthria and dysprosody independent of the degree of fluency Gestural praxis intact Rapid recovery Naeser et al. Atypical (1982) More grammatical speech and longer phrase length Brunner et al. Broca’s aphasia with transcortical fea(1982) tures Substantial improvement Wallesch et al. Dramatic increase in fluency in the (1983) first days Better preserved written than auditory language comprehension Puel et al. (1984) ‘Dissident’, subtranscortical aphasia Voice and articulation impairment Reduction of spontaneous speech ‘Bizarre’ verbal paraphasias; verbal incoherence Normal repetition ability Dissociation between anomia in spontaneous speech and good confrontation naming Kennedy and Murdoch Impaired divergent semantic behaviour (1993) Semantic paraphasias Atypical dysarthria Slow dysarthria Weiller et al. (1993) No distinct pattern of language disturbance Mega and Alexander Core profile: impairment in generative (1994) language ability and lexical selection anomia

rior and superior PVWM or genu of the internal capsule damage. Decreased speech output would be caused by anterosuperior PVWM lesions, isolating Broca’s area from supplementary motor area, and by damage to the deep anterior frontal white matter, interrupting pertinent anterior callosal pathways.

Fig. 19.1. CT templates of acute (first month) striatocapsular infarctions presenting as global aphasia (top), Broca’s aphasia (middle), and transcortical motor aphasia (bottom).

Series that included non-selected patients who had subcortical strokes, such as Puel et al. (1984) and Colombo et al. (1989) and a comprehensive review by Nadeau and Crosson (1997) found no correlation between site of lesion, type or intensity of language disturbance, failing to confirm the anatomoclinical subtypes proposed by Naeser and Alexander. Lesions of the same subcortical structures yield different neurolinguistic impairments, and comparable linguistic patterns are observed with lesions in different deep areas (Fig. 19.1). More recent reports, such as those of Weiller et al. (1993) and Mega and Alexander (1994) did not confirm the specific features of language impairment associated with damage to individual subcortical centres or tracts. Aphasia syndromes did not differ in the amount of involvement of the putamen, pallidum, caudate and different white-matter tracts. Following a striatocapsular infarction, there is a rather similar coherent aphasia profile, with impaired executive and generative

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Fig. 19.2. Hypertensive hemorrhage involving the left medial thalamus, producing transient fluent aphasia (semantic jargon) and verbal memory defect (right). Recurrent right thalamic hemorrhage 1 year later, resulting in abulia and severe dementia (left).

language functions, accompanied by a lexical selection anomia. The generative language defect features abnormal performance on verbal fluency tasks, simplified sentence structure generation with increased latencies, perseverations, echolachia, bizarre or loose content, despite almost normal fluency and syntax in conversation and responsive language. Naming and word retrieval are reduced. Semantic paraphasias are frequent while phonemic paraphasias are rare. Repetition, oral reading and word comprehension are normal (Mega & Alexander, 1994). The severity of aphasia depends on the size of the infarct. Small infarcts may present only dysarthria, hypophonia or delayed speech initiation. The prognosis of striatocapsular aphasia is favourable with usually rapid and complete recovery in about two-thirds of the cases (Démonet et al., 1991).

Thalamic aphasia Aphasia can also follow thalamic hemorrhages or infarcts of the dominant hemisphere. The first reports of thalamic hemorrhages causing aphasia stressed the decreased voice

volume, anomia, perseveration, and semantic paraphasia. Mohr et al. (1975) called attention to the fluctuating performances of such patients, who, when rendered fully alert, appeared to have virtually intact language functions, but would quickly lapse into a state of unwonted logorreic paraphasia. Some authors have talked of ‘quasi-aphasia’ or ‘aphasia delirium’ to stress that those language disturbances appeared to be related to loss of activation of some neurolinguistic functions, such as the logical control of speech and semantics. Cappa and Vignolo (1979) emphasized the transcortical features of aphasia following left thalamic hemorrhages: reduced spontaneous speech, semantic paraphasia, preserved repetition ability and partly defective auditory verbal comprehension. In summary, deficits in thalamic aphasia can tentatively be grouped into four clusters: extrapyramidal (hypophonia), lexical access (anomia, semantic paraphasia), vigilance (fluctuating performance) and comprehension defects. Posterior hematomas including the pulvinar and dorsal nuclei, are those most commonly associated with aphasia, because this is the only region of the thalamus connected with cortical language areas (Fig. 19.2.) Obviously, tha-

Neurobehavioural aspects of deep hemisphere stroke

Fig. 19.3. Mild language disturbance (scarce, poorly monitored output, anomia, semantic paraphasia) caused by an anterior thalamic infarction.

lamic infarcts offer a better source than hemorrhages to study the linguistic relevance of the different thalamic divisions. Aphasia is produced mainly by tuberothalamic infarctions, followed by paramedian and posterior choroidal infarctions (Graff-Radford et al., 1985; Bogousslavsky et al., 1988b). Reported language defects in anterior infarctions (Fig. 19.3) include aspontaneity, diminished content of speech, paraphasias, decreased generation of words, anomia, and defects of spelling, comprehension, reading and writing. Repetition ability is usually preserved. Stuss et al. (1988) described the language disturbances in several patients with paramedian thalamic infarcts: poor initiation of speech, with a general poverty of output, occasionally contaminated by confabulation and lack of monitoring of output, fluctuation and variability in performance, relatively intact repetition and comprehension abilities, a deficit in word-list generation, and naming problems, characterized more by perceptive errors, nonaphasic misnaming, intrusions, persevations and confabulation than by phonemic or semantic paraphasias (Fig. 19.4). It appears that, in most cases, the deficit is mainly one of lack of initiative of speech and disruption of speech by memory and arousal disturbances, probably due to damage to the frontal lobe-inferior thalamic peduncle–nucleus reticularis–centre median system, preventing selective focal engagement of specific cortical networks, via enhancement of selective focal thalamo-cortical transmission (Nadeau & Crosson, 1997). However, not all

Fig. 19.4. Medial thalamic infarction after aneurysm surgery: transcortical sensory aphasia and verbal incoherence.

authors agree with these linguistic–topographic correlations. Some support the thesis that there are no specific thalamic nuclei subserving specific elements of speech. Puel et al. (1984) stressed that anatomic studies do not allow thorough correlations between linguistic disturbances and distinct intrathalamic systems, but they mentioned that anterior lesions tended to produce more aspontaneity, and posterior ones more verbal incoherence. A few investigators made systematic comparisons between striatocapsular and thalamic aphasias. Alexander and La Verme (1980) found no definite difference between aphasia after hemorrhages in the putamen and in the thalamus. Wallesch et al. (1983) distinguished between patients with left basal ganglia lesions, who performed worse in tests of articulation, syntax and lexical function, and patients with left thalamic lesions, who showed impairments in speech fluency and in the Token test. In a comprehensive review of 103 patients with thalamic aphasia described in the literature up to 1990, Démonet et al. (1992) found only seven patients with classic aphasia (6%),of whom 10% had phonemic disorders and 26% had

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comprehension deficits, which contrast with the findings among those with subcortical non-thalamic lesions: 36 patients with classic aphasia, of whom 60% had phonemic disturbances and 67% had comprehension disorders. They stressed, however, that more than half of their own patients with subcortical aphasias showed some common characteristics: reduction of spontaneous speech, semantic paraphasias and persevations, relative sparing of auditory comprehension and intact word repetition. For this type of aphasia they proposed the term ‘subtranscortical aphasia’.

defects, patients with verbal spontaneity had normal cerebral perfusion, and those with pure lexical incoherence had only subcortical perfusion defects. Patients with aphasia following subcortical stroke had longer duration of middle cerebral artery occlusion, poor leptomeningeal collaterals (Weiller et al., 1993) and often have associated cortical lesions not seen on CT scan. In some series aphasia and other cortical defects were only seen in the subgroups with associated cortical lesions (Godefroy et al., 1992, 1994).

Cortical dysfunction in subcortical aphasia

Agraphia

Shortly after the ‘rediscovery’ of subcortical aphasia in CT, regional cerebral blood flow (rCBF) and PET studies showed low-flow areas and extensive zones of mild hypometabolism in the cortex overlying those deep lesions (Perani et al., 1987). Cortical low flow was confined to occluded territories, such as occlusion or stenosis of the middle cerebral artery (MCA) causing both a striatocapsular infarction and frontotemporal hypoperfusion. Although the presence of cortical hypoperfusion is in agreement with the clinical findings in acute scans, disagreement can be found in the case of late scans. Puel and associates (1992) demonstrated the importance of ‘regional’ diaschisis, as they found a relationship between left sylvian hypoperfusion and repetition impairment, as well as a relationship among mild temporoparietal hypometabolism, phonemic paraphasia, and comprehension disorders (Vallar et al., 1992). Metter et al. (1988) used pathway analysis of CT findings, glucose metabolism measured by PET, and language data to determine whether subcortical lesions produced aphasia by a direct or indirect (via cortex) effect. They concluded that, for fluency, subcortical structural damage had direct and indirect (through the frontal lobe) effects, whereas for comprehension subcortical damage had no direct effect and a slight indirect effect (through the temporal lobe). Similar results were obtained in a PET study of performance on the Token Test, revealing that basal ganglia metabolism did not contribute significantly to performance on that comprehension test. Thalamic strokes induce a significant decrease in overall cortical metabolism on both sides, more so ipsilaterally. In the fluent type of thalamic aphasia, reduced cortical flow was demonstrated in parietotemporal areas. Frontal hypoperfusion correlates with fluency, while insular, lenticular, and posterior depressions correlate with comprehension, naming, and paraphasia. Puel and co-workers (Puel et al., 1992) showed that whereas ‘subtranscortical’ or ‘dissident’ aphasias featured subcortical and cortical perfusion

Kertesz (1992) found that the severity of writing disturbance was similar in patients with subcortical and cortical lesions of the same size. As in cortical lesions, the severity of the writing defects was correlated with impairments in oral language and reading. All types of writing errors were observed. The agraphia appeared more severe in patients with putaminal infarcts, with a dissociation between spontaneous writing and writing on dictation. Agraphia tended to persist and sometimes was present even as a patient recovered from aphasia, thus producing a ‘chronic’ pure agraphia. In some of these cases, ‘subcortical’ agraphia is related to frontal cortical diaschisis. The alternative hypothesis is that the basal ganglia integrate semantic, lexical, phonological and graphemic information with motor control, being a key station for the graphomotor pathway. The error pattern, mainly orthographic and graphomotor (illegibility, errors in the shape and characteristics of letters) supports that hypothesis.

Apraxia Some of the early descriptions of apraxia linked apraxia to lesion of white-matter tracts, disconnecting relevant cortical areas. Examples are verbomotor facial apraxia due to damage to the arcuate fasciculus or the extreme capsule, disconnecting Wernicke’s area from the left premotor areas, and left-hand (or leg) sympathetic apraxia, resulting from interruption of the callosal fibres linking both premotor areas. Internal border-zone infarcts (between the territories of the MCA and the anterior cerebral artery (ACA) territories) can produce this type of apraxia. Lenticulostriate infarcts disturb the development of strategies involved in motor procedural learning. In contrast, apraxia arising from pure deep hemorrhages or infarcts is infrequent and in many of the reported cases the deep parietal and occipitofrontal fibers (in the central and parietal white-

Neurobehavioural aspects of deep hemisphere stroke

Fig. 19.5. Infarctions involving the posterior limb of the right internal capsule without (right) and with severe neglect and visuospatial disturbances (left).

matter), or frontostriatal connections were also involved. Pramstaller and Marsden (1996) analysed 82 cases (the majority due to stroke) of such ‘deep’ apraxias reported in the literature. They concluded that lesions confined to the basal ganglia rarely cause apraxia. Apraxia was most commonly seen when there was additional involvement of capsular, periventricular or peristriatal white-matter. Periventricular white-matter lesions also caused apraxia. The vast majority of ‘deep’ apraxia lesions were located in the left hemisphere. The most common type of deep apraxia was bilateral ideomotor apraxia, or of the left hand, if there was a right hemiparesis. Bucofacial and ideative apraxia were very rare. Thalamic lesions can also cause apraxia, even if there is no apparent involvement of the white-matter. Visuomotor apraxia, apparently due to interruption of the most caudal fibres of the internal capsule, was reported after a thalamic haemorrhage (Classen et al., 1995).

Neglect Shortly after the introduction of CT in clinical practice it became apparent that subcortical strokes could produce neglect. Several thalamic nuclei (Watson et al., 1981), the striatum, the anterior and posterior limbs of the internal capsule were recognized as sites at which damage could cause sensory extinction, motor extinction, hemispatial

inattention, lack of intention to explore the contralateral space, mental representational neglect, and anosognosia. The majority of those lesions were located in the right hemisphere, indicating that, like cortical regions, right subcortical structures are dominant for hemispatial attention and intention. Probably because of their larger size, pressure effects, and more extensive cortical diaschisis, neglect produced by deep hemorrhages is usually more frequent, severe and long lasting than that caused by ischemic lesions. Attempts to correlate the presence, type and severity of neglect with the involvement of specific deep vascular territories or specific subcortical structures have been relatively deceiving. Apart from its absence in single-perforator disease and its frequent association with posterior or medial thalamic infarcts, no other consistent correlation emerged (Fig. 19.5). Infarcts of the medial and lateral deep perforators of the MCA and ACA cause neglect in about one-third of patients (Ferro et al., 1987). Neglect is usually mild and transient. Infarcts of the territory of the anterior choroidal artery that involve the posterior limb of the internal capsule can cause severe neglect, displaying both intentional and attentional features, and associated with cortical diaschisis (Bogousslavsky et al., 1988a) related to damage to non-specific thalamic projections and to pulvinar–parietal disconnection. Also, no particular association was found between subcortical lesion location and neglect characteristics or components. All its features can be

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Fig. 19.6. SPECT showing frontal hypoperfusion in a patient with hypertensive right striatal intracerebral hemorrhage, without neglect.

demonstrated after subcortical lesions (Ferro et al., 1987), including some, that in theoretical models are considered as ‘cortical’, such as spatial representation and imagery. The strong interconnections among the different subcortical structures and the lack of correspondence between anatomic boundaries and deep vascular territories (which comprise more than one anatomic structure, but only a part of each) may help to explain these findings. Perfusion and metabolic investigations have demonstrated that, with a few exceptions, the presence of neglect is associated with cortical metabolic/perfusion depression, recovery from which parallels improvement in the area of neglect (Vallar et al., 1988). This explains why cortical and subcortical neglect are phenomenologically similar. Some regional differences in diaschisis can, however, be found. Medial thalamic lesions cause bilateral cortical depression. Posterior infarcts mostly depress the visual cortex and inferior limbic cortex, whereas posterolateral sensory thalamic strokes without neuropsychological deficits do not cause cortical hypometabolism (Baron et al., 1992). Striatal lesions causing localized frontal diaschisis are not

associated with neglect (Fig. 19.6), but if they cause parietal depression, the neglect disturbance will arise (Demeurisse et al., 1997). This helps to explain why apparently similar lesions can show surprisingly different neurobehavioural counterparts, varying from severe neglect to an errorless performance in an extensive neglect-testing battery. Individual variation in the degree of hemispheric dominance for hemispatial attention may also contribute to that variability.

Amnesia and abulia Behavioural and cognitive abnormalities are usually prominent following caudate, medial and anterior thalamic lesions. Following caudate infarcts (Caplan et al., 1990) and hemorrhages (Mendez et al., 1989) several types of neurobehavioural changes have been described. Acutely, patients appear confused and disoriented or, in rare cases, mute. Abulia is the most frequent behavioural change followed by ‘psychic akinesia’ and frontal system abnormal-

Neurobehavioural aspects of deep hemisphere stroke

ities (Kumral et al., 1999). Patients lack spontaneous verbal and motor initiative, and tend to speak or act only when prompted. They display increased latency in response to stimuli, and their responses are slow, although correct. They have difficulty in sustaining attention and persisting with a task. Less often, patients are restless and hyperactive or alternate periods of apathy and agitation. Formal neuropsychological testing will reveal impaired problem-solving ability, decreased attentional capacity, and moderate impairment on memory tasks, because of difficulty in recall, even with cues, but with normal recognition. These behavioral deficits tend to persist and seriously limit the ability of these patients to return to work or to their premorbid social lives. Some patients with unilateral or bilateral caudate lesions are left with permanent cognitive impairment. A significant number of patients with caudate infarction deteriorate in their intellectual function between 1 and 2 years after stroke. This phenomenon could be mediated through disruption of cortical projections to the caudate (Bokura & Robinson, 1997). Anterior and medial thalamic lesions cause a wide range of neuropsychological defects involving memory, arousal, attention, motivation, initiation and executive functions. In anterior infarcts, amnesia is combined with abulia, language disturbances or neglect. In mediodorsal infarcts, drowsiness and abulia are combined with memory defects and vertical gaze disturbances. Isolated infarcts of the dorsal intralaminar nuclei cause problems with attention, concentration, executive disturbances and memory retrieval (Van Der Werf et al., 1999). Some of these patients, especially those with bilateral paramedian infarcts (Fig. 19.2), can be labelled as demented (Katz et al., 1987). Bilateral paramedian thalamic infarcts cause a significant diffuse metabolic decrease in the whole cortex. Dementia is uncommon after unilateral infarcts, in which memory disturbances usually show considerable recovery. The memory defect impairs both verbal memory and visual memory for left-side infarcts, but only visual memory in right-side infarcts. Patients with bilateral lesions will have more severe and long-lasting defects. These patients are hypersomnolent and abulic and appear confused. They confabulate and can show reduplicative paramnesia. The memory defect affects predominantly explicit declarative memory (i.e. the acquisition and recall of new facts and events). These patients have severe anterograde amnesia and mild and transient retrograde amnesia. Thalamic amnestic patients have preserved abilities for motor learning and implicit memory, with intact priming (unconscious registration from one task to another) (Malamut et al., 1992). Remote memory can be more affected if the lesion extends outside the dorsomedial nuclei. The

memory defect is not secondary to the other behavioural abnormalities, as it can be demonstrated in single tasks requiring immediate recall. These patients can show a ‘scalloping’ effect, with alternating good-bad performances and the best performance on the first attempt, suggesting that motivation and attention influence performance (Stuss et al., 1988). Severe memory defect in those thalamic infarcts is related to simultaneous damage to the mamillo-thalamic tract and the ventroamygdalofugal pathway. Infarction of the inferior genu of the internal capsule (Tatemichi et al., 1992) can produce a syndrome featuring fluctuating alertness, inattention, memory loss, apathy, abulia and psychomotor retardation. This strategic infarct location can interrupt the inferior and anterior thalamic peduncles and causes deactivation of the ipsilateral inferior and medial frontal cortex, as shown by CBF studies. Unilateral or bilateral internal capsule genu infarctions sparing the inferior thalamic peduncle produce abulia without memory disturbance (Yamanaka et al. 1996). Considerable improvement of the neuropsychological defects occurs in the months following inferior capsular genu infarction (Madureira et al., 1999).

Depression and behavioural changes As in cases of cortical lesions, patients with right subcortical strokes usually display the indifference reaction. Some studies have found that depression is more severe in left anterior subcortical lesions than in posterior or righthemisphere subcortical sites (Starkstein et al., 1987). The spontaneous recovery rate from depression appears higher for subcortical lesions than for cortical lesions. The most depressed subjects have lesions of the head of the caudate nucleus and the anterior limb of the internal capsule. These rostral basal ganglia lesions interrupt frontocaudate connections and the biogenic amine pathways. Lesions of the caudate nucleus, particularly if bilateral, can cause abulia or, less often, agitation, with disinhibition, inappropriate and impulsive behaviour, and rarely, major affective disturbances with hallucinations. Thalamic lesions, either left or right, do not, in general, cause significant depression (Starkstein et al., 1988). However, other behavioural changes can be observed, depending on intrathalamic infarct location. Personality changes, abulia, apathia, or more rarely, euphoria or mania, are consistent findings following medial or anterior thalamic damage. A peculiar case of stereotyped, compulsive tendency to assume a sleeping behaviour was reported after bilateral anterior paramedian thalamic infarcts. Euphoria has been related to the disruption of

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dorsomedian thalamic nuclei–orbitofrontal pathways, and apathy has been the result of injury to the anterior thalamic–cingulate pathways. The rarity of depression following thalamic infarcts may be due to hypoarousal or to sparing of the ascending biogenic amine pathways that run ventral to the thalamic nuclei. Other frequent findings in patients with subcortical lesions, particularly in left or bilateral lesions, are uncontrollable fits of laugher or crying, many times devoid of emotional content and precipitated by minor affective or even neutral events. This has variously been labelled pathological or forced crying, emotional lability, emotional expression incontinence, or emotionalism. Half of the patients with bilateral capsular infarcts display emotionalism, probably because efferent fibers mediating emotional impulses to the bulbar cranial nerves do not travel in the posterior limb of the internal capsule, but rather through its anterior limb or through the thalamus. Several recent investigations established an association between subcortical vascular disease, depression, associated cognitive impairment and response to antidepressants. Silent infarcts, small basal ganglia lesions and white-matter hyperintensities on MR were found in different studies to be independently associated with geriatric depression (Fujikawa et al., 1993; Salloway et al., 1996; Steffens et al., 1999). Depressed patients with moderateto-severe deep white-matter hyperintensities had worse neuropsychological functioning (memory, language, executive functions) than depressed patients without such lesions or than normal elderly controls (Kramer-Ginsberg et al., 1999). Furthermore, confluent subcortical hyperintensities and multiple basal ganglia lesions are predictors of a poor response to antidepressants (Simpson et al., 1998).

Subcortical vascular dementia In pathological studies of vascular dementia, subcortical lesions have been found in 60–80% of patients. Subcortical vascular lesions that can cause dementia include multiple lacunes, strategic infarcts located in functionally crucial areas such as the anterior and medial thalamus, the inferior capsular genu and white-matter lesions, shown by CT as leuko-araiosis or by MR as confluent areas of increased T2 signal. Subjects with neuropathological criteria for Alzheimer disease are also more likely to have poor cognitive function and dementia if they had concomitant subcortical lacunar infarcts or deep white-matter changes (Snowdon et al., 1997).

The impact on cognition is different following a single large subcortical infarct, a single lacunar infarct or multiples lacunes. Cognitive impairment is also influenced by other variables such as age, education, the extent of whitematter changes and to a lesser degree by the severity of cortical and subcortical atrophy. In the stroke databank cohort (Tatemichi et al., 1990) the clinical diagnosis of dementia was made in 11% of patients with striatocapsular infarcts and 14% of those with thalamic infarcts, these figures being lower than those for cortical sites. Patients with single supratentorial lacunar infarcts may have a decreased capacity for mental effort (van Zandvoort et al., 1998). However, disabling cognitive impairment is uncommon and dementia very rare following a single lacunar infarct (Guerreiro et al., 1994). Loeb et al. (1992) followed, for an average of 4 years, 108 patients with CT-demonstrated lacunar infarction and found that 23% developed dementia. Dementia was more common in those with new vascular events or with evidence of cerebral atrophy, but was not associated with leuko-araiosis or frontal location of the lacunes. Dementia is more frequent after multiple lacunar strokes. Demented and cognitively impaired patients with multiple lacunar strokes had more extensive white-matter changes (Fukuda et al., 1990; van Swieten et al., 1996), and larger ventricles (Corbett et al., 1994) than those who are cognitively intact. Patients with multiple lacunar infarcts perform less well than normal controls on several neuropsychological measures (language, visuospatial function, memory, executive functions, motor programming, set/shifting, response inhibition) (Babikian et al., 1990; Wolfe et al., 1990). They are more often rated apathetic. About one-quarter might meet the criteria for the clinical diagnosis of dementia (Wolfe et al., 1990). Demented patients with multiple subcortical infarcts have more abnormalities of the motor aspects of speech (pitch, melody, articulation, rate) than Alzheimer’s patients. These abnormalities are related to lesions involving subcortical structures (Wallesch et al., 1983). Subcortical white matter changes are more frequent in older people, subjects with vascular risk factors or silent infarcts and in patients with subcortical strokes. The spectrum of their clinical manifestations ranges from totally assymptomatic subjects, to subtle cognitive and behavioural changes, gait disorders, depression, cognitive decline and dementia (Steingart et al., 1987; van Swieten et al., 1991; Schmidt et al., 1991; Breteler et al., 1994). It is difficult to disentangle the role of white-matter changes and of subcortical infarcts, because they are often associated and share several risk factors (van Swieten et al., 1996). There is a threshold effect (Boone et al., 1992) and a relationship

Neurobehavioural aspects of deep hemisphere stroke

between the intensities of white matter changes and cognitive decline (Longstreth et al., 1996). The most affected cognitive domains are attention and concentration, speed of mental processes (Junqué et al., 1990), executive functions and to a less degree verbal and visual memory (van Gijn, 1998; Leys et al., 1999)

Conclusions Several methodological flaws of many studies on the neuropsychological consequences of subcortical stroke are now evident: patients with hemorrhages should be analysed separately from those with infarcts, unselected series of patients should be evaluated and time post onset should be controlled. Hemorrhages compress overlying cortex and produce a large area of cortical diaschisis. The role of cortical hypoperfusion, due to possible occlusion of the internal carotid or middle cerebral artery must be considered. Focal cortical atrophy on MR, indicating coexistence of cortical damage should be looked for in late scans. In conclusion, the pathophysiology of neuropsychological symptoms/syndromes after subcortical vascular lesions can have several explanations: ii(i) Indirect effect on the cortex by pressure or diaschisis. i(ii) Cortical ischemia related to proximal vascular occlusion. (iii) Direct damage of centres and pathways integrating distributed networks subserving declarative memory, working memory, attention, mood and initiative. Disturbance of these functions can have an indirect effect on other cognitive ‘cortical’ process, such as language or praxis. Complex cognitive and behavioural functions are supported by large-scale, distributed neural networks that have multiple interconnections both ‘horizontal’, composed by connected cortical zones, and ‘vertical’, including cortical neurons, their efferent thalamic fibers, and the neostriatal regions that receive their projections (Alexander et al., 1990). These networks are ordered (Vallar et al., 1992), meaning that the relative weights of the cortical and subcortical components vary from one network to another. This ordered, multiple-network approach explains why (i) lesions in different cortical and subcortical sites cause similar specific cognitive deficits, (ii) recovery takes place, unless the whole loop (or, in same instances, its upper-hierarchy component) is damaged, (iii) cortical and subcortical syndromes can be distinguished on the basis of various combinations of loops disturbed by strokes of different localizations.

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Right hemisphere syndromes Stephanie Clarke Division of Neuropsychology, CHUV-Nestle, Lausanne, Switzerland

Delimiting the field Right hemisphere lesions are often associated with a number of specific syndromes, such as left hemineglect, topographical disorientation, anosognosia, visual agnosias and visuo-spatial deficits. Unlike the left hemisphere syndromes of aphasia and apraxia, none of the right hemisphere syndromes possesses a simple and clinically relevant model derived from human observations. The rare models that we have and that are gaining importance in rehabilitation, concern visual agnosias, visuo-spatial deficits or hemineglect and rely on experimental data from non-human primates. Clinical observations and experimental studies of the past 30 years show that the field of right hemisphere syndromes is far more complex than originally believed (Table 20.1). Although some of the syndromes have been repeatedly reported following right unilateral lesions, other syndromes can occur after right or left unilateral lesions, but do so more often after right than left lesions. For other syndromes the right hemispheric lesion is necessary, but not sufficient; these syndromes occur invariably after bilateral lesions, but never after unilateral left lesions. This chapter concentrates on syndromes for which right hemispheric involvement is necessary or which have been classically associated with right hemisphere damage.

Hemineglect Hemineglect is characterized by lack or decrease of attention to stimuli and events on the left-hand side of the patient following a right hemispheric lesion. In extreme cases, patients do not react when they are spoken to from the left side, do not eat food on the left half of their plate, do not shave or make up the left half of their face or read the left side of their newspaper. Hemineglect can affect,

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sometimes to a varying degree, visual, auditory, somatosensory and motor modalities (Barbieri & De Renzi, 1989). Formal testing of hemineglect consists of tests that require cancelling of items on a sheet of paper, copying or drawing of objects, dichotic listening or simultaneous tactile stimulation.

A modular deficit Experimental studies in patients with unilateral neglect suggest that perceptual processing may be intact up to the level of semantic classification, and that neglect only acts at the level of selection for action and access to awareness, e.g. preattentive vision is still able to parse the scene, to segregate figure from ground, group objects, and to define their primary axis. Several mechanisms are currently evoked as contributing to neglect, including disinhibited orienting to the ipsilesional field, a deranged representation of space, and deficits in disengaging attention, oculomotor corollary discharge, and representation of contralesional movement trajectories (for review, see Rafal, 1994). In some cases, hemineglect does not only affect perception but also mental imagery. Bisiach and Luzzatti (1978) described the case of a patient whose hemineglect affected mental images of well known Milanese landmarks. An intriguing aspect of hemineglect was described recently by Ramachandran et al. (1997) as mirror agnosia. Patients with right hemisphere stroke and left visual field neglect were shown objects that were on their left via a vertical parasagittal mirror. They confirmed seeing the object, and they understood the principle of the mirror, but remained unable to use this information to explore the left hemispace. A series of recent reports suggested that hemineglect is a modular deficit. Left visuo-spatial neglect can affect differently near and far space; selective deficits for one or the

Right hemisphere syndromes

Table 20.1. Right hemisphere syndromes

RHD necessary and sufficient Attention Awareness

Hemineglect

Vision

Topographical disorientation Apperceptive visual agnosia (⫽ deficient perceptual categorization) Prosopagnosia Supernumerary limbs

Body scheme

RHD necessary but probably not sufficient

Capgras delusion

Unilateral lesion sufficient, more often right than left

Anosognosia Acute confusional state Reduplicative paramnesia Palinopsia Astereopsis Optic ataxia

Asomatognosia

Note: RHD ⫽ right hemisphere damage.

other aspect and double dissociations were reported (Cowey et al., 1994; Beschin & Robertson, 1997; Guariglia & Antonucci, 1992). Furthermore, neglect can affect differently visual perception and visual imagery; selective deficits for extrapersonal space, but not for visual images (Anderson, 1993) and a double dissociation between vision and visual imagery (Coslett, 1997; Guariglio et al., 1993) were described. Stimuli that are correctly perceived in a type of task may be neglected in another; Marshall and Halligan (1995) described a case of a patient who perceived correctly global forms of figures that were composed of small elements, but on cancellation task this patient crossed only the right half of the small elements.

1984). The lesions in the latter locations were often associated with infarctions in the area of the right anterior choroidal artery (Bogousslavsky et al., 1988; de la Sayette et al., 1995; Masson et al., 1983). Several cases of left hemineglect following subcortical lesions were investigated by SPECT, demonstrating cortical hypoperfusion (Bogousslavsky et al., 1988; Perani et al., 1987; Weiller et al., 1993). Although left spatial hemineglect is most often discussed in terms of unilateral right lesions, most cases that are referred for clinical evaluation or for research projects on neglect may have bilateral lesions, as suggested by a recent study (Weintraub et al., 1996).

Anatomoclinical correlations

Models

Anatomoclinical correlations in cases of left-sided neglect stressed the critical role of right hemispheric lesions (Brain, 1941; McFie et al., 1950). Studies on series of neglect patients helped to identify the involved structures. The most commonly used technique was the so-called overlap of lesions. This technique lead to the identification of the most common lesion site in left visuo-spatial hemineglect, namely the inferior parietal lobule (Vallar & Perani, 1986; Fig. 20.1). However visual neglect can occur also in right frontal lesions (Heilman & Valenstein, 1972) and in these cases the most often damaged structure was the dorsal aspect of the inferior frontal gyrus and the immediate underlying white-matter (Husain & Kennard, 1996; Fig. 20.1). Hemineglect was also described in association with subcortical lesions and in particular in cases of thalamic (Watson & Heilman, 1979; Watson et al., 1981), basal ganglia (Damasio et al., 1980; Healton et al., 1982; Hier et al., 1977) or internal capsula lesions (Ferro & Kertesz,

Several theories and models of neglect proposed interpretations of the laterality bias. Kinsbourne proposed the existence of attentional gradients within hemispace (for updated review, see Kinsbourne, 1994). Mesulam (1981) proposed different roles for each hemisphere in spatial attention. Other models, more influenced by data from non-human primates, stressed the role of spontaneous eye movements in orienting attention (Gainotti, 1994). Anatomoclinical correlations identified several key structures for hemineglect. Heilman and Valenstein (1972) proposed that two subcortical loops were involved in different aspects of hemineglect: one loop was concerned with spatial perception and involved the temporoparieto-occipital junction, posterior cingulate cortex and posterolateral, dorsomedian and lateral geniculate nuclei of the thalamus; the second loop was concerned with movement and involved the premotor cortex, anterior cingulate cortex, basal ganglia and the centromedian,

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Fig. 20.1. Cortical regions identified by anatomoclinical correlations as playing a major role in hemispatial neglect.

ventroanterior and ventrolateral thalamic nuclei. Mesulam (1981, 1990) proposed a model with three components, perceptual, motor and motivational, which depended on the parietal, frontal and cingulate cortex, respectively. The models of Heilman and Mesulam were inspired by connectivity studies in non-human primates, but this approach remains unsatisfactory for a clearly lateralized function. Furthermore, recent tracing studies suggested that human cortical connectivity differs significantly from that of nonhuman primates (Di Virgilio & Clarke, 1997; Fig. 20.2).

Recovery and rehabilitation The presence of hemineglect beyond the acute stage is associated with poor outcome in terms of independence (Denes et al., 1982; Stone et al., 1992) and considerable effort is therefore devoted to its rehabilitation. The classical approaches are very pragmatic, such as verbalization and establishment of left orienting strategies. Although this approach can be adopted successfully for the trained situation, patients fail usually to generalize in other settings (Weinberg et al., 1977). Other approaches try to increase the attentional load on the left side by auditory (Robertson & Cashman, 1991), visual (Butler et al., 1990), vestibular (Cappa et al., 1987; Karnath, 1995; Rubens, 1985; Vallar & Perani, 1986), somatosensory (Karnath, 1995) or motor stimulations (Robertson & North, 1992).

Topographical disorientation Topographical recognition, orientation and memory Patients with predominantly or exclusively right hemisphere lesions were reported to suffer from topographical

disorientation (Brain, 1941; Clarke et al., 1993; Habib & Sirigu, 1987; Landis et al., 1986a; Paterson & Zangwill, 1945; Whitty & Newcombe, 1973). The disorientation can affect previously known places or can cause serious difficulties in learning to orient in previously unknown surroundings. The disorientation was reported both in relatively small spaces, mostly hospital wards, and in large spaces such as towns or complex buildings. Since Brain’s report (1941), two different aspects contributing to correct topographical orientation are distinguished. One aspect is recognition of spaces and/or their constituents; in several studies, this was explicitly reported to be impaired (Hécaen et al., 1980; Paterson & Zangwill, 1945). In several cases, lack of recognition was accompanied by a loss of familiarity in previously known (and familiar) surroundings (Landis et al., 1986a). The second aspect is the actual spatial orientation, whose impairment does not seem to occur in complete isolation, since difficulties in recognition, even if sometimes transitory, are usually reported. However, different types of navigation appear to be involved in spatial orientation and can be disrupted independently by brain lesions (for review, see, e.g. Farrell, 1996).

Right and left hemisphere strategies Topographical disorientation associated with unilateral right hemispheric lesions is characterized by the inability to use two- and three-dimensional information. For such patients the use of maps does not improve performance. We had the opportunity to investigate a patient with this type of deficit and found that the strategies that were successful relied all on a linear, speech-related approach (Clarke et al., 1993). Identification of buildings was based on verbal description and not visuo-spatial impression. Plans of buildings were analysed in a detail-by-detail fashion, without any two-dimensional understanding. Orientation in large buildings and in towns was only possible if a route could be decomposed into a linear sequence of landmarks. Similarly, orientation on maps was often based on a route-simulating strategy (‘How would I get there?’). The anatomical particularities of this patient’s lesion (lesion of the posterior part of the right thalamus and the right optic radiation; destruction of the posterior half of the corpus callosum) made it clear that the compensatory strategies were sustained uniquely by the left hemisphere.

Visual agnosias Visual agnosia denotes impaired recognition of visually presented material in a patient with normal or almost

Right hemisphere syndromes

Fig. 20.2. Recent studies of human cortical connectivity suggest major differences with non-human primates. Thus, human visual cortex of the right hemispheres has a very wide array of monosynaptic heterotopic interhemispheric connections (A, D, E) as well as homotopic connections (B, C). This means that visual information can be relayed very rapidly, and by several possible routes, to key centres in the left hemisphere, such as the speech areas. No such widely heterotopic interhemispheric connections have been described in non-human primates (From Di Virgilio & Clarke, 1997; Clarke, 1998, with permission).

normal visual acuity; auditory and tactile recognition is normally spared. The term visual agnosia was introduced in 1891 by Sigmund Freud and it stresses the role of internally represented knowledge in visual perception.

Types of visual agnosias Deficits of visual recognition following hemispheric lesions can take several forms (Fig. 20.3). Historically, the first form to be described was associative visual agnosia (Lissauer, 1890). In this condition the patient, who is unable to recognize objects, discriminates shapes perfectly well and is able, e.g. to copy drawings (Rubens & Benson, 1971). This type of visual agnosia is often associated with alexia and occurs most often in cases of bilateral inferior occipito-temporal lesions. Shape perception is severely

impaired in apperceptive visual agnosia; the patient is unable to copy drawings and reports seeing shapes of objects very poorly (Goldstein & Gelb, 1918; Landis et al., 1982; Fig. 20.3). The lesions associated with this severe type of apperceptive visual agnosia are usually disseminated and most likely bilateral as in carbon monoxide poisoning.

Deficits in perceptual categorization Two types of visual agnosias were described in association with unilateral right hemispheric lesions. One of them is characterized by deficits in perceptual categorization and is sometimes referred to as apperceptive visual agnosia (Warrington & Taylor, 1973). Patients with this type of relatively light visual agnosia perceive shapes normally when objects are presented in familiar views. Their difficulties

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Inability to recognize object by vision Visual agnosias

Inability to copy drawings Normal copy

Apperceptive visual agnosia

Normal perception of superposed figures and unfamiliar views

Inability to perceive superposed figures and to deal with unfamiliar views

Associative visual agnosia

Deficient perceptual categorization = Apperceptive visual agnosia

Fig. 20.3. Differential diagnosis of visual recognition deficits. Note that the term ‘apperceptive visual agnosia’ is used in the literature for two very different conditions.

become apparent when objects are hidden behind lines, e.g. in the classical visual discrimination task of Poppelreuter or when objects are presented in unfamiliar views. Lesions that are associated with deficient perceptual categorization are usually within the right hemisphere and more often than not centred on the parietal lobe (Warrington & Taylor, 1973).

Capgras delusion Capgras delusion denotes a peculiar syndrome in which a patient believes that familiar persons have been replaced by impersonating doubles. This syndrome was first described in psychiatric patients, but was also found in conditions suggesting right hemispheric damage (Alexander et al., 1979).

Prosopagnosia The other type of visual agnosia that was reported to occur after purely right hemispheric lesions is prosopagnosia. Prosopagnosia denotes the inability to recognize previously known faces, whereas voice recognition remains normal and allows the patients to compensate their deficit in everyday life. Testing for prosopagnosia involves use of photographs of faces of famous people (actors, politicians). A patient with prosopagnosia is typically unable to recognise the person on the photograph, although he can give fairly precise biographical details verbally. Furthermore, most prosopagnosic patients describe correctly the face on the photograph, its expression, the age of the person and the gender. The difficulty recognizing individuals can involve other categories, such as animals, plants, cars, buildings, handwriting and landscapes (e.g. Assal et al., 1984; Clarke et al., 1997). Although in most published cases of prosopagnosia the underlying lesion was bilateral, several well-documented cases show convincingly that a unilateral right lesion is sufficient (for discussion see De Renzi et al., 1994; Landis et al., 1986b, 1988; Fig. 20.4).

Models The disturbances of visual recognition associated with right hemispheric damage, namely deficits in visual categorization, prosopagnosia and Capgras delusion, were proposed to result from disruption of different aspects of visual processing. Work on non-human primates (Mishkin et al., 1983) and observations in patients with focal lesions (for review, see, e. g. Grüsser & Landis, 1991) suggested that visual information is processed at the cortical level along two distinct pathways (Fig. 20.5). Both pathways originate in the primary visual cortex; one pathway is directed towards the inferior part of the temporal lobe and is involved in recognition, but the other pathway is directed towards the parietal lobe and is involved in visuo-spatial functions. In the human, damage to the ventral pathway in the right hemisphere is often accompanied by prosopagnosia, whereas damage to the dorsal pathway by deficits in visual categorization and visuo-spatial functions. It has been recently proposed that damage to a particular aspect of the dorsal pathway, namely its link to the limbic system, plays a role in Capgras delusion (Ellis & de Pauw, 1994).

Right hemisphere syndromes

Fig. 20.4. Cortical regions identified by anatomoclinical correlations as playing a major role in prosopagnosia.

Body scheme alterations Fig. 20.5. Visual processing pathways in the right hemisphere.

Supernumerary limbs The occurrence of supernumerary phantom limbs was described in association with unilateral right hemispheric lesions. A patient with left sensory–motor hemisyndrome and neglect had a vivid impression of having a third arm (Halligan et al., 1993); the lesion was within the right basal ganglia. Another case, with six arms, was described after an infarction in the territory of the right middle cerebral artery (Sellal et al., 1996).

In studies of consecutive patients with unilateral hemispheric lesions, anosognosia was noted more often following right than left lesions, but it did occur after isolated unilateral left lesions (Starkstein et al., 1992; Stone et al., 1993). Lesions associated with anosognosia include temporoparietal junction, pre- and postcentral gyri, thalamus, basal ganglia and the internal capsula (Levine et al., 1991; Starkstein et al., 1992; Ellis & Small, 1997).

Hyperattention syndromes An exaggerated attention to the left side of the body was developed by three patients with stroke in the territory of the right anterior parietal artery (Bogousslavsky et al., 1995). One patient was reported to respond to the stimulations that were administered not to him but to the patient in the next bed (Bogousslavsky & Regli, 1988).

Anosognosia The term anosognosia was introduced in 1914 by Anton and Babinski to denote lack of interest and concern for deficits relative to the left hemispace. Typically a patient may deny left hemiplegia or left hemianopia. There appears to be no causal link with hemineglect, since anosognosia was reported in cases without hemineglect (Bisiach et al., 1986).

Acute confusional state The acute confusional state denotes a syndrome of limited duration that is characterized by temporo-spatial disorientation, distractibility, attentional deficits and often agitation. In a number of cases auditory and/or visual hallucinations have been described. Acute confusional state occurs often, but not exclusively, in cases of right hemisphere damage. The most frequently observed pathology are middle cerebral artery infarctions (Mesulam et al., 1976; Schmidley et al., 1984). Reduplicative paramnesia denotes delusional reduplication of places and people. It has been most often observed in post-traumatic encephalopathies, but also in cases with unilateral right lesions (Patterson & Mack, 1985; Kapur et al., 1988).

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21

Poststroke dementia Didier Leys and Florence Pasquier University of Lille, France

The association of stroke and dementia is frequent and can be seen either in the diagnostic work-up of patients attending a memory clinic, or during the follow-up of stroke patients. The terms ‘vascular dementia’ (VaD), and ‘poststroke dementia’ (PSD) are respectively used for these two different clinical situations. The term PSD includes any type of dementia occurring after a stroke, irrespective of its presumed cause (Pasquier & Leys, 1997). VaD is a dementia syndrome likely to be due to stroke lesions (Chui et al., 1992; Roman et al., 1993). VaD accounts only for a part of PSD (Tatemichi et al., 1994a, b; Pasquier & Leys, 1997) and may occur without any obvious clinical history of stroke. VaD is the second most common cause of dementia, as it accounts for 10 to 50% of the cases, depending on the geographic location, population and criteria used (Rocca et al., 1991; Hebert & Brayne, 1995). Strokes lead to a high risk of cognitive impairment and dementia (Tatemichi et al., 1992; Tatemichi et al., 1994). As vascular causes of cognitive impairment are common, and perhaps preventable, patients could benefit from therapy, early detection and accurate diagnosis of vascular cognitive impairment and VaD is a challenge (Bowler & Hachinski, 1995).

Epidemiology of poststroke dementia Descriptive epidemiology Prevalence Depending upon the composition of cohorts, prevalence rates of PSD vary between 13.6% (Censori et al., 1996) and 31.8% (Pohjasvaara et al., 1997) at 3 months. A study reported a prevalence rate of 32.0% after 5 years (Bornstein et al., 1996). The prevalence of dementia is higher in stroke survivors than in matched controls (Censori et al., 1996;

Pohjasvaara et al., 1997). However, a systematic evaluation of pre-existing dementia in stroke patients revealed that 16% of stroke patients aged 40 years or more had preexisting dementia (Hénon et al., 1997). Therefore, pre-existing dementia may account for some dementia recognized after stroke. Medial temporal lobe atrophy, associated with an increased risk of AD (Jobst et al., 1992), is more frequent in stroke patients who have pre-existing dementia (Hénon et al., 1998), leading to the hypothesis that most prestroke dementia are due to AD (Hénon et al., 1998).

Incidence One-fourth of stroke patients develop new-onset dementia 1 year after stroke (Andersen et al., 1996). The relative risk of new-onset dementia within 4 years is 5.5 (Tatemichi et al., 1994b). So far, there is only a single population-based study on the incidence of dementia in patients with stroke (Kokmen et al., 1996): this study was conducted over an observational period of 25 years. The cumulative incidence of PSD increased from 7% at year 1 to 48% at year 25; using a standardized mortality ratio, the relative risk of dementia was 8.8 one year after stroke and decreased to 2.0 at the end of follow-up (Kokmen et al., 1996), the incidence of AD being doubled in stroke patients (Kokmen et al., 1996). One-third of patients developing PSD already had some degree of pre-existing cognitive decline (Pohjasvaara et al., 1997).

Risk factors Stroke features associated with an increased risk of PSD are the lacunar origin and the left side of the lesion (Tatemichi et al., 1993). A major left hemisphere syndrome is also a significant and independent predictor of PSD (Tatemichi et al., 1993; Censori et al., 1996; Pohjasvaara et al., 1997).

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The volume of functional tissue loss is also important because it also includes the effect of deafferented cortex (Mielke et al., 1992). Increasing age (Tatemichi et al., 1993; Gorelick, 1997), non white race, low education (Tatemichi et al., 1993; Gorelick, 1997), diabetes mellitus, cortical atrophy (Tatemichi et al., 1990; Loeb et al., 1992; Kinkel et al. 1985) and comorbid disorders leading to hypoxemia, such as seizures, cardiac arrhythmia or pneumonia (Moroney et al., 1996), are associated with a higher risk of PSD, but not cigarette smoking (Tatemichi et al., 1993).

Influence of PSD on stroke outcome A significant reduction in survival rates has been reported in stroke patients with PSD (Tatemichi et al., 1994a): the cumulative proportion of survivors at 5 years is 39% for stroke patients with dementia and 75% for non-demented stroke patients (Tatemichi et al., 1994a). Dementia diagnosed 3 months after stroke is associated with an increased risk of stroke recurrence (Moroney et al., 1997b). A possible explanation is that dementia may be a surrogate marker for multiple vascular risk factors that may increase the risk of recurrence (Moroney et al., 1997b). However, less intensive management of stroke patients with cognitive impairment, and their lack of compliance, may also contribute to the increased risk of recurrence (Moroney et al., 1997b).

Diagnosis of PSD The cornerstones in the evaluation of a patient with suspected dementia after a stroke are traditional clinical skills to perform detailed clinical and neurological history and examination, including the interview of an informant. Assessment of social functions, activities of daily living, as well as psychiatric and behavioural symptoms are parts of the basic evaluation.

Mental status examination The bedside mental status examination includes the Mini Mental State Examination (Folstein et al., 1975), which has limitations as it emphasizes language, does not include timed elements and recognition portion of the memory tests, is insensitive to mild deficits, and is influenced by education and age. Other screening instruments for VaD include a 4 to 10 word memory test with delayed recall, cube drawing test for copy, verbal fluency test (number of animals named in 1 minute), Luria's alternating hand sequence or finger rings and letter cancellation test

(Roman et al., 1993). Usually, a more detailed neuropsychological assessment is necessary, which should cover the main cognitive domains including memory functions (short- and long-term memory), abstract thinking, judgement, aphasia, apraxia, agnosia, orientation, attention, executive functions, and speed of information processing (Erkinjuntti et al., 1997; Pohjasvaara et al., 1998).

Brain imaging Brain imaging should be performed at the initial diagnostic work-up. MRI is better than CT scan, because of its higher sensitivity and ability to demonstrate medial temporal lobe and basal forebrain areas. Depending on the criteria of VaD used, focal brain infarcts are found in 70 to 100% and more extensive white matter lesions in 70 to 100% of cases (Erkinjuntti et al., 1987; Roman et al., 1993; Erkinjuntti, 1996).

Diagnostic criteria for VaD The most widely used criteria for VaD are the DSM-IV (American Psychiatric Association, 1994), the ICD-10 (World Health Organization, 1993), the ADDTC (Chui et al., 1992), and the NINDS–AIREN criteria (Roman et al., 1993). The two key elements implemented in the clinical criteria for VaD are (i) the definition of dementia (Erkinjuntti et al., 1997), and (ii) the definition of the vascular disorder (Erkinjuntti, 1994; Wetterling et al., 1994; Wetterling et al., 1996). All the clinical criteria used are consensus criteria, which are neither derived from prospective communitybased studies on vascular factors affecting the cognition, nor based on detailed natural histories (Chui et al., 1992; Roman et al., 1993; Rockwood et al., 1994; Rockwood et al., 1994; Erkinjuntti, 1994; Erkinjuntti, 1997). All the cited criteria are based on the ischemic infarct concept and designed to have high specificity, although they have been poorly implemented and validated (Rockwood et al., 1994; Erkinjuntti, 1997). Variations in defining the dementia syndrome (Pohjasvaara et al., 1997; Erkinjuntti et al., 1997), and the vascular cause (Skoog et al., 1993; Wetterling et al., 1996), has led to a critical consequence: different definitions give different point prevalence estimates, identify different groups of subjects, and further identify different types and distribution of lesions. The DSM-IV definition requires focal neurological signs and symptoms or laboratory evidence of focal neurological damage clinically judged to be related to the disturbance (American Psychiatric Association, 1994). The course is

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specified by sudden cognitive and functional losses. Brain imaging requirements are not detailed. The DSM-IV definition for VaD is reasonably broad and lack detailed clinical and radiological guidelines. The ICD-10 criteria require unequal distribution of cognitive deficits, focal signs as evidence of focal brain damage, and significant cerebrovascular disease judged to be etiologically related to the dementia (World Health Organization, 1993). The criteria do not detail brain imaging requirements. The ICD-10 criteria specify altogether six subtypes of VaD. The ICD-10 criteria for VaD has been shown to be highly selective and only a subset of those fulfilling the general criteria for ICD-10 VaD can be classified into defined subtypes (Wetterling et al., 1994; Wetterling et al., 1996). The shortcoming of these criteria include lack of detailed guidelines, e.g. unequal cognitive deficits and neuroimaging, lack of etiological cues, and heterogeneity (Wetterling et al., 1994; Wetterling et al., 1996). The ADDTC criteria are exclusively criteria for ischemic VaD (IVD) (Chui et al., 1992). They require (i) evidence of two or more ischemic strokes by history, neurologic signs or neuroimaging studies (CT or T1-weighted MRI), or (ii) in case of a single stroke a clearly documented temporal relationship (not specified in detail), and always a neuroradiological evidence of at least one infarct outside the cerebellum. Ischemic white matter changes on CT or MRI do not qualify as brain imaging evidence of probable IVD, but may support a diagnosis of possible IVD. The criteria list features supporting the diagnosis, as well as a list of features casting doubt on a diagnosis of probable IVD. The NINDS–AIREN research criteria for VaD (Roman et al., 1993) include dementia syndrome, cerebrovascular disease and a relationship between dementia and cerebrovascular disorders. Cerebrovascular disease is defined by the presence of focal neurological sins and detailed brain imaging evidence of ischemic changes in the brain. A relationship between dementia and cerebrovascular disorder is based on the onset of dementia within 3 months following a recognized stroke, or on abrupt deterioration in cognitive functions or fluctuating, stepwise progression of cognitive deficits. The criteria include a list of features consistent with the diagnosis, as well as a list of features that make the diagnosis uncertain or unlikely. Also different levels of certainty of the clinical diagnosis (probable, possible, definite) are included. The NINDS–AIREN criteria recognize heterogeneity (Erkinjuntti, 1994) of the syndrome and variability of the clinical course in VaD, highlight detection of ischemic lesions and a relationship between lesion and cognition, as well as stroke and dementia onset. The inter-rater reliability of the NINDS–AIREN

criteria has been shown to be moderate to substantial (kappa 0.46 to 0.72) (Lopez et al., 1994). The current criteria for VaD are not interchangeable; they identify different numbers and cluster of patients labelled as VaD. The DSM-IV criteria are less restrictive compared to the ICD-10, the ADDTC and the NINDS–AIREN criteria (Wetterling et al., 1996; Verhey et al., 1996). The clinical criteria for VaD of older origin (DSM-IV and ICD-10) do not specify brain imaging requirements for the diagnosis in detail. The ADDTC requires one CT or T1 MRI infarct outside cerebellum, but white-matter lesions do not qualify for support of probable IVD. The NINDS–AIREN criteria require multiple infarcts (more than one cortico-subcortical or lacunar) or extensive white-matter lesions (CT or T1 MRI), but accept also a clinically ‘strategic’ single infarct as an evidence of ‘relevant cerebrovascular disease’. As evaluated neuropathologically, the ADDTC criteria seem to be more sensitive and the NINDS–AIREN criteria more specific, but neither are perfect (Gold et al., 1997). In a neuropathological series sensitivity of the NINDS–AIREN criteria was 58% and specificity 80% (Gold et al., 1997). The criteria successfully excluded AD in 91% of cases, and the proportion of combined cases misclassified as probable VaD was 29% (Gold et al., 1997). Compared to the ADDTC criteria, the NINDS–AIREN criteria were more specific and they better excluded combined cases (54% vs. 29%) (Gold et al., 1997).

Clinical patterns of dementia in stroke patients Cognitive syndrome The cognitive syndrome of VaD is characterized by (i) memory deficit, (ii) dysexecutive syndrome, (iii) slowed information processing, and (iv) mood and personality changes. These features are especially typical for cases with subcortical lesions. The patients with cortical lesions have in addition often a combination of different cortical neuropsychological syndromes (Mahler & Cummings, 1991). The memory deficit in VaD is often less severe than in AD, and consists impaired recall, relative intact recognition and better benefit from cues (Desmond et al., 1999). The dysexecutive syndrome in VaD includes impairment in goal formulation, initiation, planning, organising, sequencing, executing, set-sifting and set- maintenance, as well as in abstracting (Mahler & Cummings, 1991; Cummings, 1994; Desmond et al., 1999). The dysexecutive syndrome in VaD relates to lesions affecting the prefrontal subcortical circuit including prefrontal cortex, caudate,

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pallidum, thalamus, and the thalamo-cortical circuit (capsular genu, anterior capsule, anterior centrum semiovale, and anterior corona radiata) (Cummings, 1993). Relatively preserved personality and insight in mild and moderate cases of VaD is typical. Features that make the diagnosis of VaD disease uncertain or unlikely include early onset and progressive worsening of memory deficit or some other cognitive cortical deficit in the absence of corresponding focal lesions on brain imaging (Roman et al., 1993).

Associated neurological findings Frequent clinical neurological findings indicating focal brain lesion early in the course of VaD disease include: mild motor or sensory deficits, decreased coordination, brisk tendon reflexes, Babinski's sign, field cut, bulbar signs including dysarthria and dysphagia, extrapyramidal signs (mainly rigidity and akinesia), gait disorder (hemiplegic, apractic–atactic or small-stepped), unsteadiness and unprovoked falls, as well as urinary frequency and urgency (Babikian & Ropper, 1987; Roman, 1987; Erkinjuntti, 1987; Roman et al., 1993; Ishii et al., 1986). On the other hand, features that make the diagnosis of VaD uncertain or unlikely include absence of focal neurological signs, other than cognitive disturbance (Roman et al., 1993). In cortical VaD typical clinical features are sensorimotor changes and abrupt onset of cognitive impairment and aphasia, and in subcortical VaD disease pure motor hemiparesis, bulbar signs and dysarthria (Erkinjuntti, 1987).

Behavioural and psychological symptoms of dementia Depression, anxiety, emotional lability and incontinence, and other psychiatric symptoms are frequent in VaD (Roman, 1987). Depression, ablulia, emotional incontinence and psychomotor retardation are frequent in subcortical VaD (Mahler & Cummings, 1991; Cummings, 1994).

Ischemic scores Cardinal features of VaD disease are incorporated to the Hachinski Ischemic Score (Hachinski et al., 1975). In a recent neuropathological series stepwise deterioration (OR 6.0), fluctuating course OR 7.6), history of hypertension (OR 4.3), history of stroke (OR 4.3) and focal neurological symptoms (OR 4.4) differentiated patients with definite VaD from those with definite AD (Moroney et al.,

1997a). Nocturnal confusion and depression had no discriminating value. However, the ischemic score was unable to differentiate the ADv from VaD.

Heterogeneity of VaD Classification of VaD may be based according to (i) the underlying vascular pathology, (ii) the type of brain lesions, (iii) the location of brain lesions, (iv) the clinical syndrome. The subtypes of VaD included in current classifications are the cortical VaD (or multi-infarct dementia), the subcortical VaD (or the small vessel dementia), and the strategic infarct dementia (Erkinjuntti, 1987; Roman et al., 1993; Cummings, 1994; Brun, 1994; Wallin & Blennow, 1994; Loeb & Meyer, 1996; Konno et al., 1997). Many classifications also include hypoperfusion dementia (Sulkava & Erkinjuntti, 1987; Roman et al., 1993; Cummings, 1994; Brun, 1994). Further classifications include hemorrhagic dementia, hereditary VaD, and combined AD with cerebrovascular disease. The current clinical criteria for VaD differ in their classification of VaD into subtypes. None of them include detailed criteria for their subtypes. The DSM-IV (American Psychiatric Association, 1994) do not specify subtypes. The ICD-10 (World Health Organization, 1993) include six subtypes with rather superficial clinical descriptions (acute onset, multi-infarct, subcortical, mixed cortical and subcortical, other, and unspecified). The criteria are selective as only a subset of those fulfilling the general criteria for ICD-10 VaD can be classified into defined subtypes (Wetterling et al., 1994, 1996). The ADDTC (Chui et al., 1992) criteria do not specify detailed subtypes, but highlight that classification of ischemic VaD for research purposes should specify features of the infarcts that may differentiate of the disorder, such as location (cortical, white matter, periventricular, basal ganglia, thalamus), size (volume), distribution (large, small, or microvessel), severity (chronic ishemia versus infarction), etiology (embolism, aherosclerosis, arteriosclerosis, cerebral amyloid angiopathy, hypoperfusion). The NINDS–AIREN criteria (Roman et al., 1993) include without detailed description cortical VaD, subcortical VaD, Binswanger’s disease, and thalamic dementia.

Cortical VaD Cortical VaD relates to large-vessel disease, cardiac embolic events and also hypoperfusion. It shows predominantly cortical and cortico-subcortical arterial territorial

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and distal field (watershed) infarcts. Typical clinical features are lateralized sensorimotor changes and abrupt onset of cognitive impairment and aphasia (Erkinjuntti, 1987). In addition, some combination of different cortical neuropsychological syndromes has been suggested to be present in cortical VaD (Mahler & Cummings, 1991). This group shows heterogeneity in regards to the etiologies, vascular mechanisms, changes in the brain, as well as clinical manifestations.

Strategic infarct VaD Focal, often small, ischemic lesions involving specific sites critical for higher cortical functions have been classified separately. This group shows most heterogeneity. Isolated brain infarcts or hemorrhages may lead to dementia. In such cases, dementia is due to the location of the lesion, rather than the volume of brain loss. Each of the following cortical locations has been associated with neuropsychological impairment leading to dementia: left angular gyrus infarcts (Benson et al., 1982); right hemisphere angular gyrus infarcts; inferomesial temporal infarcts (Ott & Saver, 1993; Caplan et al., 1974); and mesial frontal infarcts (Alexander & Freeman, 1984; Damasio et al., 1987; Sawada & Kasui, 1995). Isolated subcortical vascular lesions consist of lacunar infarcts, deep territorial infarcts and deep hemorrhages, disrupting specific subcortical–cortical functional loops crucial for the maintenance of cognitive status (Baron et al., 1992). Dementia has been reported in thalamic (Graff-Radford et al., 1990; Barth et al., 1995), left-sided capsular genu (Tatemichi et al., 1992; Tatemichi, 1995; Pullicino & Benedict, 1996), and caudate nuclei infarcts (Bhatia & Marsden, 1994; Caplan et al., 1990; Mendez et al., 1990; Wenchiang & Caplan, 1995).

Subcortical VaD The currently proposed subtypes of VaD incorporate a variable combination of the given categories reflecting heterogeneity. The subcortical VaD incorporate small vessel disease as primary vascular etiology, lacunar infarcts and white matter lesions as primary types of brain lesions, and subcortical location as the primary location of lesions. The ischemic lesions in VaD affect especially the prefrontal subcortical circuit including prefrontal cortex, caudate, pallidum, thalamus, and the thalamo-cortical circuit (genu or anterior limb of the internal capsule, anterior centrum semiovale, and anterior corona radiata) (Cummings, 1993). Accordingly, the subcortical syndrome is the primary clinical manifestation. Dementia is not always

present in patients with a lacunar state. Lacunar infarcts appear as small miliary softenings, mostly located in the putamen, thalamus or pons (Marie, 1901), or in the deep white matter (De Reuck et al., 1980). They are small (5 to 15 mm) cavitations filled by a fine network of astrocytic processes, macrophages and siderophages, surrounded by fibrillary and protoplasmic astrocytes and sometimes also by hemosiderin pigments. They are the consequence of the occlusion of one single, deep perforating artery (Fisher, 1965). Multiple lacunes, in association with diffuse white matter changes, have been reported as the anatomical substrate of progressive cognitive decline in some patients who were clinically diagnosed as having AD, in the absence of a history of stroke and of a stepwise course of dementia (Pantoni et al., 1996). In demented with similarly progressive decline and absence of clinical strokes, diffuse whitematter changes without lacunes were neuropathologically described (Englund et al., 1989). These cases were however clinically diagnosed as VaD. Such arteriopathies are usually due to chronic arterial hypertension (Fisher, 1965, 1969). Small-vessel disease is the consequence of the occlusion of one single, deep perforating artery, caused by segmental fibrinoid degeneration with lipohyalinosis (Fisher, 1965, 1969; Olsson et al., 1996). Many perforating branches have multiple stenosis and poststenotic dilatations, suggesting that some hemodynamic events might also play a role, rather than local thrombosis (De Reuck & Van der Eecken, 1976). Stroke patients with lacunes are more likely to have white matter changes (Hijdra et al., 1990; Leys et al., 1992) and to develop dementia (Tatemichi et al., 1993) than patients with other stroke subtypes. Traditionally, VaD has been characterized by a relative abrupt onset (days to weeks), a stepwise deterioration (some recovery after worsening), and fluctuating course, e.g. difference between days of cognitive functions. This is seen in patients with repeated lesions affecting cortical and cortico-subcortical brain structures. In patients with subcortical VaD, however, the onset of cognitive symptoms is relatively insidious and course more slowly progressive (Roman, 1987; Erkinjuntti, 1987; Babikian & Ropper, 1987; Chui et al., 1992; Roman et al., 1993; Skoog, 1997). The mean duration of any VaD is around 5 years (Hebert & Brayne, 1995), and their survival is less than for the general population or AD (Skoog et al., 1993; Mölsä et al., 1995). Detailed studies on the natural history of subcortical VaD are lacking, and little is known or can be predicted about the rate and pattern of cognitive decline, and prognosis in subcortical VaD (Chui & Gonthier, 1999). The cognitive syndrome of subcortical VaD is characterized by:

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• a dysexecutive syndrome including impairment in goal formulation, initiation, planning, organizing, sequencing, executing, set-sifting and set-maintenance, as well as in abstracting (Mahler & Cummings, 1991; Cummings, 1994; Desmond et al., 1999). • mild memory deficits consisting of impaired recall, relative intact recognition, less severe forgetting, and better benefit from cues than in AD (Desmond et al., 1999). • behavioural changes including depression, personality change, emotional lability and incontinence, as well as inertia, emotional bluntness and psychomotor retardation (Roman et al., 1993; Mahler & Cummings, 1991; Cummings, 1994). The clinical neurological findings especially early in the course of subcortical VaD include episodes of mild upper motor neuron signs (drift, reflex assymetry, incoordination), gait disorder (apractic–atactic or small-stepped), imbalance and falls, urinary frequency and incontinence, dysarthria, dysphagia, extrapyramidal signs (hypokinesia, rigidity) (Ishii et al., 1986; Roman, 1987; Erkinjuntti, 1987; Babikian & Ropper, 1987; Roman et al., 1993). However, often these focal neurological signs are subtle only (Skoog, 1997).

Brain lesions associated with poststroke dementia Multiple large vascular lesions The occurrence of dementia depends mainly on the total volume of infarcts and hemorrhages (Tomlinson et al., 1970; Erkinjuntti et al., 1988; del Ser et al., 1990), and the number and location of the lesions (De Reuck et al., 1981). It has also been suggested that it may depend on the presence and volume of perifocal ischemic damage (Brun & Englund, 1997). There is no clear cutoff point on the volume of infarction resulting in dementia.

Strategic vascular lesions of the brain Each of the following cortical locations has been associated with neuropsychological impairment leading to dementia: left angular gyrus infarcts (Benson et al., 1982), right hemisphere angular gyrus infarcts, inferomesial temporal infarcts (Ott & Saver, 1993), and mesial frontal infarcts (Alexander & Freeman, 1984; Damasio et al., 1987; Sawada & Kasui, 1995). Dementia has been reported in infarcts of the following subcortical areas: thalamic (GraffRadford et al., 1990; Barth et al., 1995), left capsular genu (Pullicino & Benedict, 1996), and caudate nuclei (Bhatia &

Marsden, 1994; Mendez et al., 1990; Wenchiang & Caplan, 1995). ‘Strategic’ locations have been described in single cases or in small series (Benson et al., 1982; Alexander & Freeman, 1984); however, in case reports with first generations of computed tomographic (CT) scans, another vascular lesion of the brain cannot be excluded and may interfere with the neuropsychological profile (Godefroy et al., 1994). Moreover, in elderly patients without follow-up after stroke, the contribution of Alzheimer lesions to the neuropsychological profile cannot be excluded (Pasquier & Leys, 1997; Snowdon et al., 1997; Pasquier et al., 1998). The concept of strategic stroke should, therefore, be revisited with modern imaging techniques and a longer follow-up.

Multiple lacunar infarcts with leukoencephalopathy Small deep infarcts in the basal ganglia, centrum semiovale or brainstem, are often associated with leukoencephalopathy. Dementia is not always present in patients with a lacunar state. In 1894, Otto Binswanger described a condition characterized by dementia, recurrent strokes and white-matter changes at autopsy (Binswanger, 1894). Binswanger’s disease may be considered in patients with pathological evidence of the underlying vasculopathy, lacunes and leukoencephalopathy. Pathological examination of cases of Binswanger’s disease show diffuse or patchy rarefaction of myelin predominating in the periventricular and occipital regions of the centrum semiovale and associated with gliosis and spongiosis (De Reuck et al., 1980). The U fibres, internal capsules, and cerebral cortex are usually spared (Babikian & Ropper, 1987). White-matter changes are associated with multiple lacunes in the white-matter and basal ganglia (Babikian & Ropper, 1987). Binswanger’s encephalopathy may represent the end-stage pathology of lacunar state (De Reuck et al., 1980; Roman, 1987; Fredriksson et al., 1992; Leys et al., 1992; Pantoni & Garcia, 1995). However, the existence of Binswanger’s disease as a specific type of VaD remains controversial (Pantoni & Garcia, 1995). Dementia may occur after several strokes, when patients have dysarthria, dysphagia, ‘marche à petits pas’, incontinence, spasmodic laughing or crying, and parkinsonism. In other cases, multiple brain infarcts are recognized on brain imaging, in patients with dementia and no clear clinical evidence of stroke. Multiple lacunes in association with diffuse cerebral white-matter changes have been reported as the anatomical substrate of progressive cognitive decline in some patients who were clinically diagnosed as having AD, in the absence of a history of stroke and a stepwise course of dementia (Pantoni et al., 1996).

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Most cases of multiple lacunar infarcts with leukoencephalopathy are due to lipohyalinosis of the deep perforating arteries, which is the consequence of chronic arterial hypertension (Fisher, 1965, 1969). However, other causes may be associated with a higher risk of dementia in stroke patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant arteriopathy due to NOTCH 3 gene mutations (Joutel et al., 1996) on chromosome 19 (Tournier-Lasserve et al., 1993). Usually, lacunar infarcts occur between 40 and 50 years of age, and dementia occurs in one-third of patients with lacunes, and is almost always present before death (Chabriat et al., 1997). Mild cognitive impairment, of subcortical type, is probably present years before occurrence of dementia (Taillia et al., 1998), but dementia occurs in a stepwise fashion in a setting of several strokes, and is rarely progressive (Ruchoux et al., 1995). MRI is always abnormal in symptomatic subjects: it shows confluent hyperintensities in the white-matter and lacunar infarcts (Chabriat et al., 1998). Other rare arteriolopathies leading to multiple lacunar infarcts and dementia have been recognized. Their origin remains unknown, but genetic studies might help to classify them in the future: non-CADASIL Binswanger-like syndromes without arterial hypertension (Loizou et al., 1982; Berthier et al., 1992; Estes et al., 1991) autosomal recessive leukoencephalopathy with alopecia and lumbago (Fukutake & Hirayama, 1995), and cerebroretinal vasculopathy (Grand et al., 1988). Other hereditary vascular conditions unlinked to NOTCH 3 gene mutations and responsible for cerebral infarcts leading to dementia have also been identified (Jen et al., 1997).

Can VaD occur without detected infarcts? One-third to one-half of patients with pathologic evidence of VaD lack a history of clinically recognized stroke (Yoshitake et al., 1995; Moroney et al., 1997a). The question remains whether chronic ischemia plays an important role in VaD. Unilateral or bilateral occlusion of carotid arteries is the most common cause of hemodynamic VaD (Tatemichi et al., 1995). The role of hemodynamic factors and hypoxemia in the pathogenesis of post-stroke dementia has already been mentioned (Moroney et al., 1996). Several authors have found no evidence of chronic ischemic states in VaD, studied by means of positron emission tomography (PET) (Frackowiak et al., 1981; Brown et al., 1991). However, presence of arterial border zones in the deep white-matter and the high susceptibility of oligodendroglial cells to ischemia, along with the findings of widespread, histopathologically verified non-

infarct damage in patients with VaD, suggest that chronic ischemic leukoencephalopathies leading to VaD exist (Englund et al., 1989). Chronic ischemia without infarction in the carotid territory might be an exceptional cause of dementia, attributed to a ‘misery perfusion’ with positron emission tomography studies (Baron et al., 1981). This type of dementia might be reversible after correcting correction of the hemodynamic deficit. In a documented case, extra-intracranial arterial bypass surgery apparently improved the patient's cognitive status (Baron et al., 1981). Hemodynamic VaD is probably under-recognized, although a potential for surgical treatment in certain patients might exist (Tatemichi et al., 1995). Brun and Englund (1986) have suggested the term ‘incomplete white-matter infarction’, including rarefaction of the deep white matter, diffuse partial loss of myelin sheets, axons and oligodendroglial cells and mild astrocytic and macrophagic reactions in association with a central stenosing small-vessel disorder (Brun & Englund, 1986). It correlates to the frequent finding of white matter changes on CT and MRI scans in elderly patients (Brun & Englund, 1986; Englund et al., 1988; Janota et al., 1989). The brain damage may be more severe, and affect several of the most sensitive structures of the brain, leading to laminar necrosis of the neocortex, hippocampal degeneration, Purkinje cell loss of the cerebellar cortex and deep cerebral white matter demyelination. It is difficult to detect such lesions on macroscopic examination, and histological sections using specific staining techniques are usually necessary. Brun (1994) has also described Aa rare cortical–subcortical dementia syndrome caused by due to a hypertensive and atherosclerotic angiopathy of intracerebral and leptomeningeal vessels and leading to small infarcts located in the white matter, the basal ganglia and the brainstem, as well as in the cortex (Brun, 1994). They may represent a mixture of large- and small-vessel diseases rather than an isolated entity (Erkinjuntti, 1987; Mas et al., 1993).

Other factors contributing to dementia in stroke patients Role of white-matter changes in poststroke dementia White-matter changes are independent predictors of PSD (Tatemichi et al., 1994a, b). In first-ever lacunar infarctions, mortality, stroke recurrence, risks of dementia and of dependence are higher in presence of white-matter changes (Inzitari et al., 1995). White-matter changes may

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be associated with subtle cognitive (Skoog et al., 1996) and behavioural (Tarvonen-Schröder et al., 1996) changes. The functions which are the most sensitive to white-matter changes are memory, attention, and frontal lobe functions (Breteler et al., 1994; DeCarli et al., 1995). White-matter changes probably contribute to the cognitive decline in PSD (Pasquier & Leys, 1997).

Role of Alzheimer pathology in poststroke dementia Alzheimer and vascular lesions of the brain are frequently associated at autopsy (Jellinger et al., 1990; Victoroff et al., 1995). The links between PSD and AD are probably closer than expected (Pasquier & Leys, 1997). Shared risk factors of the two clinical entities may be responsible for their cooccurrence. Besides advancing age, one of them might be the ␧4 allele of the apolipoprotein E (APOE) gene (Frisoni et al., 1994; Saunders & Roses, 1993). The APOE ␧4 allele is a genetic risk factor for dementia with stroke, including VaD and AD with cerebrovascular disease. It may imply shared genetic susceptibility to dementia associated with stroke and AD. AD patients have some degree of vascular changes, including cerebral amyloid angiopathy (Yamada et al., 1987), which may lead to cerebral hemorrhages (Ellis et al., 1996; Lucas et al., 1992) or infarcts (Ellis et al., 1996; Premkumar et al., 1996), cerebral microvascular degeneration (and non-specific fibrohyaline thickening of the wall of the small perforating intracerebral arteries (Brun & Englund, 1986; Rezek et al., 1987; Leys et al., 1991; Erkinjuntti et al., 1996)), which may cause lacunes (Fisher, 1969), white-matter changes (Rezek et al., 1987; Hijdra et al., 1990; Leys et al., 1992; Erkinjuntti et al., 1996), or both. More recently, an increased intima-media thickness in the common carotid artery, which is associated with an increased risk of stroke in the community (Bots et al., 1996), has been found with a higher frequency in AD patients (Hofman et al., 1997). This concurs with the finding that aortic arteriosclerosis is common in autopsy verified AD subjects compared to age-matched controls (Kalaria, 1997).

The multifactorial origin of poststroke dementia From a clinical point of view, dementia is probably due to stroke alone in the following circumstances: (i) in young stroke patients who become demented after one or several strokes; (ii) when the clinician has a high level of certainty

that the cognitive functioning of the patient was normal before stroke, impaired immediately after and does not worsen over time or even slightly improve; (iii) when the lesions are located in strategic areas; and (iv) when a specific vascular condition known to cause dementia is proven by pathological data or a specific marker. Many cases of dementia occurring in stroke patients are probably the consequence of the cumulative effect of the cerebrovascular lesions, Alzheimer pathology, and whitematter changes. Even when these changes do not lead to dementia by themselves, their cumulative effect may reach the threshold of lesions required to produce dementia (Pasquier & Leys, 1997). When stroke, white-matter changes, or both, occur in a patient with asymptomatic Alzheimer pathology, the period of preclinical AD may be shortened (Pasquier & Leys, 1997). In the nun study, among 61 patients who met neuropathological criteria for AD, those with brain infarcts had poorer cognitive functions and a higher prevalence of dementia than those without infarcts, while among 41 patients who did not meet neuropathological criteria for AD, brain infarcts were only weakly associated with poor cognitive functions and dementia (Snowdon et al., 1997). Stroke lesions may play an important role in determining the presence and severity of the clinical symptoms of AD (Snowdon et al., 1997). In patients included in the dementia substudy of SYSTEUR, a beneficial effect of antihypertensive therapy on the risk of cognitive decline and of AD has been shown (Forette et al., 1998): treatment of 1000 patients aged 60 years or more, over a 5-year period, prevents 19 cases of dementia, including AD. This effect may be the consequence of the reduced incidence of infarcts by lowering of blood pressure, leading to a prevention of the anticipation of the clinical expression of AD (Leys & Pasquier, 1999).

Stroke prevention in patients with poststroke dementia Patients with dementia after stroke are significantly less frequently treated with aspirin or warfarin than nondemented patients (Moroney et al., 1998). However, trials of secondary prevention of stroke usually exclude patients with obvious dementia. As a consequence, optimal methods for the secondary prevention of stroke in patients with dementia remains speculative. Anticoagulation is not recommended in dementia, and carotid endarterectomy is thought to be associated with increased risk of the therapeutic procedure. However, this has never been evaluated. Therefore, stroke prevention trials should include dementia as a secondary end-point.

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22

Disorders of mood behaviour Florence Ghika-Schmid and Julien Bogousslavsky Department of Neurology, University of Lausanne, Switzerland

Introduction Although recognized as early as 1924 by Bleuler, depression and, more generally, mood disorders following cerebral lesions have only been studied systematically in the last 20 years. Initial studies of emotional disorders in brain injuries included patients with various lesions such as surgical incision, traumatic closed head injuries, penetrating head injury and stroke making it difficult to determine the location of the lesion. Some more recent stroke studies suggest a critical role of the anterior left hemisphere in depression, but other authors deny causal contribution of lesion location to depression. The predominant role of the right hemisphere in secondary mania is well recognized, but a consensus is still lacking and further studies are needed to determine the clinico-topographic correlation of disorders, such as apathy, anxiety, catastrophe reaction and pathological laughing and crying sometimes encountered after stroke. These affective disorders are important to consider in stroke patients, since they may negatively influence neurological recovery and may be responsive to treatment. Specific emotional behaviours, such as disinhibition, denial, indifference, overt sadness and aggressiveness, often occur during the very first days following stroke. They might be overlooked if not searched for systematically with appropriately designed scales. Some of these early behaviours, such as denial, may be related to the late development of depression and anxiety. Prospective studies of mood changes during and immediately after stroke have not been performed yet. Such studies on large samples of patients may permit the delineation of which of these acute emotional behavioural changes are markers for the delayed development of emotional disturbances (GhikaSchmid & Bogousslavsky, 1997).

Some stroke subtypes, such as cardioembolic stroke, may have a specific pattern of early emotional behaviour. Stroke occurrence itself may be related to a different individual vulnerability to stress, as in carotid artery disease. In stroke, early disregard of the symptoms by the patient or his relatives, may delay consultation and compromise acute management with new developing techniques, such as thrombolysis (Grotta & Bratina, 1995). Even after improvement some patients with denial may require much persuasion to enrol in stroke prevention therapy or be reluctant to accept rehabilitation. However, in spite of this important impact on management, little is known about the subjective experience of acute stroke patients. The current data of the acute Lausanne Emotion in Acute Stroke Study (LEASS) (Ghika-Schmid & Bogousslavsky, 1997; Ghika-Schmid et al., 1999) showed that early emotional behaviour can be quantified in acute stroke. Further analyses on a larger sample of patients may allow us to delineate which are the best markers of ulterior development of depression or anxiety and to perform detailed clinico-topographical correlation.

Depression Diagnosis The standardized diagnostic criteria of the DSM IV for mood disorders are appropriate for stroke, since poststroke depression has a similar symptomatic profile to primary depression (Starkstein & Robinson, 1989; Starkstein, 1998). Adapted depression rating scales, such as the Hamilton scale for depression, can be useful tools, with the cut-off score for poststroke depression being suggested as 13 (Andersen et al., 1994c). Other scales have been

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developed, more directly aiming at the evaluation of poststroke depression (Gainotti et al., 1997a). However, these different scales include features such as anxiety and catastrophe reaction, which may be specific clinical syndromes (see below). Special attention should be paid to autonomic disturbances, such as abnormal sleep patterns, decreased appetite and libido, vegetative anxious signs and subjective anergia (Ghika-Schmid & Bogousslavsky, 1997). No definite relationship has been established between severity of neurological impairment and presence of depressive features (Herrmann et al., 1995), but the negative influence of depression on neurological recovery is well recognized (Starkstein et al., 1990; Parikh et al., 1990; Morris et al., 1992).

Prevalence and risk factors The prevalence of depression in the acute phase of stroke is about 40% (20% major depression, 20% minor depression) (Starkstein et al., 1990; Starkstein, 1998), whereas estimates made in the chronic phases range between 18% and 54% (Astrom et al., 1993; Sinyor et al., 1986; Burvill et al., 1995a). The period of maximal prevalence and the evolution varies in the different studies; poststroke depression might be especially frequent in the acute phase of stroke, but can also occur 1 to 2 years after stroke and if left untreated, may last for up to 1 year (House et al., 1991; Starkstein et al., 1990; Starkstein, 1998; Astrom et al., 1993; Burvill et al., 1995a). Among risk factors for the development of poststroke depression, pre-existing cerebral atrophy has been suggested, but remains controversial (Herrmann et al., 1995, Starkstein et al., 1988; Astrom, 1996). An increased frequency of personal or familial history of psychiatric disorders was found in patients with poststroke depression, suggesting a personal or genetic predisposition (Starkstein et al., 1990, Starkstein, 1998; Andersen et al., 1995). Intellectual impairment might also explain some of the variation in mood scales (Andersen et al., 1995). These various risk factors may be differentially implicated in the development of depression a certain period of time after the stroke (Astrom et al., 1993).

Lesion location The left frontal anterior region, both the dorso-lateral prefrontal cortex and subcortical region, was found to be important for depression in left hemisphere (LH)damaged patients (Starkstein et al., 1990; Starkstein, 1998; Astrom et al., 1993). The severity of depression may be associated with lesion proximity to the frontal pole in the

LH, in cortical or subcortical location (Starkstein et al., 1900; Starkstein, 1998). Among patients with right hemisphere (RH) stroke, who developed depression, a positive association with a posterior lesion was found (Starkstein et al., 1990; Starkstein, 1998). However, although an association was found between major depressive disorder and left lentiform nucleus, no significant difference between depression scores in LH and RH lesions, or a correlation between the severity of depression and the anterior location or volume of the lesion, was seen in 47 patients during acute stroke (Herrmann et al., 1995). Moreover, severity of depression is not always proportional to the distance of the lesion from the frontal pole suggesting a more complex nature of association (Sinyor et al., 1986). Thus, an association between left-sided lesions and depression and right-sided lesions and hypomania is not a constant finding (House et al., 1990). Some authors even suggest that lesion location may not be a prime etiological factor for poststroke depression (Andersen et al., 1995; Burvill et al., 1996; Gainotti et al., 1997b). In the Lausanne Emotion in Acute Stroke Study (Ghika-Schmid et al., 1996, 1999), the use of previously developed precise templates of the vascular territories may shed some new light on this issue. On the other hand, electrophysiological evidence for a crucial role of left frontal activation of ‘positive affects’ (Davidson et al., 1987) and rapid-rate transcranial magnetic stimulation, showing a lateralized control of mood, following prefrontal cortex stimulation in normal volunteers (Pasqual-Leone et al., 1996), argue for the ‘localizing’ thesis. The hypothetical mechanisms considered by those authors supporting the role of lesion location are based on the observation of a higher incidence of familial psychiatric disorders in patients with right posterior lesion, which might suggest differential vulnerability to depression for right and left lesions (Starkstein et al., 1990). PET studies showed a possible compensatory upregulation of 5-HT2 (serotonin) receptors in the RH after stroke, which is not seen after left-sided lesions (Mayberg et al., 1988). Animal studies also showed a lateralized biochemical response to ischemia, suggesting asymmetry in the human biological response to injury, which supports these views (Starkstein et al., 1990). However, the findings of temporolimbic hypoperfusion in patients with depression and subcortical stroke suggests that alternative mechanisms should be considered (Grasso et al., 1994). Various mechanisms have been suggested to link depression and coronary heart disease, such as changes in lipid metabolism, in catecholamine-corticoid and serotonergic modulations, and altered sympathetic arousal in patients

Disorders of mood behaviour

with depression leading to arrhythmia (WassertheilSmoller et al., 1996). Identical physiopathological mechanisms might be present in patients with poststroke depression. In a similar way poststroke depression may be related to a higher secondary occurrence of hypertension (Jonas et al., 1997).

Double-blind placebo-controlled nortriptyline, trazodone serotonin reuptake inhibitors citalopram, fluoxetine

Treatment

Open studies methylphenidate imipramine mianserine moclobemide

Nortriptyline, trazodone and serotonin reuptake inhibitors (Lipsey et al., 1984; Reding et al., 1986; Andersen et al., 1994a; Dam et al., 1996) were shown to be effective in randomized placebo controlled studies of poststroke depression. Because of the high frequency of their contraindication and adverse effects (orthostatic hypotension, atrioventricular block), tricyclic antidepressants are not the first choice in cerebrovascular patients (Gustafson et al., 1995). Serotonin reuptake inhibitors may be the best choice (Reding et al., 1986; Andersen et al., 1994); however, adverse reactions, such as fluoxetine-induced mania, can occur in patients with poststroke depression (Berthier & Kulisevsky, 1993). Open trials have suggested the potential benefit of psychostimulants (methylphenidate), but further controlled studies are required to reach a conclusion (Gustafson et al., 1995). Imipramine and mianserine have been effective in trials and imipramine probably has a combined action on the noradrenergic and especially the serotononergic systems (Gustafson et al., 1995). The potential benefit of electroconvulsive therapy warrants confirmation (Gustafson et al., 1995, Currier et al., 1992). Treatment against spasticity, psychological assistance and social support should not be neglected (Angeleri et al., 1993).

Main studied treatments of poststroke depression (Fig. 22.1)

Fear and anxiety Historically, the word fear derived from the Old English word faer, which meant peril or calamity. The word anxiety originated from the Latin word anxius, which means troubled in mind, solicitous or uneasy. Fear is an emotional state involving physiological arousal (e.g. increased heart rate), verbal reports of distress (e.g. apprehension, worry), overt behaviour (e.g. avoidance) and cognitive disruption (e.g. hyperawareness about possible threat cues in the environment), typically triggered by specific object or situations. It is a fundamental emotion, present across ages,

Fig. 22.1. Main studied treatments of poststroke depression.

cultures, ethnic groups and species. Its functions are often described as an alarm system activating the organism in response to threat (McNeil et al., 1994).

Diagnosis of poststroke anxiety Restricted criteria from the DSM-III-R have been proposed to diagnose anxiety in stroke patients, but duration of symptoms was not included, as we wished to use the criteria for assessment immediately after stroke (Castillo et al., 1993). Anxiety involves the same emotional state as fear, but with a lesser mobilization for physical action. It is characterized by feelings of distress and worry, maladaptative shifts in attention due to off-target thinking, and the perception that aversive events are occurring in an unpredictable and uncontrollable manner. It is associated with more cognitive symptoms, and less visceral activation. Cues for its manifestation are more diffuse and changeable relative to fear (McNeil et al., 1994).

Prevalence and risk factors Anxiety is the second most prevalent mood disorder following stroke, being found in 3.5% to 24% of patients (Castillo et al., 1993; Starkstein et al., 1990; Starkstein et al., 1988b; Astrom, 1996; Burvill et al., 1995a,b). It is frequently associated with depression (Astrom, 1996). A personal history of alcohol abuse may be a significant association (Castillo et al., 1993), as well as cerebral atrophy (Astrom, 1996). According to a recent study, a combination of anxiety and depression is more frequent after left cortical stroke, whereas anxiety without depression is mainly seen following RH lesion (Castillo et al., 1993). Comorbidity with depression may impair the prognosis of depression (Astrom, 1996). One study suggested it

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may be more frequent after right hemisphere stroke (Astrom et al., 1993).

Relationship to stroke The occurrence of fear or anxiety in reaction to a stressful challenge is determined in part by the social context in which they occur and the social status of the individual, such as whether he is dominant or subordinate (Lazarus 1966; McEwen, 1996). The effect of potential stress evoking situations on the nervous system is influenced by genetic predisposition, biological development, sex and learned experience (McEwen, 1996). An unknown stress source induces physiological arousal. Known threatening may induce high-cost response such as aggression, or, if no response is available, displaced aggression, helplessness, or hopelessness, with altered physiological responses (McEwen, 1996). Alcohol and substance abuse as well as risk-taking behaviours are other coping alternatives (Sher, 1987; McEwen, 1996). The central nucleus of the amygdala is an important neural control centre for fear and conditioned fear (Aggleton, 1992). It projects to cardiovascular, facial, autonomic, respiratory and neuroendocrine control centers in the brain that affect cardiovascular, gastrointestinal and adrenocortical activity, facial expression, social interaction and cause arousal (McEwen, 1996). The hippocampus also plays an important role in controlling the secretion of adrenal steroids and in processing spatial temporal aspects of a changing environment, and maybe auditory processing of fear (Eichenbaum & Otto, 1992; GhikaSchmid & Bogousslavsky, 1997; McEwen, 1996). Stroke incidence may be related to a different individual vulnerability to mental stress, as shown in patients with carotid artery disease (Barnett et al., 1997). Cardiovascular reactivity can be assessed by measuring hemodynamic changes during a frustrating cognitive task such as the Stroop Colour Word Interference Task. In 136 untreated subjects followed for 2 years, a greater change in systolic blood pressure during the task was a strong predictor of the rate of progression of carotid arteriosclerosis measured with Doppler ultrasound (Barnett et al., 1997). In the clinical setting, patients with high blood pressure in a doctor’s office may be at similar risk. In animals, exposure to social stress and competition for dominance is associated with coronary atherosclerosis (Spence, 1996). Individual and cultural variability in the appraisal of emotion certainly plays an important role in these phenomena and would deserve further studies. When faced with the same situation, different people often respond

with different emotions. This general statement may be painfully self-evident, but appraisal theories go beyond the general statement to specify the differences (Ellsworth, 1991). For example, a person who characteristically sees his misfortunes as caused by bad luck may be more prone to depression, while one who attributes these to other people’s malice may be more prone to aggression (Roseman, 1984). Among the Utku Eskimos, feelings of anger are strongly condemned (Briggs, 1970), but in certain Arab Groups, a man’s failure to respond with anger is seen as dishonourable (Abu-Lughod, 1986). It is clear that much of atherosclerosis is genetic, the candidate gene extending from lipoprotein lipase to angiotensin receptor gene for example (Spence, 1996). In that sense, the study of vascular reactivity can be a new tool for investigating the genetics of atherosclerosis. Moreover, a significantly higher incidence of stroke was found in men reporting a higher level of stress (Harmsen et al., 1990). Life settings such as grief, mourning, loss of status or self-esteem, threat of injury, involve a response of overwhelming excitation or giving up and may be associated with neurovegetative responses, that may lead to lethal cardiac events particularly in individuals with pre-existing cardiovascular disease (Engel, 1971). Similar phenomena may be important in cerebrovascular disease, as well as certain at-risk personality features including behavioural pattern to assure satisfaction of self-set goals, difficulty in the control of anger and object-related style characterized by assumption of personal responsibility for gratification of needs. The systematic study of the personality characteristics of 32 men who had ischemic stroke occurring within a period of sustained emotional disturbance showed that some features appeared with unexpected frequency (Adler et al., 1971). These included: (i) a pressure to keep busy; (ii) a self-image of an active, hard worker; (iii) high standards and a pronounced sense of responsibility; (iv) a sense of urgency, time pressure and a need to fulfil goals and (v) a sense of determination and strong will (Adler et al., 1971). Twenty-eight of these 32 patients reported they were concerned with controlling the expression of their anger aroused mostly by a feeling of not being able to control their environment or their own bodies, which frustrated their attempts to fulfil self-set goals (Adler et al., 1971). In that group of patients, the onset of stroke at the moment of an intense peak of emotion was unusual, occurring only twice (Adler et al., 1971). These findings of psychological characteristics of stroke patients were very similar to what is reported for coronary patients, such as angina pectoris occurring in a ‘keen and ambitious man, the indicator of whose engines is always set at full speed

Disorders of mood behaviour

ahead’ (Adler et al., 1971). The main drawback of this study is its retrospective nature, leading to possible distortion by the interviewer. In a meta-analysis of the relation between psychological factors and coronary heart disease, reliable associations were found for ‘Type A behaviour’, referring to a person who is involved in an aggressive and incessant struggle to achieve more and more in less and less time, for anger, hostility, aggression, but also for depression and anxiety (Booth-Kewley & Friedman, 1987). This suggests that coronary proneness may not be the expected hurried impatient workaholic, but, instead, one person with one or more negative emotion. Other studies have emphasized the importance of hostility, especially an antagonistic interactional style, rather than the whole set of behaviours associated with type A behaviour, as a risk factor for coronary heart disease (Dembroski et al., 1989). A new experimental approach in applying the appraisal theories of emotions may prove useful in better characterizing the individual balance between fear, anger and anxiety in such a setting as well as in stroke (Ellsworth, 1991, Scherer, 1984). A relationship may exist between fear and anxiety, and anger. These three emotional states are common responses to stressful situations and are often difficult to distinguish because all involve unpleasant feelings and physiological arousal. Some evidence suggests that anxiety and fear can be differentiated from anger according to feelings along the dominance–submissiveness continuum. People who are angry may feel in control of events, while people who are anxious or fearful may feel out of control or vulnerable. Physiologically, fear and anxiety have been associated with increased skin conductance and respiratory rate, while anger has been involved in increased diastolic blood pressure (McNeil et al., 1994). Repeated and successful practice of courageous behaviour leads to a decrease in verbal reports of fear and physiological responsivity, which can lead to a state of fearlessness (McNeil et al., 1994). Stress could also affect metabolic control of diabetes, by changes in compliance behaviour and neurohumoral axis, but the findings supporting these hypotheses remain contradictory (Barglow et al., 1984). Thus the relative importance of personality features and emotional reaction, both in cardiovascular and in cerebrovascular diseases, remains debated. Precise prospective data on the emotional profile of patients with acute stroke may allow a better understanding of their characteristics and the implications. Preliminary data from the Lausanne Emotion in Acute Stroke Study (Ghika-Schmid et al., 1990) suggest that patients with acute cardioembolic stroke may have a specific pattern of early emotional disturbances. Among 85

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Anger (acute) Random etiology Cardioembolic Depression (3rd month)

0%

5%

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Fig. 22.2. Early anger reaction and delayed depression in cardioembolic vs. non-cardioembolic stroke.

patients, 23 (13 men, 10 women, age 66 ⫾ 17 years) had cardioembolic sources, 15 had stroke in the MCA territory and 8 in the posterior circulation (10 right, 13 left). They presented acute emotional reactions of disinhibition (12), denial (6), indifference (7), overt sadness (6), aggressiveness (5). On questioning, 6 patients expressed fear, 5 anger, 14 joy and 8 sadness. In the third month, 12 (52%) patients were: anxious (4), anxio-depressive (3), or depressed (5). Compared to 55 patients with stroke of random etiology, they expressed more anger during the acute phase, 21% vs. 12% and displayed more depression at 3 months, 21% vs. 5% (Fig. 22.2). No other between-group difference was observed. These data suggest that, during the acute period, patients with cardioembolic stroke express anger more often than the overall stroke population. This may be related to specific personality features, such as difficulty in the control of anger. This may suggest that such a behavioural pattern indicates a risk for cardioembolic events. In the third month, patients with cardioembolic stroke had a higher incidence of depressive, but not anxious, manifestations. Thus the expression of poststroke affective disorders may be different in relation to different stroke etiologies. This may be due to pre-existing personality features favouring a peculiar stroke mechanism, such as cardiac embolism.

Pseudodepressive manifestations Abulia The clinical characterization of apathy, or abulia, has been debated in the literature, and includes features such as flat affect, short and delayed answers, hypophonia, reduced

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motor responses, fixed gazed and blank face, perseverations and lack of awareness of condition (Fisher, 1995). Clinical scales, which can be useful diagnostic and followup tools, have been developed (Starkstein, 1998). Abulia is related to the disruption, at various anatomical sites, of fronto-subcortical pathways, such as anterior cingulate and capsular lesion (Starkstein et al., 1993a; Fisher, 1995). Apathy was reported as more frequent following stroke in the posterior arm of the internal capsule in the LH, probably because anterior cerebral artery stroke with cingulate involvement is rare (Starkstein et al., 1993a). Major depression is significantly more frequent in patients with apathy (Starkstein et al., 1993a), but should be distinguished from it (Marin et al., 1993). Poststroke apathy may be significantly associated with age and more severe impairment in activities of daily living (ADL) and cognitive functions (Starkstein, 1998), and with frontal and anterior temporal reduction in cerebral blood flow measured by 133 Xe inhalation. The therapeutic potential of agents such as bromocriptine or methylphenidate has been suggested (Watanabe et al., 1995; Muller & Von Cramon, 1994).

(Robinson et al., 1993), although this point remains controversial (Andersen et al., 1995). A corresponding lesion location is not clear (Robinson et al., 1993; Derex et al., 1997), although bilateral pontine lesions have been emphasized (Andersen et al., 1994a). Unilateral lesion, especially if subcortical, might be sufficient. Pathological laughing and crying is often delayed (Berthier et al., 1996), suggesting a mechanism similar to delayed onset movement disorders. Symptomatic improvement has been reported with serotonin reuptake agents and tricyclics (Robinson et al., 1993; Andersen et al., 1994a), being consistent with the hypothesis of stroke-induced partial involvement of the serotoninergic raphe nuclei in the brainstem or their ascending projection to the brain hemispheres (Derex et al., 1997; Andersen et al., 1994a). Emotionalism is a term preferred by some authors, defined as an increase in frequency of crying and laughing, without warning and outside normal control (Tig et al., 1998). Its presence was reported in 20–25% of patients 6 months after stroke (Tig et al., 1998). Emotional lability may follow stroke mainly if the anterior regions of both cerebral hemispheres are involved (Morris et al., 1993b).

Loss of psychic self-activation Apathetic, aspontaneous, indifferent behaviour, with loss of motor and affective drive and reversible when patients are repeatedly stimulated by another person, can be seen in toxic bilateral subcortical lesions involving the pallidum or putamen and in bithalamic infarct (Laplane, 1990; Bogousslavsky et al., 1991). Occasionally, loss of psychic self activation following bilateral thalamic infarct of venous origin may be accompanied by obsessive-compulsive behaviours (OCB) (Bogousslavsky, 1993; J. Bogousslavsky, personal observation), similar to the effects seen following bilateral basal ganglia involvement due to encephalitis, anoxia, disulfiram, carbon monoxide intoxication or trauma (Ali-Cherif et al., 1984; Laplane, 1994). OCB may be due to dysfunction of the fronto-striato-pallido frontal circuit (Laplane, 1994), and the occurrence of identical symptoms after bilateral thalamic stroke suggests an additional thalamic connection to this circuit. Patients with OCB have a low affective resonance to their symptoms and loss of projection of themselves into the future, different from the depressive state, but sometimes associated with it (Laplane, 1994).

Pathological laughing and crying This is characteristically unrelated to the patient’s inner emotional state. It can occur independently of depression

Catastrophe reactions First recognized by Babinski in 1914, catastrophe reactions were defined by Goldstein (1939) as an inability to cope when confronted with the deficit, with short-lasting sudden bursts of tears, refusal and irritation. They were initially reported predominantly in patients with left hemispheric lesions (Gainotti, 1972). However, recent studies have failed to demonstrate significant hemispheric involvement differences, but rather suggest a preferential basal ganglia involvement (Starkstein et al., 1993b). They may be associated with a positive personal and familial history of psychiatric disorder, increased frequency of major depression, and lower scores of daily living activity (Starkstein et al., 1993b).

Mania Mania, characterized by signs, such as inflated self-esteem or grandiosity, decreased need for sleep, distractibility, flight of ideas and excessive involvement in pleasurable activities with potential painful consequences (DSM-IV), is a rare occurrence following stroke. Starkstein (Starkstein et al., 1987) found the prevalence of manic patients among a consecutive series of more than 300 patients with acute stroke to be 1%. In manic syndromes following cerebral

Disorders of mood behaviour

injury, lesions were located mainly in the RH and involved the thalamus (Bogousslavsky et al., 1998a,b; Starkstein et al., 1988b; Cummings & Mendez, 1984), right temporal lobe (Starkstein et al., 1988b), head of the caudate (Starkstein et al., 1990b) or, bilaterally, the frontal cortex (Starkstein et al., 1988a,b,c). As for major depression, silent cerebral infarcts may play a role in the occurrence of lateonset mania (Fujikawa et al., 1995). Hypometabolism involving the right inferior temporal lobe was seen in a PET study of two patients with lesions of the right head of the caudate (Starkstein et al., 1990b), leading to the hypothesis of a direct or indirect role (diaschisis) of the right inferior temporal lobe in secondary mania. In primary mania, decreased blood flow to the right temporal lobe has also been found (Migliorelli et al., 1993). Poststroke mania has been reported in patients previously free of psychiatric conditions, but with a family history of psychiatric disease (Starkstein et al., 1987; Robinson et al., 1988). In a patient with previous recurrent episodes of mania, a dramatic change in symptoms, with the appearance of persisting hyperthymia has been reported following a right thalamic infarct (Vuilleumier et al., 1998). A dual mechanism of depression and mania, the former being associated with left anterior lesions and the second with RH lesions, may be related to a differential neuromodulation by serotoninergic agents and a differential adaptive mechanism of S2 receptors in both hemispheres (Starkstein et al., 1990). The influence of a positive family history of psychiatric disorders in right-sided damaged patients with secondary mood disorders suggests a genetic predisposition in this population (Robinson et al., 1988). Lithium may be effective for treating patients with secondary mania, but data from published studies show that, in this population, the associated adverse effects often limit its usefulness (Evans et al., 1995). Anticonvulsants appear to offer an effective alternative, for example, valproate has been shown an effective and well-tolerated treatment in open trials in patients with secondary mania (Evans et al., 1995). Controlled clinical trials are necessary to confirm the efficacy and tolerability of mood-stabilizing anticonvulsants in the treatment of secondary mania.

Aggressive burst Bursts of anger may occur following stroke accompanied by behaviours ranging from shouting to violence (Paradiso et al., 1996). These behaviours seem to occur preferentially in patients with higher Hamilton scores and greater cognitive impairment (Paradiso et al., 1996). They are more frequent following LH stroke (Paradiso et al., 1996).

Poststroke psychosis Hallucinations or paranoid delusions occur more often in older patients, with a positive personal and family history of psychosis in 50% of cases (Starkstein, 1998). The ventricular to brain ratio in these patients is often decreased, suggesting subcortical atrophy (Starkstein, 1998). The stroke can be parieto-temporal, occipital, frontal or subcortical in the RH, or pontine (Starkstein, 1998; Kim et al., 1995).

Subjective experience and nosognosia Even after patients improve, some may require much persuasion to enrol in follow-up and stroke prevention therapy. Moreover, patients with denial of hemiplegia are often reluctant to accept rehabilitation, sometimes to the point of refusing to use a cane to walk (Prigatano & Schacter, 1991; Ullman et al., 1960). However, in spite of this important impact on management, little is known about the subjective experience of stroke patients. In his detailed self-observation of motor hemiplegia, dysarthria and modification of handwriting following infarction in the right internal capsule and surroundings, Brodal (1973) mentioned his ‘incontinence of emotional expression’ and his ‘painful awareness of no longer being what he used to be’. Although a couple of historical stroke patients, such as Auguste Forel, have pointed to the potential importance of patient’s self-evaluation, studies of subjective experience in stroke remained exceptional (Ullman et al., 1960; Ullman & Gruen, 1961; Alajouanine & Lhermitte, 1964). Systematic prospective studies are required to evaluate the influence of subjective experience, especially in the acute phase of stroke, when this aspect may be overlooked. Since the initial descriptions, the terms anosognosia and denial have been used interchangeably, although some authors have preferred denial, to emphasize that the notion is wider than the initially recognized anosognosia for hemiplegia or hemianopia (Prigatano & Schacter, 1991). Denial is the product of an interaction, in which the observer interprets the patient’s behaviour. The type of interview can influence the degree of denial (Prigatano & Schacter, 1991). Some authors have proposed scales aimed at quantifying the severity of anosognosia (Prigatano & Schacter, 1991). On the other hand, the various entities often lumped together in the terms denial or anosognosia should be separated from each other. In order to differentiate between the patient’s own appreciation of his/her condition and observed behaviour, the terms anosognosia/anosodiaphoria can be reserved for the patients’

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25

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Fig. 22.3. Observation made among 53 stroke patients. Anosognosia may also develop after left-sided lesions. Anosodiaphoria was even more frequent following left strokes (Ghika-Schmid et al., 1999).

display euphoria and indifference towards their symptoms (anosodiaphoria and anosognosia). Gainotti suggested that depression in patients with RH lesions, may be underdiagnosed due to a tendency to denial and failure to express affects (Gainotti, 1989). However, no significant difference was found in depression scores between patients with anosognosia for hemiplegia (common with right parieto-temporal or basal ganglia involvement) and patients who were nosognosic, suggesting that anosognosic patients do not deny depression (Starkstein et al., 1990a). Thus, anosognosia, neglect and major depression may coexist. A longitudinal case study suggested that they are independent phenomena (Starkstein et al., 1990a). The coexistence of anosognosia and depression challenges the psychological theory of depression (Gainotti, 1989; Ramasubbu, 1994).

Behavioural reactions of denial own assessment of their deficits during questioning, while denial reactions can be used to describe activities observed by an external examiner, such as attempts to stand in spite of hemiplegia. In addition, subjective experience, defined as the patients’ own appreciation, of their affective state (happiness, sadness, anger or fear), should be emphasized. In a recent study assessing subjective experience in acute stroke to correlate it with stroke features, acute emotional behaviour, and impact on medical care seeking, we studied all patients with acute first-ever stroke. During the first 4 days, we rated subjective experience (happiness, sadness, irascibility, fear), mood (Hamilton) and behavioural reactions using a specifically designed scale. Fifty-three patients (30 men, 23 women, 60 ⫾ 19 years) completed 3month follow-up. Strokes were in the anterior (32/53) or posterior circulation (21/53) (17 right, 33 left, 3 bilateral). Seventeen (32%) patients failed to seek medical care spontaneously (Ghika-Schmid et al., 1999).

Anosognosia and anosodiaphoria Anosognosia has been shown to be frequent in right-sided lesions, but may also develop after left-sided lesions (Fig. 22.3). Anosodiaphoria was even reported to be more frequent following left strokes (Ghika-Schmid et al., 1999). The lack of recognition of the deficit was manifested in various functions, such as hemianopia, dysarthria, aphasia or sensory loss (Prigatano & Schacter, 1991). Babinski (1914) noted that patients with RH lesions may

Acute behavioural signs of denial were independent of anosognosia. They were not related to the side of the lesion, but were significantly more frequent in patients with deep lesions on either side. This confirms a clear distinction between the behavioural manifestations of denial and nosognosia. It suggests that these two aspects may also be independent in terms of their neuroanatomic substrate, since nosognosia, but not behavioural signs of denial, related to the side of the lesion. This may imply a dissociation between behavioural display and insight of physical impairment. Thus, the behavioural signs of denial and nosognosia should be distinguished in further studies; their confusion may have accounted for some of the discrepancies in the literature (Ullman & Gruen, 1961). Denial reactions were inversely correlated to subjective experience of fear. The possibility of a relationship between anxiety, fear and denial has been raised, but has remained ambiguous (Ullman et al., 1960). In Ullman’s widow patient, the rejection of denial (realizing that her paralysed arm was not her dead husband’s) decreased her fear. In contrast, in another patient, initial feelings of fright were relieved by the identification of the arm upon her breast (her arm) as that of her husband (Ullman et al., 1960). The presence of denial may be related to a reduction of the patient’s experience of fear (Ghika-Schmid et al., 1999). An impact of denial on the patient’s outcome, as shown by a worsening record of employment, has been reported in follow-up studies of patients with head injury (Prigatano & Schacter, 1991). The presence of an acute denial reaction may be correlated with delayed occurrence of depression and anxiety (Ghika-Schmid et al., 1999).

Disorders of mood behaviour

Subjective experience For all other emotions than fear (joy, sadness and anger), the patients’ subjective experience was not related to the behaviour displayed during the acute phase of stroke (Ghika-Schmid et al., 1999). Such an independence of nosognosia from the emotional reactions supports a similar dissociation observed over time in a prospective longitudinal single case study (Starkstein et al., 1990). The coexistence of anosognosia and depression challenges the psychological theory of depression (Ramasubbu, 1994). This seems to confirm the hypothesis that a decreased experience of fear may relate to the manifestation of denial, which is sometimes interpreted as a defence mechanism. Fear may be mediated by a different neuronal network, accounting for the dissociation we observed between subjective experience of fear (which related to behaviour of denial) and the independent subjective experience of other emotions in regard to the observed behavioural response. Impaired recognition of fear in emotional faces has been noted in patients with selective bilateral damage to the amygdala (Adolphs et al., 1994; Calder et al., 1996), whereas the hippocampus and adjacent whitematter may play a crucial role in the vocal perception of fear (Ghika-Schmid, 1997), see Fig. 22.3. This suggests that there may be multiple emotion systems for different aspects of emotion (Adolphs et al., 1994; Damasio, 1994). Abnormal fear reactions may be related to affective disorders such as anxiety and stress (Le Doux, 1996).

Recall of the acute event A third of the patients could only partially recall or did not recall at all the acute event (Ghika-Schmid et al., 1999). These results are consistent with a study on patients showing dramatic recovery following thrombolysis (Grotta & Bratina, 1995). This impaired recall of the acute phase certainly adds to the difficulties encountered in trying to motivate patients to enroll in regular follow-up.

Medical-care seeking Patients with preserved nosognosia did spontaneously better at seeking medical attention on their own initiative than those with anosognosia, suggesting that a lack of insight may indeed be the cause of the failure to consult. The presence of subjective experience was related with appropriate care-seeking. Its impairment may contribute, as for anosognosia, to increase delay in consultation. In conclusion, patients with acute behavioural denial

reactions may have a decreased frequency of subjective experience of fear. Preserved subjective experience of fear relates with appropriate care-seeking and its impairment may contribute, as for anosognosia, to increase delay in consultation. All other emotional reactions seem to be dissociated from the patients’ subjective experience, suggesting that emotional behaviour should be distinguished from the subjective emotional experience, which may be closer to affective disorders. This distinction, which was not made previously (Ullman & Gruen, 1961), should be confirmed in further studies.

Mood disorders and cognition in acute brain lesions On rare occasions, the relationship between mood disorders and cognitive impairment has been studied in stroke (Downhill & Robinson, 1994; Iacoboni et al., 1995; BollaWilson et al., 1989). Studies based on the Mini-Mental State Examination are not sufficient, since this test mainly depends on language abilities and left hemispheric function and does not allow a proper estimation of cognitive function due to RH lesion. A study using a complete neuropsychological battery of tests has shown impaired orientation, language and visuo-perceptive and executive functions in LH damaged depressed patients, while no significant correlation between depression and a specific cognitive defect was found in RH patients (Bolla-Wilson et al., 1989). Poststroke depression might contribute to cognitive impairment in the late phase after stroke (Iacoboni et al., 1995). Further studies would be needed to confirm these findings and to demonstrate a possible improvement of cognitive symptoms following treatment. Moreover, the possibility of a positive adrenergic effect on neurological signs and cognition following physical therapy has been suggested (Feeney, 1997). As diagnosis of depression among patients with aphasia is difficult, these patients have been excluded from most studies of poststroke depression. Patients with non-fluent aphasia may show a higher frequency of depression than patients with fluent aphasia, but this may be related to the sharing of a lesion location (left frontal) between non-fluent aphasia and depression (Starkstein et al., 1990; Starkstein, 1998). Cognitive functions and mood may be related to each other and share common neuronal networks and neurotransmitter systems. However, the way in which these different brain functions interact and their relationship to the possible occurrence and clinical features of poststroke

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mood disorder are far from understood and require further investigation.

Mood and emotional perception and expression Emotional aptitudes in patients with stroke and their relationship to mood disorder and cognition have rarely been studied (Starkstein et al., 1994). Emotional aprosody may not necessarily be associated with poststroke depression (Starkstein et al., 1994). One limitation of this study (Starkstein et al., 1994) was the exclusion of patients with comprehension disorder, which may explain the finding of an association between aprosody and right hemisphere lesion; this observation therefore needs to be confirmed. A relationship between memory dysfunction and emotional perception is suggested by studies on the role of the amygdala in acquiring and storing long-term associative memory to link sensory information and affective significance (Ono et al., 1995). The role of the lateral nucleus of the amygdala in fear is recognized in animals (Le Doux, 1996). Recognition of fear in emotional faces may be mediated by the amygdala (Adolphs et al., 1994; Calder et al., 1996). Animal studies suggest that the emotional functions of the amygdala and hippocampus may be relayed through amygdalo-hippocampal interconnections (Aggleton, 1986). Recent observations suggest that the amygdala may process emotional aspects of events (Starter & Markowitsch, 1985). These studies on the role of the amygdala in fear challenge the septohippocampal theories of fear and anxiety (Gray, 1987). On detailed testing of the recognition of facial and vocal expression of emotion (Ekman & Friesen, 1971; Pittam & Scherer, 1993) an impairment of the vocal perception of fear, but not that of other emotions, such as joy, sadness and anger was found in a patient with bihippocampal hemorrhage (GhikaSchmid et al., 1997b). Such selective impairment of fear perception was not present in the recognition of facial expression of emotion. Thus, emotional perception varies according to the different aspects of emotions and the different modality of presentation (faces vs. voices). Evidence about the origin and universality of the production of particular facial expressions (Ekman & Friesen, 1971) initially led to the claim of the existence of a ‘specialized perceptual system tuned to the peculiar movements that signal them’ (Etcoff & Magee, 1992). However, the possibility of a distinct processing of emotion according to the modality of perception should be considered, consistent with the idea that there may be multiple emotion systems

for different aspects of emotion (Adolphs et al., 1994; Damasio, 1994). The hippocampus and adjacent whitematter may play a critical role in the recognition of fear in vocal expression, possibly dissociated from that of other emotions (Ghika-Schmid et al., 1997b). A critical role of the right hemisphere in acquired deficit of emotional expression and comprehension (prosody, emotional faces and lexical emotional expression) has been suggested by numerous studies (Heilman et al., 1975; Ross & Mesulam, 1979; Ross, 1981; De Kosky et al., 1980; Borod et al., 1992; Ahern et al., 1991), but remains controversial (Stone et al., 1996). Other authors emphasized the role of basal ganglia (Cancelliere & Kertesz, 1990). A relative superiority of the visuo-spatial (70) vs. verbal (54) IQ on the Weschler memory scale, observed in a patient with bihippocampal hemorrhage and impaired recognition of fear in vocal expression was not suggestive of a predominant right-side dysfunction (Ghika-Schmid et al., 1997b). Data from tachistoscopic presentation of emotional faces in the right and left hemisphere also challenge the view that the right hemisphere is uniquely involved in all emotional behaviour (Davidson et al., 1987). In Klüver–Bucy syndrome (kBS – first described in rhesus monkeys following bilateral temporal lobectomy, with tendency to examine all objects orally, loss of anger and fear responses and increased sexual activity) an interesting feature has been called ‘psychic blindness’. In the human, psychic blindness may be characterized by an inability to differentiate strangers from friends. It may be associated with sensory agnosia. Cummings and Duchen (1981) suggested that sensory agnosia results from disruption of the temporal neocortex or its connections, and that the other components of the syndrome (hyperorality, hypersexuality) are caused by disturbances of the amygdala functions. Loss of recognition of persons has been reported following lesions in the anterior temporal region and in the limbic structures of the mesial temporal region (Corkin, 1984; Damasio, 1989). Patient HM was unable to learn the identity of the face he had come into contact with since he sustained bilateral ablation of entorhinal cortex and hippocampus (Corkin, 1984). Another patient with bilateral mesial limbic system structures and bilateral higherorder neocortical damage was unable to recognize the identity of the people she met, not only in the visual modality, but also with the help of vocal or sensory clues (Damasio, 1985). These findings support the critical role of the anterior temporal lobe in the formation of binding codes, which allow the reconstruction and retrieval of unique memories (Damasio, 1989). The rare occurrence of complete KBS after a lesion restricted to the left temporo-

Disorders of mood behaviour

mesial region (see Fig. 22.4), may suggest that some aspects of facial recognition such as a sense of familiarity may require the integrity of the left temporal-mesial region. This may represent a distinct network from the one involved with the recognition of facial expression, which may relate more specifically with the function of the right fusiform gyrus.

Prognostic impact of mood disorders Mortality is more frequent in stroke patients with initial depression (70%) than without (40%), even when signs of depression were no longer present at the time of death (Morris et al., 1993a). The suicide rate remains low; when present, its risk factors are insomnia and cognitive impairment (Kishi et al., 1996). The evolution may be dependent on stroke location and a better prognosis of depression was found following stroke in the posterior circulation (Starkstein et al., 1988). The presence of negative affective signs an aspect responding to treatment may lengthen hospital stay, (Galynker et al., 1997). Depression is associated with an increased risk of low responses on Activities of Daily Living (ADL) (Paolucci et al., 1998). Anxiety significantly reduces outcome of ADL and social functioning (Astrom et al., 1993), especially in interaction with depression (Shimoda & Robinson, 1998). The etiopathogeny of these findings may relate to observations that agents which block catecholamines in the central nervous system seem to delay recovery. The description and assessment of emotional and related behavioural changes in acute stroke is very poorly known, although they may be associated with specific prognostic correlates. The potential role of very acute, or ‘during stroke’, behavioural changes as markers for the ulterior development of mood disorder is the subject of an ongoing study (the Lausanne Emotion in Acute Stroke Study; Ghika-Schmid et al., 1996, 1999). Emotional reactions can be already present during the very first days following acute stroke and include a wide range of reactions, which include: overt sadness, passivity, aggressiveness, indifference, disinhibition, denial, adaptation and abnormal sleep or feeding pattern. These reactions can be quantified using a specifically designed scale, the Behavioural Index Form validated for its inter-examiner fidelity (see Fig. 22.4), and may be predictors of the later development of depression (Ghika-Schmid et al., 1997a, 1999). In a prospective study on 53 patients with strokes in the anterior (32) or posterior circulation (21) (17 right, 33 left, 3 bilateral), analysis suggests that acute behavioural

EMOTIONAL BEHAVIOUR INDEX A – overt sadness cries looks sad complains shouts whines B – passivity gives up isolated C – aggression tensed agitated angry rebellious oppositional aggressive revolted D – indifference indifferent neglected apathetic E – disinhibition jokes disinhibited laughs impatient F – denial minimized denial of all symptoms partial denial G – adaptation smiles socializes quiet makes sensible demands pudic interested looks serious sensitive to what happens helpful active collaboration expressive clean, self-attentive obeys H – abnormal sleep/feeding

Fig. 22.4. Emotional behaviour index.

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signs of denial may be regarded as markers of delayed poststroke depression and anxiety (Ghika-Schmid et al., 1999).

Conclusions Studies in patients with focal acute brain lesion, suggest that the left frontal anterior region, both dorso-lateral prefrontal cortex and white-matter, may be strategically important for depression (Bogousslavsky, 1993; Starkstein et al., 1990; Starkstein, 1998; Astrom et al., 1993). These findings could not always be replicated (Bogousslavsky, 1993; House et al., 1990), and some authors even deny any causal contribution of lesion location to depression (Burvill et al., 1996; Gainotti et al., 1997b). In secondary mania, lesion location was mainly in the right hemisphere (Bogousslavsky et al., 1998a; Starkstein, 1998; Cummings & Mendez, 1984), but a consensus is still lacking concerning a possible clinico-topographical correlation of disorders, such as apathy, anxiety, catastrophe reaction and pathological laughing and crying, sometimes encountered after stroke. Important methodological problems and difficulties in comparing the data certainly account for some of the discrepancies found in the literature. Psychiatric diagnosis has not always been made using standardized criteria (DSM-III-R or DSM-IV). The prevalence and correlation of mood disorders may change over time, and studies considering only the acute or chronic phase might not be accurate (Starkstein, 1998). The psychiatric assessment of aphasic patients remains problematic, although these patients may be evaluated through their behavioural changes, such as sleep and food intake (Ross & Rush, 1981). Their exclusion from studies may induce a bias. Studies including patients with previous stroke or multiple lesions may introduce confusing variables in trying to correlate clinical and topographic information (Starkstein et al., 1990; Starkstein, 1998). Also, the classification of stroke subtype and localization has been variable and often simplistic, leading to much difficulty in repeating studies. Further studies using precise templates of vascular involvement in large series of patients are still needed to clarify these points. The systematic study of mood change during and immediately after stroke, as assessed in the on-going Lausanne Emotion in Acute Stroke Study (Ghika-Schmid et al., 1996, 1999), remains poor. However, early thymic alterations may be useful markers of the late functional prognosis. Appropriately designed scales, such as the Behavioural Index Form, make it possible to quantify early emotional reactions (GhikaSchmid et al., 1996, 1999). Systematic studies on large

samples of patients may allow the delineation of acute emotional behaviour, which may be markers for the delayed occurrence of emotional disturbances. Studies in animals suggest that stress-induced biological modification of the hippocampal and hypothalmic responsiveness to glutamate may play a critical functional role (Bartanusz et al., 1995). In humans, a selective reduction in a serotonin metabolite (5HIAA) was found in the CSF of depressed, but not non-depressed, poststroke patients, supporting the hypothesis of a serotoninergic mechanism in poststroke depression (Bryer et al., 1992). Studies on the overall stroke population showed a higher level of glutamate and glycine in the plasma and CSF of patients with large cerebral infarcts, cortical infarcts and severe neurological deficit, supporting the concept of the excitotoxic activity of glycine and glutamate in these patients (Castillo et al., 1996). These findings suggest that neuroexcitatory amino acids may not only be a useful parameter to monitor the severity of stroke, but that measurement of other metabolites such as serotonin metabolites, might allow more selective measures of the differential biological response in patients prone to develop poststroke mood disorders. Further systematic studies, with careful monitoring of stroke and measurement of monoamine metabolites and neuroexcitatory amino acids, may give a better understanding of the biological mechanism underlining poststroke emotional disturbances. In conclusion, although most stroke studies on mood disorder agree on the critical role of the anterior LH in depression and the predominant role of the RH in manic syndromes, controversy exists concerning the exact clinical characterization of poststroke mood disorders in relation to the site of the lesion. Further studies are needed to determine the clinico-topographic correlation and to define predictors of handicap in connection with the different patterns of emotional behaviour.

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Agnosias, apraxias and callosal disconnection syndromes Patrik Vuilleumier Department of Neurology, University of California, Davis, USA

Introduction and definitions Lesions in primary sensory or motor cortices and pathways disrupt cerebral input or output functions, producing anesthesia, blindness, deafness, or paralysis. Most other brain areas are concerned with higher level processes that organize sensory input into meaningful perception and motor output into goal-directed action. Specialized streams of processing deal separately with different kind of information for different purposes (Fig. 23.1). For instance, visual cortical areas are divided into two major pathways: a ventral stream along occipito-temporal areas extracts object properties such as shapes or colour, allowing recognition and long-term memory of visual stimuli; whereas a dorsal stream along occipito-parietal areas encodes the spatial location, orientation, and motion of objects, subserving a variety of visuospatial capacities and visuomotor coordination. Besides, in right-handed subjects, the left hemisphere is usually dominant for linguistic and semantic functions, while the right hemisphere is dominant for spatial, attentional, and emotional behaviour. Focal damage to secondary and associative cortices, or to their connections in the white-matter and corpus callosum, cause specific behavioural and cognitive disorders, which have useful diagnostic value (Table 23.1), and often represent a major burden for patients and their relatives. Agnosias are disorders in the recognition of objects not due to an impairment of elementary sensory processes, memory, language, and other general intellectual functions, and can be specific for a modality (vision, audition, touch) and a class of stimuli (e.g. objects, faces, or words). Visual agnosias follow damage to ventral visual areas, whereas spatial and visuomotor disorders follow damage to dorsal areas. Apraxias are disturbances in skilled and purposeful movements not due to elementary motor, sensory, or extrapyramidal dysfunction, and can involve

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one or more effectors (limb, orofacial, or eye movements). In some cases, elementary sensory or motor defects may coexist with agnosia or apraxia but in themselves cannot account for the disorder. Callosal disconnection syndromes reflect impaired transmission of information from one hemisphere to the other, so that lateralized cortical functions fail to interact with operations carried out in the contralateral side. Disconnection can also occur between cortical areas within one hemisphere and contribute to agnosia, apraxia, as well as other cognitive disorders. This chapter focuses on clinical and anatomical correlates of these disorders. The underlying neurocognitive mechanisms are only briefly discussed.

Agnosias Visual agnosias Distinct capacities are mediated by the ventral visual pathways of the two hemispheres. Schematically, left-side processes are specialized for representing numerous local parts, critical for word recognition and reading; right-side processes are specialized for representing global configurations, critical for face recognition (Farah, 1990). Both of these capacities participate in the processing of other common objects. Depending on hemispheric side and topography, a lesion will impair visual recognition for different classes of stimuli unequally, and result in a specific combination of deficits (e.g. agnosia for faces but not words, with or without agnosia for objects, after a rightside lesion). Ischemic or hemorrhagic strokes in the distribution of the posterior cerebral arteries (PCA) are the most common causes of visual agnosia (Fig. 23.2). Transient agnosia can occur during migraine, or vasospam after vertebral angiography.

Agnosia, apraxia and disconnection

Shape and object agnosia Patients with visual agnosia fail to identify visually presented objects or pictures of objects (i.e. name, point to, describe, or pantomine their use). Knowledge about objects and recognition through other modalities are intact. Some patients may complain that their vision is ‘foggy’ or behave as if blind, but others deny their difficulties. Visual field defects are usually associated, typically in the upper quadrants, and careful ophthalmologic examination must exclude an impairment of elementary perception (e.g. acuity, brightness and contrast discrimination) in the spared fields. As first proposed by Lissauer (1890), it is useful to distinguish between apperceptive and associative agnosia, although the distinction may be both theoretically and clinically blurred (Grüsser & Landis, 1991) .

Apperceptive agnosia This is a failure to integrate elementary visual features into coherent shapes. Even though visual acuity can be normal, patients cannot match pairs of similar objects or shapes, and fail to copy drawings. They have particular difficulties in extracting forms from fragmented, incomplete, or overlapping figures (Fig. 23.3(a)–(c)). Judgments of length, size, orientation, or surface texture may be also impaired. These patients have large and bilateral strokes in the territory of the posterior cerebral arteries (occipital and parietooccipital branches), involving secondary visual areas in the lateral and inferomedial occipital lobes. This often occurs after a second stroke in a patient who has suffered a previous unilateral posterior stroke in the other hemisphere. Occlusion of the basilar artery (top of the basilar) and anoxia after cardiac arrest are also common causes. Many cases follow recovery from cortical blindness. CT scan occasionally fails to demonstrate extensive focal damage in patients with diffuse cortical laminar necrosis, or after carbon monoxide intoxication.

Associative agnosia This is a failure to retrieve the precise identity of objects, while the perception of shape and other constituents is relatively unimpaired. Patients can match pairs of similar objects or drawings, and copy them in a slavish manner, but remain unable to figure out what it is (Fig. 23.3(d )). As Teuber (1968) put it, the visual percept ‘has somehow been stripped of its meaning’. Some patients may be able to match different views of the same object, but matching two exemplars that are visually dissimilar or different objects from the same category is not possible. Recognition difficulties may occasionally be restricted to certain categories, e.g. worse for living things (fruits, animals) than for manufactured artifacts (tools, furniture). The lesions typically

Right hemisphere

S1 where V1

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Left hemisphere

when

why

A1 who

S1 how A1 what

which Fig. 23.1. Schematic illustration of specialized cortical streams that process specific attributes of sensory information in the right and left hemispheres. The occipital and inferior–medial temporal lobes subserve the recognition of visual stimuli (who it is, e.g. face agnosia; or what it is, e.g., object agnosia). The lateral and superior temporal lobe subserves auditory recognition (who, e.g. voices; what, e.g. object sounds and spoken words). The parietal lobes are involved in spatial perception and action onto stimuli (where it is, e.g. visual spatial agnosia for localization, orientation, or motion; how to use it, e.g. ideomotor apraxia). The frontal lobes are involved in higher cognitive and strategic processes, such as organizing and monitoring information and actions (when, e.g. confabulation and dyschronology; why, e.g. reasoning and self-attribution of actions). Finally, limbic structures, including the hippocampus, subserve the formation of episodic memories for unique entities and events (which). V1 ⫽ primary visual sensory cortex; A1 ⫽ primary auditory sensory cortex; S1 ⫽ primary somatosensory cortex.

involve the inferior and medial temporo-occipital areas in ventral visual pathways, in particular the fusiform and lingual gyri, vascularized by posterior temporal and anterior occipital branches from the posterior cerebral arteries. The fusiform and lateral aspects of the inferotemporal cortex appear critical, since bilateral destruction of the lingual gyri does not to cause a major recognition deficit but impairs colour perception and/or learning. Damage is most often bilateral, but unilateral cases have been reported, more often with left than right-side damage. Left-side cases are accompanied by pure alexia, while right-side cases are associated with prosopagnosia; it is considered to be exceptional, if not impossible, that agnosia for objects occurs without agnosia for words or faces. Agnosia after multifocal infarcts in the posterior circulation has been reported in patients with MELAS.

Optic aphasia This should be distinguished from associative agnosia, although some authors considered the distinction to be one of degree rather than kind. It is a modality-specific anomia: patients cannot name visually presented objects (often producing circumlocutions or gross semantic errors) but can recognize them, e.g. describe or pantomine

V1

Table 23.1. Summary of typical lesion sites in agnosia, apraxia, and callosal syndromes Lesion Vascular territory

Left-hemisphere

Right-hemisphere

Bilateral

Corpus callosum

PCA -leptomeningeal

R-hemianopia/ superior quadranopia Pure alexia

L-hemianopia/superior quadranopia

Cortical blindness

L-hemialexia

Prosopagnosia (apperceptive, associative)

Apperceptive object/shape agnosia Associative object agnosia

L-hemianomia (object/colour)

Associative object agnosia Optic aphasia R-hemiachromatopsia Colour anomia Colour agnosia Ventral simultanagnosia

L-hemiachromatopsia

-deep

Opticosensory alien hand (Ideomotor apraxia)

Topographical agnosia (perceptual, spatial, mnesic) Opticosensory alien hand (Constructional apraxia)

MCA -leptomeningeal (superior division)

Subangular alexia

Visual spatial agnosias

Finger agnosia/ Gerstmann syndrome

Agnosia for noncanonical views

(inferior division)

(Neglect dyslexia) R cortical astereognosia R tactile agnosia (R palpatory apraxia) Ideomotor apraxia Orofacial apraxia Associative–semantic auditory agnosia (Arrhythmia) Pure word deafness

-deep

Ideomotor apraxia Paradoxical L ear suppression (dichotic) Bilateral tactile anomia/ tactile aphasia

Agnosia for orientation Neglect dyslexia L cortical astereognosia L tactile agnosia (L palpatory apraxia) Constructional apraxia Dressing apraxia Apperceptive–acoustic auditory agnosia Amusia (amelodia) Receptive aprosodia Phonagnosia (Constructional apraxia)

Bilateral crossed optic ataxia

Central achromatopsia

Opticosensory alien hand? Dorsal simultanagnosia (Balint)

Akinetopsia

Cortical deafness Complete auditory agnosia and amusia Pure word deafness

Bilateral tactile alexia (Pure word deafness) ACA -callosomarginal/ frontopolar -pericallosal

R-hand grasping

L-hand grasping

R palpatory apraxia

L palpatory apraxia

Gait apraxia

Frontal alien hand

Callosal alien hand Impaired crossed touch localization Impaired bimanual coordination Impaired crossed replication of hand/finger postures Impaired crossed tactile matching L-hand non-ownership (‘alien hand sign’) Unilateral L tactile anomia Unilateral L tactile alexia L-hand tactile extinction (dichaptic) L ear suppression (dichotic) Unilateral L ideomotor apraxia Unilateral L agraphia (apraxic or aphasic) Unilateral R constructional apraxia

Notes: ACA, MCA, PCA = anterior / middle / posterior cerebral arteries; L = left: R = right; parentheses indicate deficits that are uncommon, and question marks indicate deficits that have been only rarely described.

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Fig. 23.2. Anatomical correlates of visual agnosias.

their use. Oral language is preserved, including naming through other modalities (although tactile naming is sometimes altered in the acute stage). Anomia for colour and alexia are usually associated (De Renzi et al., 1987). Whether precise and complete semantic knowledge can be accessed from all seen objects is still unknown, but patients with optic aphasia usually interact with objects in their

everyday surrounding much better than agnosic patients do. This rare disorder results from a disconnection between some form of visual semantic knowledge and verbal lexical knowledge. The lesion always involves the territory of the left PCA and encroaches upon interhemispheric callosal fibres in the splenium or the paracallosal white-matter. As a right hemianopia is usually present, all visual information

Agnosia, apraxia and disconnection

(a )

(e )

(b) (f )

(c )

(g )

(h )

(d )

(i ) Fig. 23.3. Examples of stimuli used to test for visual agnosia. Apperceptive agnosia impairs the extraction of shapes from fragmented contours, overlapping figures, or crossed-out masked stimuli ((a), (b), (c)). Associative agnosia impairs the semantic identification of objects whose shapes are correctly perceived and can even be copied (d ). Visual spatial disorders entail various difficulties in judging the spatial location (e) or orientation ( f ) of visual stimuli; patients fail to recognize objects seen in noncanonical orientation (g), or recognize objects but fail to judge their orientation (h). In dorsal simultanagnosia, only one object is perceived at a time but apperceptive mechanisms extracting and grouping their shape constituents are preserved (i ): although the patients detects only one of two or three unconnected shapes (either one of the round shapes or the bar, but not the two or three of them; left-side panel), he sees accurately all shapes when connected in a single object (asymmetrical eye glasses; right-side panel).

must be processed by the right hemisphere before transiting to the left hemisphere language areas. Preservation of dorsal visual pathways in apperceptive or associative agnosia may allow a better recognition of objects that move, as well as appropriate grasping (e.g. correct shaping of the hand and fingers) for unrecognized objects. Similarly, it has been suggested that the preserved evocation of sensorimotor representations in dorsal parietal areas might explain why some patients with agnosia or optic aphasia are better in recognizing and naming drawings that depict actions rather than static objects, or manual tools rather than other object categories.

selective loss in the ability to recognize faces, including previously known faces (relatives, celebrities) or newly seen faces (physician, hospital staff). Recognition of people using other cues (voice, gait, dressing) and knowledge about their identity or biography is intact. As for object agnosia, this takes two clinical forms (De Renzi et al., 1991).

Face agnosia

Associative prosopagnosia

Faces constitute special visual stimuli whose recognition relies on dedicated neural mechanisms. Prosopagnosia is a

This results either from a loss or a disconnection of stored representations of known faces (‘face recognition units’);

Apperceptive prosopagnosia This results from a deficit in the structural encoding of facial traits; patients are unable to discriminate between two different individuals or match two different pictures of the same individual, known or not.

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patients can match pairs of identical faces but fail to identify who the person is, provide any information about him/her, or even tell if he/she’s familiar or not. New faces cannot be learned. Recognition difficulties may be specific to faces or sometimes extend to other visual categories that are made of many perceptually similar exemplars, like flowers, dogs, glasses, famous buildings, or car makes. Stockfarmer patients unable to recognize their cows have been reported. Reading is normal in pure cases, but identification of familiar (or own) handwritings may be impaired. Achromatopsia or left hemianopia are often associated. Prosopagnosia is always caused by a lesion in the territory of the PCA. While the medial fusiform gyrus in both hemispheres is specifically involved in processing faces, unilateral damage to the right inferior temporo-occipital cortex appears both necessary and sufficient to cause prosopagnosia, particularly in the acute stage (De Renzi et al., 1994). According to some authors, bilateral damage might be more common in long-lasting cases (Damasio et al., 1982). In apperceptive prosopagnosia, the lesion is usually large and extends to the inferolateral temporo-occipital convexity; in associative prosopagnosia, the lesion is centered on the medial temporo-occipital region and tends to include the inferior longitudinal fasciculus. Many prosopagnosics are still able to discriminate gender, age, facial expression, and direction of gaze. Conversely, impaired recognition of expressions (prosopoaffective agnosia) follows damage to the temporal lobe, amygdala, thalamus, or orbitofrontal cortex. Impaired recognition of gaze direction may occur with lesions in the lateral temporal lobe, close to the posterior superior sulcus, or the amygdala. Misidentification syndromes comprise a group of delusional disorders initially described in psychiatric cases, but often associated with organic brain damage. Patients with Capgras syndrome believe that a familiar person is replaced by a disguised impostor, whereas patients with Frégoli syndrome believe that a known person disguises himself as others. Recognition of known faces is preserved, but subjective familiarity is altered, and memory and matching abilities for unfamiliar faces may be impaired. Unilateral right or bilateral temporal damage, as well as bifrontal lesions and diffuse cerebral atrophy have been implicated. A visuolimbic disconnection in the presence of intact ventral occipitotemporal pathways is postulated, whereby recognition of identity is preserved but not familiarity. Another unusual disorder with false familiarity for unknown faces without misidentification or delusion (face paragnosia) has been observed in a patient with a left temporo-occipital venous stroke (inferior anastomotic vein thrombosis).

Pure alexia Reading can be selectively lost due to impaired recognition of written words in the absence of other language disturbance, and in particular without writing disorder (alexia without agraphia, or pure word blindness). Although different subtypes may exist, there is no clear classification. Typically, patients can name individual letters, and read words letter by letter, being eventually able to utter a word correctly after spelling it (aloud or covertly). Hence, word-length rather than word-class (e.g. abstract vs. concrete, or regular vs. irregular) strongly affects error rate and reading time. A few visual errors in identyfing single letters (G → C, h → b) sometimes occur. Discriminating real words from non-word letter-strings is usually impaired. Reading is normal for words that are spelled orally by the examiner, or tactually written on their hand, indicating that lexical ‘word-form’ representations are preserved but not activated by visual inputs. Reading may be variably spared for arabic numbers (1998), iconic symbols ($, %, ideographic Kanji characters in Japanese), familiar acronyms (USA), or familiar proper names (people, cities), probably because these stimuli are still recognized as a whole through other ‘global’ perceptual processes. Inability to read a written text may contrast with the correct identification of a known person’s handwriting. Pure alexia is practically always caused by a lesion in the territory of the left PCA. While the lateral part of both fusiform gyri appears crucial for processing letter-strings, a lesion involving the left inferomedial temporo-occipital region together with the (ventroposterior) splenium of the corpus callosum is the most common (Damasio & Damasio, 1983) . Thus, pure alexia is usually accompanied by right hemianopia (or superior quadranopia), colour anomia, and/or optic aphasia. However, the minimal critical area of damage involves the paraventricular whitematter around the left occipital horn, including fibres from the inferior forceps major of the corpus callosum but sparing the splenium (Fig. 23.2). Visual fields can be intact if the left optic radiations are spared. In either case, such lesions disconnect the right occipital lobe from the left hemisphere, or interrupt both inter- as well as intrahemispheric transfer of visual inputs to word-form representations in more anterior temporo-occipital regions and to the angular gyrus of the left hemisphere (Benito-León et al., 1997; Verstichel & Cambier, 1997). An involvement of more anterior and dorsal parts of the splenium seems necessary to produce associated optic aphasia. Colour anomia is usually absent if the posterior temporo-occipital cortex is spared. Rarely, when there is no visual field defect, the lesion responsible for pure alexia may involve the left subangular

Agnosia, apraxia and disconnection

region in the posterior sylvian territory, undercutting association fibers in the vertical occipital fasciculus (Fig. 23.2). Some elements of Gerstmann syndrome may be then present (e.g. finger agnosia, right–left confusion). Damage to the left angular gyrus itself causes a different disorder, alexia with agraphia, that is, a defect of written language rather than visual recognition.

Neglect dyslexia This is a distinct disorder, common with left hemispatial neglect after right parietal damage, but also seen in isolation after unilateral right or left hemisphere lesions. It is characterized by omissions of the first left-side letters (in right hemisphere cases) or last right-sided letters (in left hemisphere cases) in the reading of words, which is typically worse for nonwords than real letter-strings. It reflects a disorder of visual attention rather than a problem of recognition or language.

lexical codes and object semantic representations, or from impaired mental imagery. Anatomical correlates are unclear, but lesions usually involve the inferior, more than the mesial, temporo-occipital cortex in the left hemisphere (Grüsser & Landis, 1991).

Colour anomia This is less uncommon, and consists of a selective inability to name seen colours that is not due to impaired colour perception. It is usually accompanied by optic aphasia or pure alexia, but can dissociate from them. It correlates with damage to the posterior mesial occipitotemporal region of the left hemisphere, centred on the lingual and posterior parahippocampal gyri, underneath the splenium of the corpus callosum. This results in a right hemianopia by concomitant damage to the optic radiations (or a right upper quadranopia plus a lower hemiachromatopsia) and prevents the transfer of all visual colour information to the left hemisphere’s language areas (Damasio & Damasio, 1983).

Colour agnosia Several disturbances of colour perception and colour recognition must be distinguished. Any of these can be associated with one of the above recognition disorders.

Central achromatopsia This is a selective loss in the perception of colours (colour blindness), affecting one quadrant, one hemifield, or both hemifields. Objects and shapes are recognized but perceived in shades of grey. Congenital (inherited) colour blindness should be ruled out. The lesion must involve areas specialized in colour processing in the posterior part of the lingual gyrus and collateral sulcus, in either hemisphere. Other perceptual defects also occur in the absence of complete achromatopsia, in particular in colour constancy (the ability to identify the same colour under different illuminations).

Colour agnosia This means a loss in the knowledge about colours that are associated with objects, while perception and discrimination of colours are preserved. This is manifest in visual, verbal, or visuoverbal association tasks (e.g. matching appropriate colours to line drawings of objects, indicating verbally the colour of common objects, or listing objects that have a given colour). Colour categorization may be impaired (e.g. sorting hues into groups of ‘related colours’) despite intact hue discrimination. Knowledge of abstract conceptual associations to colours (e.g. red–anger, green–youth) should be also tested. Naming of seen colours may be normal. Colour agnosia is a rare condition, resulting either from a disconnection between colour

Visual spatial disorders Various disorders of spatial perception are associated with damage to the dorsal visual pathways. Most of them are much less well characterized than ventral visual agnosias, both in neuropsychological and anatomical terms.

Simultanagnosia Dorsal (or competitive) simultanagnosia This is a rare condition that results from bilateral damage to the posterior parietal lobes and/or superior occipital lobes. In the former case, it is associated with optic ataxia (an inability to reach for, or point to, visual targets) and gaze apraxia (‘psychic paralysis of gaze’, an inability to direct voluntary eye movements to visual targets), this triad constituting Balint’s syndrome. Visual disorientation (inability to localize objects in space) is also a prominent feature. As the term coined by Wolpert (1924) suggests, the patient with simultanagnosia is unable to see more than one object at a time. He behaves like a blind person and often complains that objects disappear, or that he loses sight of them. Yet, acuity is normal and visual fields may be intact. He recognizes objects, pictures, or faces (unlike in visual agnosia), although in a piecemeal fashion. If two objects are shown, whatever their position, he perceives only one and fails to reach for it. Objects’ size does not matter. Perception of spatial relationships and depth is virtually abolished. The patient may detect only one of several overlapping figures (Fig. 23.3(b)), and remain unaware of others. Which visual stimuli reach awareness can be modulated by grouping factors, so that although only one of

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two unconnected shapes is perceived, the two same shapes are perceived if they form a single connected object (Fig. 23.3(i )). Likewise, real or familiar words can be read or spelled aloud, whereas non-word letter-strings yield greater difficulty because their letters cannot be grouped in a single known entity. The patient may also miscombine features from an unseen object to another that is reported (e.g. perceive a blue X when there is a red X and a blue O). Simultanagnosia is regarded as a bilateral disorder of spatial attention, that is, a form of bilateral neglect or extinction. Attention and fixation become locked on a single object, unable to shift to others in the field so as to afford conscious perception, and direct arm or eye movements to them. Lesions always involve the posterior and superior angular region, including the posterior intraparietal sulcus, and extending into the precuneus in the superior occipital lobe, in both hemispheres. A common cause is cardiac arrest or bypass cardiac surgery with severe hypotension, producing watershed infarction between the posterior and middle cerebral arteries. Sequential embolic infarcts in the distribution of the posterior parietal and angular branches of the middle cerebral artery (MCA) may have the same result. Acute Balint’s syndrome also occurs with venous thrombosis (posterior superior longitudinal sinus), MELAS, or reversible posterior leukoencephalopathy associated with eclampsia, malign hypertension, immunosuppressive therapies, or AIDS.

Ventral (or integrative) simultanagnosia This is even rarer, associated with left inferior temporooccipital damage and pure alexia. Patients perceive more than one object in their visual field but have difficulties in identifying and integrating multiple components into a meaningful whole. Hence words are spelled letter by letter, and pictures are described in a piecemal fashion (e.g. reporting wheels, pedals, and a face, without seeing the whole scene of a man standing beside his bike). There is no disturbance in reaching, gazing, or walking around obstacles.

Topographical (or environmental) agnosia An inability to recognize familiar places and find one’s way, not due to impaired general memory, visual loss, or neglect, may take several different forms: a perceptual type where previously familiar buildings and landmarks are not identified; a mnesic type where known places and layouts are not recognized; and a spatial type where familiar buildings and places are recognized but their location and relationship in space are not retained (Grüsser & Landis, 1991). Most often, lesions involve, respectively, the medial

temporo-occipital lobe and the parahippocampal gyrus in the right hemisphere (perceptual and mnesic type, often associated with prosopagnosia); the right posterior cingulate cortex (mnesic type); the right retrosplenial region and medial posterior parietal lobe (spatial type) (Takahashi et al., 1997). A particular form of transient topographical amnesia has been described, often in middle-aged women, somehow similar to transient global amnesia but with preserved recall; a vascular etiology is debated (Stracciari et al., 1994).

Visuospatial agnosia A heterogeneous collection of disturbances involves the perception of spatial location, orientation, layout, or size. These are assessed by tasks such as judging the relative positions of objects in space (e.g. single or multiple dots on cards), discriminating the relative orientation of straight lines, or mental rotation tasks (Fig. 23.3(e)–(h)). All correlate with right parieto-occipital damage (Fig. 23.4).

Agnosia for non-canonical views This is a failure to recognize objects presented under unsual viewpoints, though recognition is normal under a prototypical view. This might reflect a deficit in a perceptual categorization stage deriving a viewer-dependent representation of objects’ shapes, carried out in the right posterior hemisphere before being available for semantic identification in the left hemisphere. Hence, this is observed after right temporoparietal lesions or callosal disconnection by splenial damage (Grüsser & Landis, 1991).

Agnosia for object orientation This is a failure to recognize the correct orientation of known objects, with a striking inability to discriminate upright oriented objects from rotated, upside-down inverted, or mirror-inverted ones. Drawings are copied accurately but similarly rotated. Recognition of objects themselves is normal, whichever their orientation. This might result from mechanisms in ventral visual areas subserving viewer-independent recognition of objects without coding orientation information. Accordingly, such disorders occur after right inferior parietal and frontal strokes (Turnbull et al., 1996).

Akinetopsia Patients with selective motion blindness perceive only static stimuli, and fail to perceive visual motion; their vision is thus a succession of stroboscopic images. Complete loss of motion perception is exceptional, and follows bilateral damage to a motion-specific area in the

Agnosia, apraxia and disconnection

Fig. 23.4. Anatomical correlates of visual spatial disorders.

parieto-temporo-occipital fossa, just anterior to the lateral occipital gyrus. This has been reported after venous thrombosis of the occipital superior cerebral veins, or bilateral sequential hemorrhages in the parieto-temporo-occipital junction. Effects from unilateral damage are unclear, but a partial ipsidirectional impairment may occur.

Finger agnosia and Gerstmann syndrome This complex syndrome includes: (i) finger agnosia, (ii) right-left disorientation, (iii) acalculia, and (iv) agraphia. Finger agnosia refers to an inability to identify, name, individuate, or designate the individual fingers of both hands (and toes) not due to sensorimotor loss or aphasia. The presence of the four symptoms with concomittant absence of other disorder strongly correlates with lesions in, or adjacent to, the left angular gyrus. But each symptom may occur independently, or the four symptoms may occur together with other deficits such as aphasia, apraxia, or spatial disorders, in cases with various lesions elsewhere (e.g. left frontal, left thalamic, right parietal). In pure Gerstmann syndrome, a deficit in the mental manipulation of internal spatial representations (e.g. relative position of body parts) might underlie both finger agnosia and right–left confusion, and perhaps acalculia as well (Mayer et al., 1999).

Auditory agnosias As for vision, lesions may impair auditory recognition at different stages of processing and affect specific classes of sounds (objects, spoken words, voices, music) in isolation or combination, depending on the hemispheric side and site of damage. Schematically, the left hemisphere is specialized for analysing speech and other sequentially organized sounds, and attributes semantic meaning; the right hemisphere is better for non-verbal sound patterns and fine discriminations, and attributes emotional value. Auditory agnosia is rare. It is diagnosed in the absence of significant hearing loss as measured by standard audiometry. Tape-recorded material is required for a precise assessment of auditory capacities, but bedside testing may use common objects (e.g. crumpling paper, shaking a bunch of keys) or a walkman. The primary auditory cortex (Heschl’s gyrus) must be relatively spared at least on one side, with lesions variably involving the auditory association areas in the superior temporal gyrus and/or their connections from Heschl’s gyrus. Most often, damage is bilateral and results from sequential strokes in the sylvian territory (Fig. 23.5). An occlusion in the distribution of the inferior leptomeningeal division of the MCA (supplying

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Fig. 23.5. Anatomical correlates of auditory agnosias.

the temporal cortex and adjacent white-matter) or the deep perforating lenticulostriate branches (supplying the auditory radiations in the rentrolenticular part of the internal capsule) can both be seen. Subcortical hemorrhages in the posterior capsulo-lenticular region are also possible. Auditory agnosia sometimes follows an acute stage of cortical deafness, in which the function of the primary auditory cortex and/or its afferents in the auditory radiations are compromised on both sides. In the case of lefthemisphere damage, impaired auditory recognition of nonverbal sounds is most often accompanied by some degree of receptive aphasia.

Amusia

Sound agnosia

Pure word deafness

Impaired identification of non-verbal environmental sounds (telephone ringing, animals scream, car engine, etc.) is shown by naming or matching pictures to sounds. There are two types of deficit (Schnider et al., 1994). Patients with the apperceptive–acoustic type have difficulty in discriminating between pairs of meaningless sounds and make predominantly acoustic errors in identifying meaningul sounds (e.g. a cat meowing mistaken for ‘a crying baby’). This occurs with unilateral right temporal damage. Patients with the associative–semantic type perform normally in discrimination tasks, but make recognition errors with semantically related sound sources (e.g. plane takeoff mistaken for ‘a train’). This occurs with unilateral left temporal damage, usually associated with language and other associative-semantic disturbances (e.g. word–picture or picture–picture matching tasks).

This refers to a selective auditory agnosia for speech (auditory verbal agnosia) without other language disturbance. The patient fails to understand spoken words but can read, speak, and write relatively normally. He/she can often discriminate speech from other sounds but complains that it sounds muffled or foreign. Occasionally, he/she may be anosognosic and develop paranoid psychotic disturbances. Discrimination of phonemes is severely impaired. Typically, this follows recovery from a severe Wernicke’s aphasia. It is caused by a disconnection of Wernicke’s area, in the left posterior superior temporal gyrus, from all auditory inputs coming from both left and right primary auditory cortices. Two loci of damage are possible: (i) bilateral cortical and subcortical lesions involving the superior temporal gyrus in both hemispheres, but sparing Heschl’s gyrus; (ii) a single lesion in the dominant temporal lobe

Perception of music is impaired in most patients with auditory sound agnosia, but a disproportionate difficulty in recognizing melodies is referred to as sensory (or receptive) amusia. Involvement of the right or left superior temporal gyrus disrupts, respectively, the discrimination of melody contour and pitch (amelodia) or the discrimination of interval duration and rhythmic temporal grouping (arrhythmia). Individual differences in musical expertise and gender affect the degree of lateralization. Expressive amusia, or inability to sing, is not necessarily associated with receptive amusia.

Agnosia, apraxia and disconnection

Fig. 23.6. Anatomical correlates of tactile recognition disorders. Each can occur in either hemisphere, hence affect only the contralateral hand, except for tactile anomia which can be bilateral after unilateral left hemisphere damage.

involving the primary auditory cortex and/or the ipsilateral auditory radiations from the medial geniculate nucleus, together with callosal fibres from controlateral auditory areas.

Paralinguistic agnosia Receptive aprosodia (affective auditory agnosia) is a difficulty in understanding affective tone in people’s speech. Phonagnosia is a difficulty in identifying voices from known people. In both cases, there is no defect in understanding linguistic speech content. These disorders follow right hemisphere damage, in particular in the temporoparietal region homologous to Wernicke’s area.

Tactile agnosias Tactile recognition of objects can be disrupted in the absence of elementary sensory loss (e.g. touch, temperature, pain, vibration) and impaired manipulation. Astereognosia is common, resulting from impaired discrimination of haptic properties of objects (simple forms, size, texture, weight), and may be considered as an apperceptive disorder of tactile recognition. Deficits in twopoint discrimination and agraphesthesia are usually present. True tactile agnosia has been very rarely reported and studied. The diagnosis implies a specific failure to identify objects and complex shapes with preserved perception of haptic properties, metric length, and spatial localization, and may be considered as an associative dis-

order of tactile recognition. Such patients can eventually draw or match tactually the objects that are placed in their hand (out of sight). Tactile recognition disorders occur in the hand contralateral to a brain lesion on either side, but bilateral impairment has been often observed after extensive right hemisphere damage (i.e. left-hand anesthesia or astereognosia with right-hand tactile agnosia) for unclear reasons. Right or left hemisphere lesions might produce more frequently an apperceptive or associative disorder, respectively, as in audition and vision. These disorders are associated with strokes in the superficial territory of the MCA (anterior or posterior parietal branches), but uncommonly accompanied by conduction aphasia or ideomotor apraxia unlike elementary (‘pseudothalamic’) sensory defects (Fig. 23.6). As for the visual system, there might be two streams of somatosensory processing from the primary sensory cortex on, including a ventrolateral pathway concerned with shape and object identification and learning, and a dorsomedial pathway concerned with sensorimotor and spatial integration (Caselli, 1993). Prominent astereognosia and agraphesthesia typically follow lesions close to the hand area of the somatosensory cortex, in the middle postcentral gyrus, although complex sensory loss after subcortical or brainstem lemniscal lesions sometimes produces similar defects. Tactile agnosia implicates the ventrolateral somatosensory association areas, which extend from the parietal operculum, posterior insula, and retroinsular cortex, to the anterior and inferior parietal lobe. On the other hand, the

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Table 23.2. Examples of gestures to test ideomotor and orofacial apraxia Meaningless Meaningful transitive

Meaningful intransitive

Unimanual:

Bimanual:

Ideomotor apraxiaa Use a scissor Use a saw Use a hammer Use a screwdriver Comb one’s hair Brush teeth Eat with a spoon Drink with a glass Open a bottle Open a door with a key Cut bread Write with a pencil

Wave good-bye Hitchhike Military salute Come here Go away Silence, hush Scold, threaten Thumb one’s nose OK, all going well Be quiet Someone is crazy Cross oneself

Hand under chin Hand’s back on ear Fist on head Hand on shoulder Thumb to little finger

Double ring with fingers L- and R-hand’s back next to another L- and R-hand fingers next to another L-hand forefinger to R-hand middle finger Butterfly-shaped crossed hands

Orofacial apraxiab Blow out a match Suck on a straw Smoke a cigarette Kiss Lick one’s lip

Whistle Yawn Frown Wink Wrinkle forehead

Open mouth Stick out tongue Puff out cheeks Click tongue “Pa-ta-ka”

Notes: a Ideomotor apraxia may be also tested for the lower limbs with appropriate gestures (e.g. pedalling, shooting, stubbing a cigarette out, etc.). b Orofacial apraxia may be also tested for respiratory movements (e.g. sniff, cough, pant as if exhausted, clear throat as if embarassed, breathe in and out deeply, etc.).

dorsomedial somatosensory areas, including the superior parietal lobe and medially situated supplementary sensory area, are related to atypical loss of tactile recognition and localization with an impairment of skilful manipulative movements (palpatory apraxia); these areas are partly vascularized by the anterior cerebral artery (ACA).

Tactile anomia (or tactile aphasia) This must be distinguished from the preceding disorders, representing a modality-specific inability to name objects presented by touch, although these are correctly recognized (as shown by normal use, matching, or association abilities). A similar deficit has been reported selectively involving letter tactile reading (pure somesthetic alexia). These exceptional disorders are associated with subcortical lesions in the left inferior parietal lobe, placed so as to produce a somatosensory–verbal disconnection. Unilateral left tactile anomia is usually due to callosal disconnection (see below).

Apraxias Ideomotor apraxia Patients with ideomotor apraxia fail to execute purposeful, skilled or learned movements without this being due to elementary sensorimotor, extrapyramidal, or other cognitive disturbances. The disorder affects both the limbs contralateral and ipsilateral to a unilateral lesion which practically always involves the left hemisphere (in righthanded subjects). In patients with a right hemiparesis, it is best seen in the left hand (ipsilateral ‘sympathetic apraxia’). If possible, both sides of the body must be tested separately for pantomimes of meaningful transitive (pretending objects use), meaningful intransitive (symbolic signs), and meaningless, gestures (Table 23.2). Pantomimes should be examined on verbal command and imitation, as well as in response to visual, tactual, and visual–tactual presentation of objects. Apraxic errors include substitutions (e.g. hammering instead of

Agnosia, apraxia and disconnection

Fig. 23.7. Anatomical correlates and mechanisms of ideomotor apraxias; m1 ⫽ primary motor cortex; pm ⫽ premotor cortex and supplementary motor area; slf ⫽ superior longitudinal (arcuate) fasciculus; sof ⫽ superior occipito-frontal fasciculus; smg/apa ⫽ supramarginal gyrus and anterior parietal area; wa ⫽ Wernicke’s area.

combing), perseverations, incorrect spatial posturing of the limb, incorrect temporal sequencing, or body part used as an object (e.g. hammering with a clenched fist). Specific anatomical correlates for the different subtypes of gestures or errors are still imprecise, however. Both meaningful and nonsense movements are poorly performed after lefthemisphere damage with little improvement to imitation, but habitual actions like actual object use and intransitive gestures are often better than transitive and novel gestures. On the contrary, right hemisphere damage may sometimes impair the production of intransitive gestures and imitation of novel meaningless gestures, as well as actions in naturalistic settings (e.g. meal), probably because of spatial and attentional difficulties (Rothi & Heilman, 1997). Since Liepmann (1900), it has been assumed that the (left) hemisphere opposite to the preferred (right) hand is dominant for the organization of skilled motor activities (Rothi & Heilman, 1997). The parietal cortex holds action patterns (‘movement formula’ or ‘visuokinesthetic engrams’) that represent specific spatiotemporal parameters of skilled

movements, and areas in the left supramarginal gyrus appear particularly crucial for the selection and temporal sequencing of these patterns. Goal-directed gestures require these action patterns to be activated (e.g. by visual or auditory–verbal inputs) in left parietal areas and then transmitted to supplementary motor and premotor areas, which in turn control the primary motor cortex both ipsilaterally and (through callosal connections) contralaterally (Fig. 23.7). Ideomotor apraxia is therefore usually accompanied by aphasia of varying type, but the two disorders can dissociate. Broca’s and conduction aphasics may have more severe apraxia than Wernicke’s aphasics, even though their comprehension is much better. However, some righthanded subjects have bilateral representations of movement patterns, and show no apraxia after large unilateral lesions, while exceptional cases may have a right hemisphere dominance and show ‘crossed ideomotor apraxia’ after right-side damage. Left-handed subjects are more likely to have action patterns represented in their right

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hemisphere (independently of language functions) and may demonstrate apraxia after a right-side lesion with or without aphasia. Ideomotor apraxia follows a variety of lesions in the dominant hemisphere (Fig. 23.7). It is common after cortico-subcortical strokes in the superficial MCA territory, particularly with involvement of frontal branches (associated with Broca’s aphasia or aphemia and hemiparesis) or anterior parietal branches (associated with conduction aphasia and hemisensory loss). It is also common after deep lesions in the paraventricular or peristriatal whitematter, involving the superior longitudinal (arcuate) fasciculus (coursing adjacent to the insular and lenticular region) and/or the superior occipito-frontal fasciculus (adjacent and superior to the body of the lateral ventricle). Such lesions produce a disconnection of posterior language areas and visual associative areas of the parietal lobe from anterior premotor areas (Alexander et al., 1992). Ideomotor apraxia is rarely, if ever, caused by lesions confined to the basal ganglia (putamen, caudate, or globus pallidus), but a few cases were reported after thalamic hemorrhage or infarct in the distribution of the polar artery (involving the ventral anterior, ventral lateral, and reticular nuclei) or the posterior choroidal artery (involving the pulvinar), together with mild language disturbances (Pramstaller & Marsden, 1996). It has been suggested that apraxic patients with parietal lesions fail to recognize gestures performed by the examiner (‘pantomime agnosia’) due to the loss of stored action patterns, whereas apraxic patients with frontal or subcortical lesions show intact recognition of correct gestures.

Apraxic agraphia This is characterized by a specific impairment in writing with preseved sensorimotor function, spelling, and typing, most often associated with but dissociable from ideomotor apraxia; it follows parietal lesions superior to the angular gyrus or lesions in the middle frontal gyrus, superior to Broca’s area (Exner’s area).

without ideomotor apraxia, is caused by contralateral damage to the anterior bank of the intraparietal sulcus.

Ideational apraxia This is uncommon and ill-defined, characterized by impaired knowledge of object use (‘conceptual apraxia’ or ‘agnosia of usage’) or impaired execution of correct steps in familiar actions (e.g. put a letter in an envelope to send, prepare a cup of tea). This has been reported, respectively, after focal lesions in the left temporoparietal region, or bifrontal damage and confusional states.

Orofacial apraxia Orofacial apraxia This is an impairment in skilled purposive execution of bucco-lingual and facial movements. As for limb apraxia, testing should assess meaningful, transitive and nontransitive, and meaningless movements involving the lips, tongue, face, or eyelids (Table 23.2). Automatic–voluntary dissociation is common (e.g. failing to mimic a kiss but succeeding when the hand is brought close to the mouth). Ideomotor limb and orofacial apraxia occur together in only a third of cases. Orofacial apraxia is typically associated with nonfluent aphasia and almost constant in Broca’s aphasics, but dissociations have been reported. Lesions involve the frontal and central opercular cortex, the anterior insula, or the anterior paraventricular whitematter (Alexander et al., 1992). Orofacial apraxia must be distinguished from Foix–Chavany–Marie syndrome due to bilateral anterior opercular damage, where all voluntary orofacial movements are impaired but automatic movements are preserved.

Speech apraxia This is a distinct linguistic disorder, similar to anarthria, in which the articulation and sequencing of phonemes is impaired.

Constructional apraxia Melokinetic apraxia This is a unilateral difficulty in making fine finger movements (e.g. pick up a coin, buttoning up a shirt), often disregarded as a ‘true’ apraxia and probably related to impaired sequencing of elementary motor segments. It may be seen with lesions in the supplementary motor and somatosensory areas, premotor cortex, basal ganglia, or superior parietal lobe (afferent kinesthetic apraxia, associated with sensory disturbances and pseudodystonic– ataxic components). A selective defect in the adjustement of hand and fingers posture during object grasping, with or

An inability to execute or copy simple drawings (cube, clock, house), or to arrange elements (blocks or sticks) in an appropriate spatial relationship, is a very sensitive sign of brain damage but relatively non-specific. It implicates a number of basic skills, including visual and spatial perception, visuomotor integration and coordination, motor manual skills, and monitoring responses. Therefore, it can result from a variety of lesions, and often indicates coexistent general intellectual deterioration. However, when present as a prominent disturbance, constructional apraxia strongly correlates with damage to

Agnosia, apraxia and disconnection

the right hemisphere, in particular in the superior and posterior parietal lobe (Villa et al., 1986). It also occurs with right-side subcortical and thalamic damage (anterior nuclei supplied by the polar artery). Deficits in visuospatial perception or hemispatial neglect can be associated but are not sufficient to account for the constructive disorder. Typically, drawings show a lack of global structure, piecemeal approach, or rotated orientation, and do not improve with a model or landmarks. Constructional apraxia is also found in patients with left parietal damage and aphasia, usually correlated more with visuoperceptive difficulties than ideomotor apraxia, but present in all reported cases with apraxic agraphia. Typically, drawings show a preserved global structure but are oversimplified, and often better with a model or landmarks. Finally, constructional performance may be impaired after frontal lesions due to defective planning, but typically improve to normal when sequential steps are provided by a model.

Other apraxic disorders Dressing apraxia This is an inability to dress not due to sensorimotor loss or impaired recognition of garments, usually related to neglect, visuospatial, or visuomotor disorders.

Gait apraxia This is a difficulty to initiate and maintain the automatic sequences of walking, seen with diffuse damage to frontal white-matter and corticostriatal connections, common in vascular dementia.

Callosal disconnection syndromes Callosal fibres connect homologous cortical areas, allowing interhemispheric transfer of information, as well as integrative and reciprocal inhibitory influences that determine coherent behaviour. Callosal disconnection signs result from an interruption of these fibres by damage either directly to the corpus callosum, or to the paracallosal white matter. As noted in previous sections, a loss of interhemispheric transfer plays a critical role in several agnosic and apraxic disorders after lateralized hemispheric lesions that compromise callosal fibers (e.g. pure alexia, optic aphasia, color anomia, pure word deafness, ideomotor apraxia). Strokes involving the corpus callosum are not uncommon, but the large majority are associated with extracallosal lesions in the distribution of the ACA or the PCA. Only rarely, damage is confined to the corpus callosum due to embolic occlusion of the pericallosal and/or callosomarginal branches of the ACA, or the splenial branches of the PCA.

Callosal damage is common after a ruptured aneurysm of the anterior communicating artery (secondary vasospasm), or bleeding from an arteriovenous malformation fed by pericallosal or splenial arteries. Small, multiple, lacunar infarcts limited to the corpus callosum or associated with hemispheric subcortical lacunes have been described, attributed to small vessel disease (Giroud & Dumas, 1995). Callosal infarction without injury to the adjacent hemispheres has been observed with bilateral occlusion of the internal carotid arteries (Kumral et al., 1995). More commonly, interhemispheric fibres may be undercut by watershed infarction in the deep white-matter between the anterior and sylvian circulation. Chronic hypoperfusion from severe carotid stenosis or occlusion also results in a progressive atrophy of white-matter fibers in the corpus callosum, the neuropsychological consequences of which are still unknown. Also, acute presentation with disconnection signs due to callosal necrosis and demyelinisation is encountered in Miarchafava–Bignami disease.

Posterior disconnection and ‘split-brain’ syndromes Each hemisphere has specialized processing capacities, and controls only contralateral sensory inputs (visual, tactile, etc.) and contralateral distal limb movements. The left hemisphere has a well-known dominance for linguistic functions, and usually for motor praxis as well. The right hemisphere possesses only a moderate capacity for the comprehension of auditory and visual verbal material, and practically no capacity to produce oral or written language, but is dominant for a number of visuospatial and visuocontructive abilities. Clinical callosal signs reflect the lack of communication between areas in the right hemisphere that can see, hear, touch, or move the left hand, and areas in the left hemisphere that can speak or write. Signs that can be assessed at the bedside will be described below, but some deficits may require special procedures to be demonstrated, such as rapid (tachistoscopic) presentation to each visual hemifield. Most disconnection deficits follow lesions of the posterior half of the corpus callosum, i.e. the trunk (vascularized by the ACA) and the splenium (vascularized by the PCA). Various combinations are found depending on the extent and location of damage (Fig. 23.8), although precise anatomical-clinical correlations remain incompletely settled. Individual differences in cerebral lateralization may exist in both right- and left-handed subjects, and modulate the occurence of these deficits.

Splenial split signs Loss of interhemispheric visual transfer follows spenial lesions. Left visual hemianomia, an inability to name or

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Fig. 23.8. Anatomical correlates of callosal disconnection syndromes.

verbally describe stimuli presented in the left hemifield (pictures, colours, faces), correlates with the most posterior and dorsal damage. Normal perception of stimuli by the right hemisphere can be demonstrated by the ability to point to a corresponding picture, match a tactually presented object, or draw them with the left hand (but not with the right). Left hemialexia, an inability to read words in the left visual field with normal reading in the right field, correlates with more ventroposterior damage; the ability to copy letters with the left hand may be preserved. Matching of pairs of stimuli presented across hemifields is always impaired. Bilateral crossed visuomotor ataxia refers to an inability to reach for objects in the left visual hemifield with the right arm, which is controlled by the opposite hemisphere, and vice versa. When left occipital damage and right hemianopia are associated to splenial damage (PCA

infarction), the presentation is that of pure alexia, optic aphasia, and/or colour anomia.

Posterior trunk split signs Loss of auditory transfer correlates with damage to the posterior trunk or isthmus. It is demonstrated by an extinction of auditory-verbal stimuli presented to the left ear in dichotic listening (left ear suppression), even though ipsilateral auditory pathways can mediate normal reception of left-sided material in the absence of right-sided competitors. Note that paradoxical left ear extinction occurs with unilateral lesions in the deep white-matter of the left hemisphere, which interrupt fibers crossing the callosum; bilateral ideomotor apraxia and right hemisensory defect are then often associated. Loss of tactile transfer follows damage to the posterior

Agnosia, apraxia and disconnection

half of the trunk and causes unilateral left tactile anomia, an inability to name objects palpated with the left hand (blindfolded). The right hemisphere can none the less recognize the objects, as shown by correct manipulation, pointing, or matching abilities. In unilateral left tactile alexia, naming of letters drawn upon skin is impaired, but perception of the letter shapes is preserved in same/different judgements on successive stimulations (unlike in agraphesthesia). Touched left-hand fingers can be moved but not named. Tactual extinction of objects held in the left hand may arise with bilateral simultaneous palpation, suggesting a role of attentional factors. Loss of somatosensory transfer also disrupts crossed tactile matching of objects, crossed replication of hand or finger posture, and crossed point localization (fingers tips) in both directions (right-toleft, and vice versa). A failure to recognize one’s own hand (vs. the examiner’s) when held by the other hand (with eyes closed or behind one’s back) was termed alien hand sign (not to confound with the alien hand syndrome described below) by Brion and Jedynak (1975).

Left unilateral agraphia This is an inability to write orthographically correct words with the left hand, and may result from different disconnection defects. In unilateral left aphasic agraphia, individual letters are well formed but incorrect. Writing with anagram block letters and typing are similarly impaired, suggesting impaired transfer of linguistic spelling information from the left to the right hemisphere (i.e. probably disconnecting the two angular gyri). Lesions involve the isthmus and anterior splenium. In unilateral left apraxic agraphia, letters are replaced by illegible scrawls. Writing with anagram block letters and typing are preserved, suggesting impaired transfer of graphomotor patterns but not spelling information (i.e. probably disconnecting superior parietal areas). Lesions are more anterior, in the posterior end of the trunk. Unilateral apraxic agraphia and left ideomotor apraxia may occur independently.

damage to the genu (unilateral ‘disassociation apraxia’). Unilateral ideational-conceptual apraxia of the left hand may or may not be associated.

Unilateral constructional apraxia Unilateral constructional apraxia of the right hand is also observed with posterior trunk damage, reflecting a disconnection of the left motor cortex from visuospatial competences of the right hemisphere. Drawing, copying, or stick construction are possible only with the left hand. Finally, a loss of sensorimotor transfer disrupts bimanual coordination (e.g. synchronous or alternating tapping, clapping hands, bimanual tasks) and voluntary control of the left hand. The latter disturbances are described below.

Anterior disconnection and ‘alien hand’ (AH) syndromes The function of the anterior half of the corpus callosum is still unknown, but presumably involves organizing coherent motor contol, decision making, and strategic memory retrieval processes. Usually, damage to the anterior trunk and genu produces no apparent clinical sign. In some cases, problems in response initiation and left ‘dissociation apraxia’ were attributed to genu lesions. Gait disorders with wide base, shuffling, and astasia–abasia have been reported following acute infarction limited to the anterior callosum (Giroud & Dumas, 1995; Kumral et al., 1995), but could result from associated bifrontal dysfunction or diaschisis. Albeit rare, the alien-hand syndrome(s) constitute(s) the most common disturbance ascribed to anterior callosal lesions. The term refers to a variety of abnormal motor behavior and action of one’s hand dissociated from conscious volition, not due to an extrapyramidal movement disorder. There is a considerable confusion about the terminology, symptomatology, and anatomy of this syndrome. It seems that the following distinctions should be made (Feinberg et al., 1992).

Left unilateral ideomotor apraxia This usually follows a lesion centered on the mid-posterior callosal trunk, anterior to those producing left agraphia, which disconnects the right motor cortex from language and praxic networks of the left hemisphere. It is typically associated with a right crural paresis after ACA infarction. Left limb apraxia is most severe to verbal command, and does not improve to imitation after callosal trunk damage (except in patients with bilateral representation of motor action patterns). A severe inability to produce left hand movement on verbal command (including writing and typing) with normal performance on imitation may follow

Motor AH syndromes ‘Pure’ callosal AH syndrome occurs with focal damage to the midtrunk (especially its ventral part), just anterior to that associated with unilateral ideomotor apraxia (Geschwind et al., 1995; Tanaka et al., 1996). Hence, the latter was present in most reported cases. There is no extracallosal damage and no elementary sensorimotor loss. The characteristic features best correspond to those of a ‘wayward hand’: (i) The left hand makes unintended movements during actions performed with the right hand; these can be antagonistic to the right (intermanual conflict, e.g.

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unfolding a letter put in an envelope by the right hand), irrelevant but non-antagonistic (e.g. slapping on the table while drawing with the right), or mirror-symmetric (e.g. reaching simultaneously for the same target and colliding with the right). (ii) The left hand does not make the intended movements; this can be a failure to initiate a willed action (e.g. trying hard to grasp a given object), a failure to interrupt a current action (e.g. letting go of an object held in the hand), or another movement being executed instead, inconsistent with verbally stated purposes (e.g. drawing circles instead of a line). The combination of intermanual conflict and inconsistencies with overt intentions has been referred to as diagonistic dyspraxia. The left (non-dominant) hand is seemingly always involved. Abnormal movements of the left leg and whole-body have been occasionally described. Typically, the patient is aware of and concerned by his problems, verbally commenting and reproving the abnormal hand’s behavior, and often talking to it so as to guide it. There is a loss of intentional motor control and separate programming of the left limb. Spontaneous actions appear semi-purposeful, targeted towards objects, and triggered by the evocation of a motor action schema (perhaps generated in both parietal areas), especially when a volitional act is intended with the right hand. The lateral motor cortex on each side is under dual control from posterior parietal areas (providing external environmental cues to action) and the supplementary motor area (SMA) in the medial frontal lobe (providing internal sources of selection to action), and transcallosal inhibitory influences (possibly between SMAs) may be required to select and coordinate the appropriate limb movements so as to execute coherent actions. Alien hand behaviour might reflect a loss of transcallosal inhibition of superior parietal areas and/or premotor areas in the non-dominant (right) hemisphere, normally exerted by homologous regions in the opposite (left) hemisphere which is dominant for motor activities. The right-side premotor–motor system controlling the left hand, deprived of contralateral signals from the dominant side due to interhemispheric disconnection, might then function in an autonomous responsive mode, alien to the patient’s will. The disorder is usually transient and recovers after a few months, but ill-defined complaints about left hand use may persist for years. ‘Frontal’ AH syndrome occurs with larger lesions that encompass the anterior callosum as well as the medial frontal lobe, on one or both sides (Goldberg et al., 1981). It is best characterized as an ‘anarchic hand’ with (i) forced grasping of objects, (ii) impulsive reaching and groping movements towards objects in near sight, and (iii) occasional compulsory manipulation of tools, i.e. unilateral

involuntary handling and utilization of objects within reach. This abnormal motor behavior manifests as reflexive, stereotyped, and often perseverative movements triggered by nearby stimuli through vision or touch, with little evidence of purpose or adequacy towards the target objects. The alien hand’s action cannot be refrained by will, but restraining manoeuvres using the opposite hand are common. Although this has been more often reported in the right (dominant) hand, either hand can be affected contralaterally to the damaged hemisphere, and bilateral cases have been reported after bilateral lesions. Paradoxically, unilateral limb motor neglect (hemiakinesia) may coexist, in particular in the acute stage and after right hemisphere damage. This might initially suppress the alien hand disorder which becomes apparent only later when hypokinesia is decreasing, and explains the rarer occurence in the left (non-dominant) hand. Usually the frontal alien hand slowly abates during the 6–12 months postonset, but recovery depends on the size of extracallosal brain damage. Leg weakness, transcortical aphasia, mutism, apathia, and incontinence are other common associated symptoms indicating medial frontal dysfunction. The frontal alien hand syndrome probably results from a unilateral release of elementary, reflexive exploratory motor behavior. The relative role of callosal disconnection and medial frontal lesions is unclear. Grasping correlates with lesions relatively confined to the contralateral SMA for some investigators and involvement of the anterior cingulate gyrus for others, whereas groping and compulsive manipulation of tools both have been found to be associated with extensive lesions of the anterior cingulate gyrus adjoining the callosal genu (De Renzi & Barbieri, 1992; Hashimoto & Tanaka, 1998). Patients with damage confined to the corpus callosum do not exhibit grasping or groping. However, alien hand seems not to occur after medial frontal damage without coexisting anterior callosal damage. Destruction of medial premotor areas (SMA) combined with anterior callosal disconnection might release the primary motor cortex simultaneously from ipsilateral and contralateral inhibitory control, resulting in an abnormal externally driven activation of manual exploration and prehension motor patterns. Possibly, a mixed ‘frontocallosal’ AH syndrome may occur with more extensive lesions in the ACA territory. Rarely, involuntary grasping and alien hand phenomena have been also observed after subcortical lesions involving the striatum and anterior limb of the internal capsule without cortical or callosal damage, suggesting a participation of these structures in the control of voluntary actions, consistent with their connections with medial premotor areas (Pageot et al., 1997).

Agnosia, apraxia and disconnection

Sensory alien hand syndromes Unintentional and uncontrollable movements of the upper limb opposite to a unilateral brain lesion occur in patients who show a complex combination of disturbances in proprioceptive sensation (sensory ataxia) and visuomotor coordination (optic ataxia), constituting an ‘opticosensory’ alien hand syndrome. This was reported after large posterior infarcts or hemorrhages involving the right thalamus (ventroposterolateral and ventrolateral nuclei) and subthalamic region, and/or the posterior parietal lobes (Levine & Rinn, 1986; Ventura et al., 1995). Callosal damage (splenium) may be associated with infarction in the territory of the PCA but does not seem obligatory, as it was absent in a few cases with isolated thalamic or parietal lesion. Spontaneous motor activities are non-goaloriented but often self-directed, and include scratching, hitting, choking, as well as drifting, catatonia, synkinesis, and exaggerated automatisms. These movements are subjectively perceived by the patient as autonomous and out of control, commonly attributed to someone else’s action. Feeling of foreigness or non-ownership of the affected limb (asomatognosia), hemispatial neglect, or anosognosia are associated. There is no grasping or groping. A dystonic or myoclonic component has been described with thalamic–subthalamic injury.

iAckowledgementsi Illustration work realized thanks to S. Schwartz. Supported by grant 81–GE-50080 from the Swiss National Science Foundation.

iReferencesi Alexander, M.P., Baker, E., Naeser, M.A., Kaplan, E. & Palumbo, C. (1992). Neuropsychological and neuroanatomical dimensions of ideomotor apraxia. Brain, 115, 87–107. Benito-León, J., Sánchez-Suárez, C. & Díaz-Guzmán, J. (1997). Pure alexia could not be a disconnection syndrome. Neurology, 49, 305–6. Brion, S. & Jedynak, C.P. (1975). Les Troubles du Transfert Interhimisphirique. Paris: Masson. Caselli, R.J. (1993). Ventrolateral and dorsomedial somatosensory association cortex damage produces distinct somesthetic syndromes in humans. Neurology, 43, 762–71. Damasio, A.R. & Damasio, H. (1983). The anatomic basis of pure alexia. Neurology, 33, 1573–83. Damasio. A.R., Damasio, H. & Van Hoesen, G.W. (1982).

Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology, 32, 331–41. De Renzi, E., & Barbieri, C. (1992). The incidence of the grasp reflex following hemispheric lesion and its relation to frontal damage. Brain, 115, 293–313. De Renzi, E., Faglioni, P., Grossi, D. & Nicelli, P. (1991). Associative and apperceptive forms of prosopagnosia. Cortex, 27, 213–21. De Renzi, E., Perani, D., Carlesimo, G.A., Silveri, M.C. & Fazio, F. (1994). Prosopagnosia can be associated with damage confined to the right hemisphere – An MRI and PET study and a review of the literature. Neuropsychologia, 32, 893–902. De Renzi, E., Zambolin, A. & Crisi, G. (1987). The pattern of neuropsychological impairment associated with left posterior cerebral artery infarcts. Brain, 110, 1099–116. Farah, M.J. (1990). Visual Agnosias: Disorders of Object Recognition and What They Tell Us About Normal Vision. Cambridge: MIT Press. Feinberg, T.E., Schindler, R.J., Gilson Flanagan, N. & Haber, L.D. (1992). Two alien hand syndromes. Neurology, 42, 19–24. Geschwind, D.H., Iacoboni, M., Mega, M.S., Zaidel, D.W., Cloughesy, T. & Zaidel, E. (1995). Alien hand syndrome: interhemispheric motor disconnection due to a lesion in the midbody of the corpus callosum. Neurology, 45, 802–8. Giroud, M. & Dumas, R. (1995). Clinical and topographical range of callosal infarction: a clinical and radiological correlation study. Journal of Neurology, Neurosurgery, and Psychiatry, 59, 238–42. Goldberg, G., Mayer, N.H. & Toglia, J.U. (1981). Medial frontal cortex infarction and the alien hand sign. Archives of Neurology, 38, 683–6. Grüsser, O.J. & Landis, T. (1991). Visual Agnosia and Other Disturbances of Visual Perception and Cognition, Vol. 12, ed. J. R. Cronly-Dillon. London: MacMillan. Hashimoto, R. & Tanaka, Y. (1998). Contribution of the supplementary motor area and anterior cingulate gyrus to pathological grasping phenomena. European Neurology, 40(3), 151–8. Kumral, E., Kocaer, T., Sagduyu, A. et al. (1995). Infarctus calleux après occlusion bilatérale des artères carotides internes avec syndrome d’héminégligence et astasie–abasie. Revue Neurologique, 151, 202–5. Levine, D.N. & Rinn, W.E. (1986). Opticosensory ataxia and alien hand syndrome after posterior cerebral artery territory infarction. Journal of Neurology, Neurosurgery and Psychiatry, 36, 1094–7. Liepmann, H. (1900). Das Krankheitsbild der Apraxie. Monatsschrift für Psychiatrie und Neurologie, 8, 15–44. Lissauer, H. (1890). Ein Fall von Seelenblindheit nebst einem Beitrage zur Theorie derselben. Archiv Psychiatrie und Nervenkrankenheiten, 21, 222–70. Mayer, E., Martory, M.D., Pegna, A.J., Landis, T., Delavelle, J. & Annoni, J.M. (1999). A pure Gerstmann syndrome. Brain, 122, 1107–20. Pageot, N., Nighoghossian, N., Derex, L., Bascoulergue, Y. & Trouillas, P. (1997). Activité motrice involontaire ou ‘alien hand syndrome’ à l’issue d’une lésion ischémique respectant le cortex frontal médian. Revue Neurologique, 153, 339–43.

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Pramstaller, P.P. & Marsden, C.D. (1996). The basal ganglia and apraxia. Brain, 119, 319–38. Rothi, L.J.G. & Heilman, K.M. (1997). Apraxia: The Neuropsychology of Action. Hove, UK: Psychology Press. Schnider, A., Benson, D.F., Alexander, D.L. & Schnider-Klaus, A. (1994). Non-verbal environmental sound recognition after unilateral hemispheric stroke. Brain, 117, 281–7. Stracciari, A., Lorusso, S. & Pazzaglia, P. (1994). Transient topographical amnesia. Journal of Neurology, Neurosurgery, and Psychiatry, 57, 1423–5. Takahashi, N., Kawamura, M., Shiota, J., Kasahata, N. & Hirayama, K. (1997). Pure topographic disorientation due to right retrosplenial lesion. Neurology, 49, 464–9. Tanaka, Y., Yoshida, A., Kawahata, N., Hashimoto, R. & Obayashi, T. (1996). Diagonistic dyspraxia: clinical characteristics, responsible lesion and possible underlying mechanism. Brain, 119, 859–73. Teuber, H.L. (1968). Alteration of perception and memory in man.

In Analysis of Behavioural Change, ed. L. Weiskrantz. New York: Harper and Row. Turnbull, O.H., Beschin, N. & Della Salla, S. (1996). Agnosia for object recognition: implication for theories of object recognition. Neuropsychologia, 35, 153–63. Ventura, M.G., Goldman, S. & Hildebrand, J. (1995). Alien hand syndrome without a corpus callosum lesion. Journal of Neurology, Neurosurgery and Psychiatry, 58, 735–7. Verstichel, P. & Cambier, J. (1997). Letter-by-letter alexia after left hemispheral lesion without hemianopsia nor callosal involvement: 2 cases. Revue Neurologique, 153, 561–8. Villa, G., Gainotti,G. & De Bonis, C. (1986). Constructive disabilities in focal brain-damaged patients: influence of hemispheric side, locus of lesion and coexistent mental deterioration. Neuropsychologia, 24, 497–510. Wolpert, I. (1924). Die Simultanagnosie-Stvrung der Gesamtauffassung. Zeitschrift für Gesamte Neurologische und Psychiatrie, 93, 397–415.

24

Muscle, peripheral nerve and autonomic changes Thierry Kuntzer1 and Bernard Waeber2 Service de Neurologie and Division of Clinical Pathophysiology, Lausanne, Switzerland

1

Introduction This chapter discusses the diseases of muscle and peripheral nerve that are associated with cerebrovascular events. The peripheral nervous system, defined anatomically by neural structures enveloped by a Schwann cell plasma membrane, includes cranial nerves III to XII, the spinal roots, the nerve trunks, the dorsal roots, the autonomic centers, ganglia and their nerves. Involvement of muscle or peripheral nerve or autonomic system associated with cerebrovascular events, designated herein as multiple neurological complications (MNCs), may occur with varying frequency and pattern and may be seen as primary or secondary (Table 24.1). Early diagnosis of primary MNCs can give valuable information about a patient’s causal disease, a vasculitis, for example, cardiomyopathy or mitochondrial changes in both muscles and central nervous system (CNS) cells. Secondary MNCs may induce increased mortality and morbidity rates of stroke. The large variety of presentations of these disorders means that the MNCs represent a potentially frequent problem in neurologic practice. The full characterization of MNCs, however, needs investigations, including radiological, immunological, biochemical and genetic analyses, as well as electrophysiologic and autonomic function tests coupled with muscle or nerve biopsies.

Primary changes Primary MNCs can result from vascular and cardiogenic embolisms, dissection of large vessels, primary and secondary vasculitis and mitochondrial cytopathies (Table 24.1). Prognosis will be determined by, and therapy tailored to, each specific cause.

Vascular and cardiogenic embolism Simultaneous or delayed involvement of the neuromuscular system and the CNS in embolism has received little attention except in infective endocarditis (IE) where neuropathy is known to be a possible initial complication of the disease. The signs and symptoms are extremely variable owing to the diversity of the etiologic agents and of the various organs involved (Francioli, 1997). Patients may have fever or be afebrile, may or may not have evidence of pre-existing heart disease, may have a very acute or rather chronic course. Fever with a murmur is the most frequent clinical presentation. More than one-half of patients will have some degree of congestive heart failure. Distant complications such as major emboli, lumbar pain, or rupture of a mycotic aneurysm may be the first presenting manifestations of IE. The reported overall incidence of CNS complications of IE varies between 20% and 40%. Stroke is the most common presentation and accounts for one-half to two-thirds of the neurologic manifestations. The majority of these cases are due to cerebral emboli with infarction, but some are also due to intracerebral hemorrhage. Meningitis, either septic or aseptic, decreased level of consciousness, seizures, headache, psychiatric abnormalities, spinal cord involvement, in relation to ischemic lesions or secondary to extramedullary compression by metastatic abscesses can be observed. Peripheral nerve and muscle involvement, as a result of embolism may account for cases of mononeuropathy or localized pain (Pamphlett & Walsh, 1989). The nerves and muscles may be involved as an ischemic monomelic neuropathy, that refers to an infarction of the distal-extremity nerve tissues in which the extent of the abnormality varies with the location of occlusion (Wilbourn & Levin, 1993), or as a cholesterol emboli neuropathy that may resemble polyarteritis nodosa

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Table 24.1. Primary and secondary neuromuscular and autonomic changes seen in multiple neurological complications with stroke as the main clinical presentation Frequency

Type of neuromuscular changes

Remark

Primary changes, where neuromuscular or autonomic, and CNS may be simultaneously involved Vascular and cardiogenic embolisms (infective endocarditis, High Cranial neuropathies, Peripheral See Table 24.2 Ischemic monomelic neuropathy, cholesterol emboli neuropathies, muscular embolisms neuropathy, myocardial involvement in neuromuscular disorders) Dissection of carotid and vertebral arteries

Rare

Horner’s syndrome, cranial neuropathies, cervical radiculopathies and spinal cord ischemia

See Chap. 51

Primary and secondary vasculitis

Rare

Peripheral neuropathies and myopathies

See Table 24.2

Mitochondrial encephalomyopathies

Rare

Myopathies, myalgia, cardiac conduction abnormalities

See Chap. 44 (Uncommon Causes)

Secondary changes, as a consequence of a cerebrovascular event Cardiovascular dysfunctions High

Dysautonomia

Muscle atrophy contralateral to cerebral lesions

High

Muscle changes

Peripheral nerve compression

Rare

Peripheral neuropathies

Reflex sympathetic dystrophy

Rare

Sympathetic dysfunction

Disorders of micturition, faecal continence and sexual changes

High

Somatic and autonomic dysfunction

Sweating disorders and temperature dysregulation Others: dysregulation of respiration, hiccup

Rare Rare

Autonomic dysfunction

(Bendixen et al., 1992). The clinical presentation is remarkably stereotyped. Persistent deep, burning pain is the most prominent symptom. Sensory and motor deficits are found, with a distal to proximal gradient of change. The causes of vascular and cardiogenic embolisms are the same as those usually observed with embolism to the brain, but involvement of the heart in neuromuscular disorders is often overlooked. Cardiac involvement may be subclinical or present as a life-threatening manifestation early or late in the natural history of the underlying disorder (Swash & Schwartz, 1996) (Table 24.2). In some neuromuscular disorders, e.g. Becker X-linked muscular dystrophy, myocardial involvement is unrelated to the severity or duration of skeletal muscle weakness and may even precede the onset of skeletal muscle weakness. In myotonic dystrophy, two-thirds of patients show ECG abnormalities, but only one-quarter have cardiac symptoms. In acute, acquired disorders, e.g. in Guillain–Barré syndrome and in acute polymyositis, cardiac complications may be simultaneous with neuromuscular disorder.

See Chap. 51 (Uncommon Causes)

In recent years, molecular genetics has brought completely new insights into the understanding of the pathogenesis of cardiomyopathies and congenital arrhythmias.

Familial hypertrophic cardiomyopathies (FHC) These are genetically heterogeneous and all the known diseases encode sarcomeric proteins (Bonne et al. 1998) (Table 24.2). There is also a striking allelic heterogeneity, and more than 100 mutations have been found so far. The recent development of animal models have allowed a better understanding of the pathophysiological mechanisms associated with FHC. The mutation leads to a poison polypeptide that would be incorporated into the sarcomere. This would alter the sarcomeric function that would result first, in an altered cardiac function, and then secondly, in the alteration of the sarcomeric and myocyte structure. Some mutations induce functional impairment and support the pathogenesis hypothesis of an hypocontractile state followed by compensatory hypertrophy. Other mutations induce cardiac hyperfunction and

Muscle, peripheral nerve and autonomic changes

Table 24.2. Myocardial involvement in neuromuscular disorders Cardiac involvementa

Mode of inheritance

Gene location

Symbol

Gene product

Limb-girdle dominant Limb-girdle recessive

+++ +++ + + + +

XR XR AD AD AD AR

Desmin-related myopathy Steinert myotonic MD Myotonic MD type 2

++ ++ ++

AD AD AD

Xp21.2 Xq28 4q35 ? 5q, 1q, 3p 15q, 2p 13q, 17q 4q, 5q 11q22 19q13 3q

DMD EMD FSHD FSHD2 LGMD1A-C LGMD2A, 2B LGMD2C, 2D LGMD2E, 2F DRM DM DM2

Dystrophin Emerin ? ? ?, ?, caveolin-3 calpain 3, dysferlin ␥, ␣ sarcoglycan ␤, ␦- sarcoglycan ␣␤-crystallin Myotonin-kinase ?

Hereditary cardiomyopathies +++

AD

14q11

FHC1

+++ +++

AD AD

1q32 11p11

FHC2 FHC3

+++ +++

AD AD

15q22 12q23

FHC4 MYL2

+++

AD

3p21

MYL3

+++ +++

AD AD

19q12 15q14

TNNI3 ACTC

cardiac myosin heavy-chain ␣ or ␤ cardiac troponin T cardiac myosin binding protein C ␣-tropomyosin regulatory myosin light chain Essential myosin light chain Cardiac troponin I Cardiac actin

+++

AD

2q35

DES

Desmin

++

AD

17q13

SCN4A

+++

AD

3p21

LQT3

+++ +++

AD AD

7q35 11p15

LQT2 KVLQT1

Sodium channel ␣-subunit Sodium channel ␣-subunit Potassium channel Cardiac potassium channel

Inherited polyneuropathies Friedreich ataxia Familial amyloid neuropathy

++ +

AR AD

9cen-q21 18q11

FA PALB

Acquired neuromuscular disorders

Guillain–Barré syndrome, diphtheria, diabetic neuropathy, alcoholic neuropathy. Inflammatory, endocrine, drug-induced myopathies, infections and infestations

Muscular dystrophies Duchenne/Becker Emery-Dreifuss Facio-scapulo-humeral

Idiopathic dilated cardiomyopathy Desmin-related cardioskeletal myopathy Ion channel muscle diseases Hyperkalemic periodic paralyses Long QT syndromes

Frataxin Transthyretrin

Note: a +++: frequent, ++: rare, +: extremely rare. The nosology and molecular genetics of the neuromuscular diseases is changing rapidly, and the current classification will inevitably require frequent updating. The journal Neuromuscular Disorders (Pergamon Press) provides regular information on genetic aspects.

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determine a hypercontractile state that would directly induce cardiac hypertrophy. The diagnosis of FHC is usually based on ECG and echocardiography (Maron et al., 1998; Bonne et al., 1998). Mutations in another sarcomeric gene, cardiac actin, cause dilated cardiomyopathy in humans. This raises the important issue of whether hypertrophic and dilated cardiomyopathies are inherently independent diseases or whether dilatation is part of the FHC spectrum. The identification of the genetic origin of congenital arrhythmias has enhanced our understanding of these hereditary diseases, as has been the case for the long QT syndromes (LQTS), the Jervell and Lange Nielsen (JLNS) and the Romano–Ward (RWS) syndromes (Maron et al., 1998) (Table 24.2). These syndromes, characterized by prolongation of the QTc interval on the ECG and syncopes or sudden death triggered by stress, are differentiated by their modes of transmission, recessive or dominant, and by the presence or absence of deafness. The discovery of genetic origin of the hereditary arrhythmias will open new perspectives for the management of patients by providing basis for new criteria and novel therapeutics.

Dissection of internal carotid artery and vertebral artery Dissection should be considered whenever a stroke is associated with a notable headache or neck pain or is complicated by Horner’s syndrome or a cranial nerve palsy. The existence of ischemic cranial nerve syndromes has been well demonstrated (Lapresle & Lasjaunias, 1986).Three systems play a role in the vascularization of cranial nerves: the inferolateral trunk (IIIrd, IVth, VIth and V1), most often arising from the internal carotid artery, the middle meningeal system (V2,V3, and VIIth), and the ascending pharyngeal system (IXth to XIIth), both derived from the external carotid artery. Peripheral cranial nerve palsy and Horner’s syndrome caused by internal carotid dissection is rarely observed (see Chap. 51). Palsies of the IXth to XIIth nerves are more frequently found, probably as the result of the compression by an enlarging artery due to mural hematoma. The IIIrd, IVth and Vth (facial pain) nerves are seldom affected by ischemia. Only about one-third of the patients culled from the literature showed concomitant cerebral involvement. Carotid dissection might have been underestimated as a cause of isolated lower cranial nerve palsies (some of the reported Vernet, Villaret, Collet Sicard syndromes) before the advent of magnetic resonance imaging (MRI). The extracranial vertebral artery is the second most common location for a cervicocephalic dissection.

Headache and ischemic stroke are the most frequent symptoms. Vertebral artery dissection can lead to ischemia to the spinal cord or spinal brainstem and cranial nerves (see Chap. 52). On the other hand, tiny pontine lesions can cause isolated (nuclear) neuropathies without other neurologic deficits. These well-placed small pontine infarctions are increasingly reported thanks to their confirmation by MRI, with involvement of the VIth, VIIth and VIIIth nerves (see Chap. 39 and 40).

Vasculitis There have been several proposals for the classification of vasculitis (Ferro, 1998), but all have limitations because of the frequent overlap between different syndromes. In 1994 the Chapel Hill International Consensus Conference proposed names and definitions for selected categories of vasculitis (Jennette & Falk, 1997); however, no diagnostic criteria were suggested. Vasculitis is usually considered as primary and secondary (Table 24.3). Involvement of the peripheral nerves, muscles and CNS occurs with varying frequency and pattern among vasculitis, and therefore the clinical presentation of ‘neurologic’ vasculitis is variable, with CNS symptoms and signs (headaches, meningeal signs, encephalopathy, psychiatric syndromes, dementia, cranial nerve palsies, seizures, strokes), alone or in combination with painful neuropathy and myopathy, multiorgan involvement (purpura, nephritis, arthralgia, abdominal pain), and non-specific systemic symptoms with fever, anorexia and weight loss. Neurological symptoms and stroke may be the inaugural manifestations of vasculitis or may complicate the clinical course of a previously diagnosed case . Vasculitis is a rare cause of stroke, even in the young age groups. Therefore, routine screening of stroke patients for vasculitis is not cost effective (see Chap. 1–3, 7–8, Uncommon Causes for specific entities). If the diagnosis is suspected, a comprehensive medical history and physical examination, appropriate laboratory tests and other ancillary procedures must be performed to assess organ damage. This requires the knowledgeable integration of clinical and laboratory data, both positive and negative. Laboratory assessment for ANCA (cytoplasmic and perinuclear), antinuclear antibodies (ds-DNA, anti-SM, anti-RNP, anti-Ssa/Ro, anti-SSb/La, anticentromere, anti-Scl-70, anti-nRNP, anti-Jo-1, anti-PM-Sd), complement, cryoglobulins, fecal blood, antibodies to hepatitis B and C, rheumatoid factor, azotemia, hematuria, and proteinuria is useful. Either ANCA specificity may occur in a patient with any type of ANCA-associated small-vessel vasculitis; however,

Muscle, peripheral nerve and autonomic changes

Table 24.3. Classification of vasculitis CNS involvementa

Neuro-muscular involvementa

Primary large vessel vasculitis Giant cell arteritis

+++

+++

Primary angiitis of the CNS

+++

Takayasu’s disease

++

Associated autoantibody

Anti-endothelial

Remark

Granulomatous inflammation of the aorta and its branches.

Primary medium-sized-vessel vasculitis Polyarteritis nodosa

++

+++

Hepatitis B

Kawasaki disease

++

Primary small-vessel vasculitis Churg–Strauss syndrome

++

+++

c-ANCA

Asthma and eosinophilia

Wegener’s granulomatosis

++

+++

c-ANCA

Necrotizing glomerulonephritis is common

Microscopic polyangiitis

++

++

c-ANCA

Necrotizing glomerulonephritis and pulmonary capillaritis are common

Henoch–Schönlein purpura

+

Essential cryoglobulinaemia vasculitis

++

Coronary arteries are often involved. Usually occurs in children

Typically involves skin, gut, and glomeruli and is associated with arthralgia ++

Rheumatoid factor Hepatitis C

Cutaneous leukocytoclastic angiitis

Isolated cutaneous angeiitis without systemic vasculitis

Secondary vasculitis Lupus vasculitis

++

+++

ANA, ds-DNA, anti-SM

Rheumatoid vasculitis

++

+++

Rheumatoid factor

Sjögren’s vasculitis

+++

+++

Anti-SSA/Ro

Hypocomplementemic urticarial vasculitis Behcet’s disease

++

+

Goodpasture’s syndrome Serum-sickness vasculitis

+

+

Drug-induced immune-complex vasculitis

++

++

Infection-induced immune-complex

+

+

Note: a +++: frequent, ++: rare, +: extremely rare.

Skin and glomeruli are often involved

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most patients with Wegener’s granulomatosis have cytoplasmic ANCA, whereas most patients with microscopic polyangiitis or Churg–Strauss syndrome have perinuclear ANCA. It is very important to realize that approximately 10% of patients with typical Wegener’s granulomatosis or microscopic polyangiitis have negative assays for ANCA; thus, ANCA negativity does not completely rule out these diseases (Jennette & Falk, 1997; Ferro, 1998). The addition of serologic tests for ANCA to the diagnostic armamentarium provided a positive marker for certain types of pauci-immune small-vessel vasculitis. Testing for ANCA, along with other immunopathologic markers such as vascular IgA deposits and serum cryoglobulins, facilitates the diagnostic categorization of small-vessel vasculitis. Chest and sinus radiographs and computed tomographic scans may reveal occult respiratory tract disease. Nerve conduction studies can document peripheral neuropathy. Evidence of conditions that are known to cause vasculitis, such as drug hypersensitivity, infection, rheumatoid arthritis, systemic lupus erythematosus, cancer, and inflammatory bowel disease, should be sought. Pathological examination of involved tissue, such as skin, muscle, nerve, lung, or kidney, may document small-vessel vasculitis. Immunohistologic evaluation may yield more specific information, such as the presence of IgA-dominant vascular immune deposits indicative of Henoch-Schonlein purpura, or IgM and IgG immune complexes that are consistent with cryoglobulinemic vasculitis. Normal MRI almost excludes intracranial vasculitis (Ferro, 1998). There are, however, no pathognomonic MRI findings in vasculitis. Single or multiple territorial infarcts and hemorrhages and non-specific T2 hyperintense lesions involving the cortex, the basal ganglia and the white-matter can be seen. These lesions are less numerous and periventricular changes are milder than in multiple sclerosis. The angiographic aspects characteristic of vasculitis include multiple arterial occlusions (in particular of the small vessels over the convexity) and segmental stenosis of intracranial vessels, sometimes separated by dilatations (‘sausage’ appearance), avascular areas and intracranial aneurysms. A normal arteriogram does not exclude vasculitis, because vessels under 100–200 ␮m cannot be visualized by this method.

tion with methamphetamine, and other sympathomimetic drugs, heroine, crack and cocaine (see Chap. 17, Uncommon Causes, for specific entities). A careful investigation should be done to rule out endocarditis and angiography should be performed in hemorrhagic strokes to rule out an aneurysm or arteriovenous malformation.

Drug-induced vasculitis

Secondary changes

Although the mechanisms are disputed, there is no doubt that drug abuse increases the incidence of ischemic and hemorrhagic cerebral events, atraumatic multiple neuropathy and rhabdomyolysis. The risk is not confined to any one variety of drug or to a particular route of administration. The condition has been particularly noted in associa-

Other vasculitis A necroziting vasculitis may occur in patients with herpes zoster or neurosyphilis, acquired immunodeficiency syndrome, either directly or due to nonvasculitic etiologies with focal signs of encephalitis (see Chap. 3, Uncommon Causes). It is noteworthy that other meningovascular diseases may induce cerebrovascular events as well as peripheral neuropathies, such as listeriosis (Uldry et al., 1993) and Lyme disease (Kuntzer et al., 1991).

Mitochondrial encephalomyopathies Mutations in mitochondrial DNA (mtDNA) are associated with a number of diseases, in which clinical symptoms reflect a primary defect in tissues with high oxidative demand (Poulton, 1998). In these tissues, such as in muscle, there is a massive proliferation of mitochondria, which clump together in abnormal muscle cells. As the disease progresses, these can be stained to give a characteristic ‘ragged red’ appearance, which may not be evident in the early stage. Immunohistological staining may show decreased cytochrome oxidase (cox) activity. Although primarily affecting muscle, these disorders may also have profound effects on brain, eyes, heart, endocrine organs, liver, kidney, pancreas and blood. In general, single partial deletions of mtDNA are found in isolated patients, in contrast to point mutations in mtDNA, which are usually found to be associated with familial disease. In MELAS patients (see Chap. 44, Uncommon Causes), strokes have been explained by the proliferation of abnormal mitochondria in the smooth muscle and endothelial cells of the small arteries, arterioles of the brain and the pia matter. Other symptoms have to be explained by a combination of abnormal cellular metabolism and capillary angiopathy or cardiogenic emboli due to an associated cardiomyopathy.

Cardiovascular dysfunction Neuroanatomy of cardiovascular regulation The CNS plays a key role in the regulation of autonomic functions. The brainstem, the pons and the hypothalamus

Muscle, peripheral nerve and autonomic changes

are the main levels contributing to the neural control of cardiovascular homeostasis. At each of these brain levels are located integrative sites that are interconnected by afferent and efferent pathways (Lowey & McKellar, 1980). Any lesion involving this complex network may provoke cardiovascular disturbances.

sion. The natural tendency of blood pressure is to decline within a few days in hospital, down to around 170/100 mmHg. Ten days following the acute event, blood pressure is expected to be still elevated in no more than one-third of the patients with poststroke hypertension.

Neurally induced cardiac damage Arterial hypertension in response to acute elevation in intracranial pressure An acute rise in intracranial pressure, for instance, following subarachnoid hemorrhage, may cause severe hypertension with an accompanying bradycardia and occasionally apnea. This life-threatening condition, known as Cushing response, is due to a distorsion of the stretchsensitive area under the floor of the fourth ventricule (Magnus et al., 1977). The distorting force renders the brain stem ischemic, eliciting a marked sympathetic discharge. It is generally associated with a fatal outcome unless the raised intracranial pressure can be effectively lowered.

Blood pressure course in patients with acute stroke Blood pressure is abnormally elevated in approximately 70 to 80% of patients admitted to the hospital for acute stroke (Talman, 1985; Powers, 1993). Several mechanisms might be responsible for this phenomenon. They include an activation of sympathetic nerve activity secondary to the brain damage, an impaired autoregulatory vasodilatation and decreased perfusion in the ischemic border zone of the cerebral lesion. Pre-existing hypertension is a strong predictor of elevated blood pressure on admission. The patients with increased blood pressure after stroke are at higher risk of early mortality, but the severity of hypertension on admission and that of the clinical outcome are not related. Lesions involving the nucleus of solitary tract typically have hypertension and an enhanced blood pressure lability. Yet, in most cases, the occurrence of hypertension after stroke does not allow attribution of the elevation of blood pressure to a welldefined localization of the brain damage. In patients with ischemic stroke, worsening of neurological deficits might occur if blood pressure is lowered too drastically during the first few days after the event. This is mainly because cerebral autoregulation is impaired during the early phase of stroke. Cerebral blood flow could therefore become unsufficient if blood pressure is lowered below a critical level. Blood pressure achieves often very high levels immediately following intracerebral hemorrhage. Restoring blood pressure to previous levels is appealing in this condition to avoid early rebleeding but, as with acute ischemic stroke, it is recommended to lower blood pressure cautiously only in patients with extreme hyperten-

Electrocardiographic (ECG) changes consistent with myocardial ischemia or necrosis are commonly seen after stroke, even in the absence of established coronary heart disease (Talman, 1985; Valeriano & Elson, 1993). Abnormalities on ECG can be found in 60 to 70% of patients with intracerebral hemorrhage and 15 to 40% of cases with ischemic stroke. Increased activity of cardiac enzymes, indicating cardio-myocytolysis, is also frequently seen after stroke. ECG changes in patients with acute cerebrovascular events are associated with an increased mortality even in the absence of coronary lesion. The ECG and enzyme changes may revert partially or totally to normal. They are thought to be the consequence of focal myocardial necrosis. Another frequent complication of stroke is cardiac arrhythmia, with an estimated incidence of more than 75%. Most rhythm problems are benign but the risk of developing severe ventricular arrhythmia is increased about fourfold after stroke, representing a major cause of sudden death. Rhythm disturbances should therefore be treated aggressively when required. Of note is that the QT interval is frequently prolonged in stroke patients. This repolarization abnormality is often associated with potentially malignant polymorphic ventricular tachycardia such as the ‘torsades de pointes’. ECG abnormalities, as well as myocardial cell necrosis encountered after stroke are due most likely to a centrally mediated increase in sympathetic nerve activity. The diffuse, focal areas of myocardial necrosis are similar to those observed in patients with pheochromocytoma and very high catecholamine concentrations in the circulation. Parasympathetic overactiviy may, however, prevail in some patients, accounting for the occurence of sinus node suppression or atrio-ventricular blocks.

Neurogenic pulmonary edema A protein-rich alveolar pulmonary edema can develop rapidly in patients with intracranial hypertension or subarachnoid hemorrhage (Simon, 1993). Theoretically, a massive and sudden systemic hypertension may increase left atrial pressure and, by this way, pulmonary capillary hydrostatic pressure, to a point that pulmonary edema occurs. Neurogenic pulmonary edema can, however, occur even if blood pressure is normal, showing that the

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hemodynamic response to systemic hypertension is not the causal factor. Sympathetic overactivity is probably an important factor. Thus, sympathetic stimulation increases pulmonary capillary permeability to proteins and might cause, by contracting the capacitive system, a shift of blood to the pulmonary circulation.

Hypotension Strokes may occasionally produce hypotension. The lesions responsible for the fall in blood pressure are located principally in the rostral, ventrolateral medulla (Talman, 1985).

Muscle atrophy contralateral to cerebral lesions We have attempted to demonstrate that muscle atrophy .. may be seen in hemiplegia .., and that this atrophy is more frequent than previously thought (E. Brissaud, 1879).

Hemiplegic atrophy in humans is a long-established observation made as early as 1850 by Romberg and then by Charcot (for review, see Brissaud, 1879). Lesions in the cerebral hemisphere interrupting descending projections to the brainstem and spinal motoneurons are associated with a variety of structural changes in the spinal cord and muscles. These changes have been seen in both small cortical lesions, lacunes, and large lesions of the hemispheres. Histologic studies of hemiplegic muscles have shown type II muscle fibre atrophy and increased complexity of endplates, suggestive of collateral sprouting. In some instances, type I fibre hypertrophy was also seen (for review, see Brown & Snow, 1990; Brown, 1984). Atrophy of muscles contralateral to cerebral lesions or pyramidal tract sections is also well documented in primates. The appearance of denervation supersensitivity in hemiparetic muscles, i.e. fibrillation potentials seen in electromyographic studies, was described by Goldkamp and then by several other authors (for review, see Brown & Snow, 1990); they suggest that ‘transsynaptic degeneration’ of motor neurons may explain the development of fibrillation and contribute to the development of atrophy. The afferent axons’ influence on the postsynaptic cell is due partly to transmitter-mediated mechanisms and partly to trophic ones that may modulate voltage-dependent ion channels or regulate gene expression (for review, see Clarke & Clarke, 1996). Physiologically, up to 50% losses of functioning spinal motor units were observed on the weakened side within 2 months of the cerebrovascular event (McComas, 1995). Fibrillation potentials are accompanied by reduced maximum motor-response size and are seen as early as the

second and third week and may last many weeks thereafter. Reports vary as to the frequency of this denervation activity, but it was found in the hemiplegic muscles in as much as two-thirds of the patients in one study (Brown & Snow, 1990). The denervation activity is most common in more distal muscles (for review, see Brown & Snow, 1990; Brown, 1984). In one single-fibre EMG study, it was demonstrated that increased jitter may persist over years (Chang, 1998). The distribution of the fibrillation and the normal conduction studies suggest that trauma of peripheral nerves is not a causal factor. The possibility that descending motor pathways other than the corticospinal tract might also exert a trophic influence on spinal motoneurons is suggested by the severe losses of motor units, which may occur after transection of the spinal cord (for review, see McComas, 1995). Since cord transection in animals is often not followed by histological evidence of motoneuron loss, it is likely that, in humans, the motoneurons are still present, albeit in a dysfunctional state. The changes observed in human muscles might also be secondary to inactivation of motoneurons and disuse. Close correlation between the number of motor units and the time, size and location of the cerebrovascular events is needed to evaluate the influence of hemidenervation on the outcome of these patients.

Peripheral nerve compression Moderate to severe paresis of contralateral muscles as the result of an acute cerebrovascular event may induce trauma to various components of the peripheral nerves. External pressure is probably the cause of ulnar and peroneal neuropathies in certain bedridden patients. Neither the reason why the patient is confined to bed, nor the severity of his illness, are essential factors (Mumenthaler & Schliak, 1991). Bedridden patients who develop these neuropathies exhibit often a constellation of weight loss, underlying polyneuropathy and pressure on hard hospital mattresses or bed railings. In patients without underlying factors it is not known whether a neuropathy may develop acutely or later in the course of the weakness. We have estimated the relative proportion of denervated nerve fibres, surviving but blocked fibres and fibres affected by conduction slowing alone, by quantifying the axon loss and conduction blocks in both peroneal and ulnar nerves in 20 weakened sides with the unaffected limb as control. We have found reduced conduction velocity in 5% of the cases with no conduction blocking within the 15 days following the onset of the cerebrovascular event (T. Kuntzer, unpublished data). Management designed to unload the ulnar

Muscle, peripheral nerve and autonomic changes

and peroneal nerves is thus important to avoid multiple and repeated pressures on these nerves that may induce later muscle atrophy.

Reflex sympathetic dystrophy Reflex sympathetic dystrophy (RSD) is a progressive illness characterized by pain, edema, autonomic dyfunction, movement disorder and trophic changes. The illness evolves in stages and there is no consensus for its diagnosis. In any stage of RSD, the symptom complex may be dissociated: the autonomic dysfunction may be minimal while the patient suffers great pain. Conversely, patients may have severe livedo reticularis and circulating abnormalities of muscle and skin with little pain and no movement abnormality. RSD in patients with cerebrovascular events is well recognized but its prevalence is not known. In these patients, the RSD symptoms may be difficult to recognize early as patients may be unable to express or localize pain, underlying the role of early proximal and distal movings of the involved extremity. Sensitization of neurons in the central nociceptive pathway has been proposed as a key element in pathophysiologic mechanisms of this disorder (Schott, 1998).

Disorders of micturition, fecal continence and sexual changes Normal bladder function requires the integrated activity of the somatic and autonomic pathways that extend from the frontal lobes and the pons to the sacral spinal cord (Kuntzer, 1998). The neural control of micturition in humans is essentially similar to what is established in cats and other animals (Fowler, 1998). The symptoms and findings in neurological impairment of urinary bladder function depend more on the site of the lesion than on the specific disease. Cerebral disorders can affect bladder function by causing loss of control over the transition between filling and voiding states. This leads to loss of inhibition and facilitation of the detrusor reflex, resulting in urgency, incontinence, hesitancy, or more rarely, retention because of a failure of voluntary initiation of the voiding reflex. After studying patients with cerebral lesions, it was deduced that the cortical loci controlling micturition are in the superomedial part of the frontal lobes in the region of the anterior cingulate and superior frontal gyri. Also important are white-matter tracts that run to and from the genu of the corpus callosum. In stroke syndromes, incontinence is said to be common, but transient in about half of

the patients. Incontinence can be a continuing problem for about 15% of the patients at 1 year poststroke stage and is associated with a poor outcome with severe functional loss. The incontinence with incomplete emptying of the bladder is also related to other factors rather than directly to the brain damage, such as inability to walk, speech disorders, and mental changes. The pontine or brainstem micturition centre lies in the dorsal tegmentum of the pons, and abnormalities affecting this area give rise to disorders of voiding usually with other neurological deficits, but occasionally a lesion can be sufficiently dorsal and discrete to produce predominantly a defect of bladder function. An internuclear ophthalmoplegia is a frequent additional sign, due to the proximity of the median longitudinal fasciculus. Any spinal cord lesion involving the lateral columns bilaterally, such as trauma, multiple sclerosis, transverse myelitis, vitamin B12 deficiency, cervical spondylotic myelopathy, tethered cord syndrome will also result in urinary disturbance. Here, the bladder is more or less isolated from the pontine micturition centre, and the coordination of the voiding act itself, as well as its inhibition, initiation, and completion, is impaired, and the normal coordinated relaxation of the sphincter that precedes and accompanies a detrusor contraction is lost, so that the disorder of ‘detrusor–sphincter dyssynergia’ occurs. Retention alone is uncommon, except in the early phase of spinal shock. Thus in a chronic spinal lesion, abnormal voiding is common, accompanied by detrusor hyperreflexia, with urgency and frequency, difficulty of voluntary initiation or interrupted stream and incomplete emptying. Because of the relative levels at which the innervation of the lower limbs and the bladder arise, it is unusual to have a lesion between the pons and the sacral part of the cord giving rise to a neurogenic bladder that does not also produce other neurological signs in the lower limbs. A possible exception might be expected from a conus or cauda equina lesion affecting only S2–S4. It is clear that the human has the ability of responding to the conscious sensation of rectal filling by retaining fecal matter, and defecation is initiated as a voluntary act. Its cortical representation is mapped but the higher-level processes concerned with suppression and initiation of reflex and voluntary defecation in human are unknown (Swash & Henry, 1991). The descending pathways through brainstem and spinal cord are thought to be closely related to those subserving micturition. Control of defecation or continence is lost in diffuse lesions of the brain, especially those associated with frontal or bifrontal dysfunction. Fecal incontinence needs symptomatic management to prevent fecal impaction with overflow and to maintain

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adequate stool consistency. Cerebrovascular events are generally followed by some important alterations in sexual life, concerning both behavior and the subject’s feeling about sexuality. Clinical features, as well as the side of hemispheric lesion, do not seem to play a crucial role (Boldrini et al. 1991).

Sweating disorders and temperature regulation Asymmetric sweating has been reported to be a common phenomenon after both brain and pontine vascular lesions, reflecting sympathetic hyperfunction on the paretic side of the body (Korpelainen et al., 1995). This asymmetry seems to be a long-lasting consequence of autonomic failure occuring in the majority of patients with hemispheral brain infarction. Hyperhydrosis correlates with the severity of paresis and may be significant in estimating recovery of the patients. Interruption of a descending sympathoinhibitory system might cause excessive sweating. Unilateral sweating dysfunction in patients with Horner’s syndrome is discussed elsewhere. Bilateral lesions in the hypothalamus or its pathways seem necessary to produce thermic dysregulation, both hyper- and hypothermia as seen in patients with pontine hemorrhages. Failure of the homeostatic mechanisms that generate and conserve heat, and lesions of the pyretic or antipyretic areas are known in animals but not in humans (Andersen & Moser, 1995).

iReferencesi Andersen, P. & Moser, E.I. (1995). Brain temperature and hippocampal function. Hippocampus, 5, 491–8. Bendixen, B.H., Younger, D.S., Hair, L.S. et al. (1992). Cholesterol emboli neuropathy. Neurology, 42, 428–30. Boldrini, P., Basaglia, N. & Calanca, M.C. (1991). Sexual changes in hemiparetic patients. Archives of Physical Medicine and Rehabilitation, 72, 202–7. Bonne, G., Carrier, L., Richard, P., Hainque, B. & Schwartz, K. (1998). Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circulation Research, 83, 580–93. Brissaud, E. (1879). De l’atrophie musculaire dans l’hémiplégie. Revue mensuelle de Médecine et Chirurgie, 3, 616–25. Brown, W.F. (1984). Electromyography and disorders of the central nervous system. In The Physiological and Technical Basis of Electromyography, pp. 459–89. Boston: Butterworth. Brown, W.F. & Snow, R. (1990). Denervation in hemiplegic muscles. Stroke, 21, 1700–4. Chang, C.W. (1998). Evident trans-synaptic degeneration of motor

neurons after stroke: a study of neuromuscular jitter by axonal microstimulation. Electroencephalography and Clinical Neurophysiology, 109, 199–202. Clarke, P.G. & Clarke, S. (1996). Nineteenth century research on naturally occurring cell death and related phenomena. Anatomy and Embryology, 193, 81–99. Ferro, J.M. (1998). Vasculitis of the central nervous system. Journal of Neurology, 245, 766–76. Fowler, C.J. (1998). Brain activation during micturition. Brain, 121, 2031–2. Francioli, P. (1997). Complications of infective endocarditis. In Infections of the Central Nervous System, eds. W.M. Scheld, R.J. Whitley & D.T. Durack, pp. 523–53. Philadelphia: LippincottRaven. Jennette, J.C. & Falk, R.J. (1997). Small-vessel vasculitis. New England Journal of Medicine, 337, 1512–13. Korpelainen, J.T., Sotaniemi, K.A. & Myllyla, V.V. (1995). Asymmetrical skin temperature in ischemic stroke. Stroke, 26, 1543–7. Kuntzer, T. (1998). Neuro-urological and anal sphincter dysfunction. In Textbook of Neurology, ed. J. Bogousslavsky & M. Fisher, pp. 277–86. Boston: Butterworth–Heinemann. Kuntzer, T., Bogousslavsky, J., Miklossy, J., Steck, A.J., Janzer R. & Regli, F. (1991). Borrelia rhombencephalomyelopathy. Archives of Neurology, 48, 832–6. Lapresle, J. & Lasjaunias, P. (1986). Cranial nerve ischemic arterial syndromes. Brain, 109, 207–15. Lowey, A.D. & Mckellar, S. (1980). The neuroanatomical basis of central cardiovascular control. Federation Proceedings, 39, 2495–503. McComas, A.J. (1995). Motor unit estimation: anxieties and achievements. Muscle and Nerve, 18, 369–79. Magnus, O., Koster, M. & Van der Drift, J.H.A. (1977). Cerebral mechanisms and neurogenic hypertension in man, with special reference to baroreceptor control. Progress in Brain Research, 47, 199–218. Maron, B.J., Moller, J.H., Seidman, C.E. et al. (1998). Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association. Circulation, 98, 1460–71. Mumenthaler, M. & Schliak, H. (1991). Peripheral Nerve Lesions, Stuttgart: Thieme Verlag. Pamphlett, R. & Walsh, J. (1989). Infective endocarditis with inflammatory lesions in the peripheral nervous system. Acta Neuropathologica, 78, 101–4. Poulton, J. (1998). Mitochondrial myopathies and related disorders. In Neuromuscular Disorders: Clinical and Molecular Genetics, ed. A.E.H. Emery, pp. 203–16. Chichester: John Wiley. Powers, W.J. (1993). Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology, 43, 461–7. Schott, G.D. (1998). Interrupting the sympathetic outflow in cau-

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salgia and reflex sympathetic dystrophy. British Medical Journal, 316, 792–3. Simon, R.P. (1993). Neurogenic pulmonary edema. Neurocardiology, 11, 309–23. Swash, M. & Henry, M. (1991). The colon and anal sphincters. In Clinical Neurology, ed. M. Swash & J. Oxburg, pp. 614–23. London: Churchill Livingstone. Swash, M. & Schwartz, M.S. (1996). Cardiac involvement in neuromuscular disease. In Handbook of Muscle Disease, ed. R.J.M. Lane, pp. 655–62. New York: Marcel Dekker.

Talman, W.T. (1985). Cardiovascular regulation and lesions of the central nervous system. Annals of Neurology, 18, 1–12. Uldry, P.A. Kuntzer, T., Bogousslavsky, J. et al. (1993). Early symptoms and outcome of Listeria monocytogenes rhombencephalitis: 14 adult cases. Journal of Neurology, 240, 235–42. Valeriano, J. & Elson, J. (1993). Electrocardiographic changes in central nervous system disease. Neurocardiology, 11, 257–72. Wilbourn, A.J. & Levin, K.H. (1993). Ischemic neuropathy. In Clinical Electromyography, ed. W.F. Brown & C.F. Bolton, pp. 369–90. London, Ontario: Butterworth–Heinemann.

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Dysarthria Paola Santalucia and Edward Feldmann Brown University School of Medicine, Rhode Island Hospital, Providence, USA

Introduction Dysarthria is a pure motor disorder of speech, occurring in 24–29% of patients with cerebral ischemia (Arboix et al., 1990; Melo et al., 1992). It is characterized by dysfunction of the structures implicated in the control, initiation and coordination of speech output: lips, tongue, jaw, and palate, which are innervated by the facial, glossopharyngeal, vagal, and hypoglossal nerves. The dysarthric patient exhibits intact cortical language mechanisms and comprehension, is able to understand perfectly what he hears and has no difficulty in reading and writing, although his speech is inarticulate and may be unintelligible. Lesions that cause dysarthria may occur in one of several locations along the neuraxis (Schiff et al., 1983; Yorkston et al., 1988). The upper and/or lower motor neuron may be involved as well as the extrapyramidal system from the basal ganglia to the cerebellum. Each region may receive blood supply from more than one artery. The examination of the patient with dysarthria is used to identify the specific type of abnormality. It is conducted by listening to the patient’s speech during ordinary conversation, after testwords, or in the attempt of rapid repetition of lingual, labial, and guttural consonants. The clinical features of the dysarthria and the associated neurological findings identify the responsible lesion. Dysarthria has also been described as an isolated symptom (Ozaki et al., 1986; Caplan et al., 1990); in such circumstances the responsible lesion is suggested by the characteristics of the dysarthria itself and by imaging studies. Defects in articulation may be subdivided into several types: upper motor neuron or spastic (pseudobulbar), lower motor neuron (neuromuscular), cerebellar–ataxic, hypo- and hyperkinetic. This chapter reviews the clinical features of dysarthria resulting from stroke and its associated neurologic signs. The classification and features of

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the different types of dysarthria, along with their associated neurological signs, are listed in Tables 25.1–25.6. These tables were developed by analysing 38 features of speech and voice for each subclass of dysarthria, and have been adapted from Darley et al. (1969a). According to the authors, dysarthria comprises a group of speech disorders resulting from disturbances in muscular control. Because there has been damage to the central or peripheral nervous system, some degree of weakness, slowness, incoordination, or altered muscle tone characterizes the activity of the speech mechanism. The muscles involved in respiration and phonation (sound production at the laryngeal level) may also be affected. Prosody (musical or melodic characteristics of speech including stress and intonation pattern) may also be disrupted (Darley et al., 1969a). A description of these features is provided in Table 25.7. The characteristics of each type of dysarthria are listed in rank order, with the most prominent feature listed first. Although any individual feature may occur in more than one class of dysarthria, Darley and colleagues identified clusters of speech abnormalities that conform to the presumed disorder of neuromuscular physiology seen with each subclass of dysarthria. These clusters of speech dysfunction provide each dysarthria subclass with unique clinical features (Darley et al., 1969b).

Upper motor neuron lesions The corticospinal fibres originate from the motor cortex (area 4), the supplementary motor area (area 6), and part of the parietal lobe (areas 1, 3, 5, and 7). They converge in the corona radiata and descend through the posterior limb of the internal capsule, crus cerebri, basis pontis, and medulla oblongata. Within the corticospinal tract the fibres are somatotopically arranged. However, overlapping

Dysarthria

may occur. Fibres to the cranial nerve nuclei are located more anteriorly near the genu, followed by the cervical, thoracic, lumbar and sacral segments located successively more dorsally. In the brainstem, the corticospinal tract is accompanied by the corticobulbar tracts, which are distributed to the motor nuclei of the cranial nerves, ipsilaterally and contralaterally. As the corticospinal and corticobulbar fibres have a similar origin and the motor nuclei of the brainstem are the homologues of the motor nuclei of the spinal cord, the term upper motor neuron may be applied to both of these systems. Ischemic lesions of the upper motor neuron system may be unilateral or bilateral, cortical or subcortical. Cortical strokes that produce dysarthria may involve the territory of the anterior and middle cerebral arteries (Ropper, 1987). Subcortical dysarthria may be seen following strokes occurring in the territory of anterior, middle or posterior cerebral arteries, as these vessels nourish the corticopontine and corticobulbar fibres in their subcortical locations (Bogousslavsky & Regli, 1990; Sohn et al., 1990; Ichicawa & Yasutumi, 1991). The dysarthria produced by lesions of the upper motor neuron, whether cortical or subcortical, has been classified as spastic dysarthria. Lesions that involve both corticobulbar tracts result in a syndrome known as spastic bulbar (pseudobulbar) palsy. Since the bulbar muscles on each side are innervated by both motor cortices, there may be no impairment in speech or swallowing following a unilateral corticobulbar lesion. The patient may have had a clinically silent vascular lesion in the past, affecting the corticobulbar fibres on one side; should another stroke then occur, involving the other corticobulbar tract, the patient immediately becomes dysphagic, dysphonic and anarthric or dysarthric, often with paresis of the tongue and facial muscles (Adams & Victor, 1993). Unilateral upper motor neuron lesions may cause supranuclear dysarthria, with or without swallowing difficulty and lower facial paresis, without significant motor weakness. This is usually transient. Considerable improvement occurs in 6 weeks to 6 months. Bilateral strokes involving the pyramidal tract may produce supranuclear palsy without significant motor weakness; this is usually a permanent deficit, although the patient may experience some improvement (Darley et al., 1969b). In individual case reports of patients with dysarthria due to supratentorial strokes, the lesions were located in or near the anterior limb, (Ozaki et al, 1986; Ichikawa et al., 1991), the genu (Ozaki et al. 1986; Bogousslavsky & Regli 1990; Ichikawa et al., 1991), the posterior limb of the internal capsule (Decroix et al., 1986; Combarros et al., 1992), corona radiata and lower motor cortex (Tonkonogy & Goodglass,

1981; Ichikawa et al., 1991). However, even when the site of the lesion is obvious from imaging studies, it may not be possible to reach a definitive conclusion concerning the involvement or sparing of individual corticospinal or corticobulbar fibre subpopulations due to the close proximity of the fibre tracts (Urban et al., 1997). Various headings, such as isolated facial palsy, pure or isolated dysarthria (Ozaki et al., 1986; Ichikawa et al., 1991), and ‘capsular genu syndrome’ (Bogousslavsky & Regli, 1990) have been used to describe these case reports. In a series of 13 patients, all complaining of dysarthria, most of them had a combination of dysarthria and facial paresis, due to corticolingual and corticofacial tract involvement, given the proximity of the two tracts during their entire course from the motor cortex to the brainstem. The degree of dysarthria was usually mild or moderate and none of them had unintelligible speech. The facial paresis was also mild and transient, likely to be unnoticed by conventional neurological testing, especially when the patients were not examined early enough. Therefore, the authors concluded that pure dysarthria and isolated facial paresis syndrome, if they exist, were quite rare. Pure dysarthria and isolated facial paresis syndrome may be considered the two extremes of this syndrome, which is attributed to small unilateral strokes involving the corticobulbar tract but sparing the corticospinal fibres in the regions of the corona radiata, basal ganglia–internal capsule and subcortical–cortical motor regions (Kim, 1994). Bogousslavsky et al. reported six patients with acute stroke limited to the genu of the internal capsule. The constant feature was the combination of contralateral faciolingual paresis with dysarthria. The authors assumed, therefore, that the location of the corticopontine and corticobulbar fibres within the internal capsule can be considered quite constant and that faciolingual paresis, whether or not associated with masseter, palatal, pharyngeal, laryngeal, or hand weakness, is highly suggestive of stroke limited to the genu of the contralateral internal capsule (Bogousslavsky & Regli, 1990). Damasio et al. investigated the anatomo-clinical correlation in six cases of atypical aphasia and five cases of speech disturbance without aphasia. In all but two cases there were lesions consistently involving three structures: (i) the anterior limb of the internal capsule, (ii) the head of the caudate nucleus, (iii) the putamen. They concluded: (i) right-handed patients with left-sided lesions that involve the anterior limb of the internal capsule, the head of the caudate, and the putamen had aphasia, right hemiparesis, and often dysarthria and dysprosody; (ii) a right-handed patient with a lesion that failed to involve the previously mentioned areas but did compromise more posterior

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Table 25.1. Features of spastic (upper motor neuron) dysarthria listed in order of importance, and associated neurological signs Speech features Imprecise consonants Monopitch Reduced stress Harsh voice Monoloudness Low pitch Slow rate Hypernasality Strained voice Short phrases Associated signs Spasticity Hyper-reflexia Babinski signs Tongue, face, hand weakness Gaze preferences Hemianopia Aphasia Neglect Hemiparesis Source: Adapted from Darley et al. (1969a).

aspects of the internal capsule, corona radiata, caudate nucleus, and putamen had dysarthria and right hemiparesis but no aphasia; (iii) right-handed patients with righthemisphere lesions, involving the anterior limb of the internal capsule, head of the caudate, and putamen had dysarthia and left hemiparesis but not aphasia. (Damasio et al., 1982). The association of dysarthria with either contralateral hemiparesis or brachial monoparesis has been described in a series of 49 patients with acute paramedian pontine infarcts in the territory of the paramedian branches of the basilar artery. Regardless of the topographic distribution of the lesions within the pons (paramedian basal, paramedian basal–tegmental or paramedian tegmental), the most frequent motor abnormality was dysarthria (Kataoka et al., 1997). A stereotyped combination of dysarthia and clumsiness of one hand, the dysarthria-clumsy hand syndrome, has been described by Fisher in a series of 20 patients (Fisher, 1967). Usually no prodromal symptoms precede the rapid onset of neurologic deficit. The clinical picture consists of dysarthria, central weakness of one side of the face and

tongue, dysphagia, clumsiness and mild weakness of the ipsilateral hand (Wanger et al., 1979). The features of dysarthria produced by supranuclear lesions are shown in Table 25.1. The speech is slow and labored, the word articulation is imprecise, especially with complicated groups of consonants. The voice quality is harsh and strangled, the voice pitch is low and monotonous. These features can be attributed to the reduced range, speed, and force of movement and hypertonus typical of upper motor neuron disorders (Darley et al, 1969a). Cortical and subcortical dysarthria can be differentiated by their associated neurological findings. Dysarthria following cortical strokes may be associated with aphasia, gaze preference or neglect. Features shared by dysarthria due to cortical and subcortical strokes include facial, tongue, or hand weakness, hemiparesis, hyperreflexia, spasticity, hemianopia, and Babinski sign. These findings may occur as a result of a lesion in either the left or the right hemisphere.

Lower motor neuron lesions Lower motor neuron dysarthria can result from lesions of the motor nuclei of the cranial nerves VII, IX, X, and XII, following ischemia in the vascular territory of the vertebrobasilar system and its branches (Adams & Victor, 1993). The seventh cranial or facial nerve is mainly a motor nerve supplying all the muscles concerned with facial expression. The ninth cranial or glossopharyngeal nerve has a somatic efferent component that contributes to the motor innervation of the striated musculature of the pharynx, mainly of the stylopharyngeus, which elevates the pharynx. The tenth cranial or vagus nerve has two important branches: the pharyngeal branch, which innervates the muscles of the palate and pharynx, and the laryngeal branch, which innervates the muscles of the larynx. It also conveys sensory information from the pharyngeal and laryngeal mucosa. The twelfth cranial or hypoglossal nerve is a pure motor nerve which supplies the musculature of the tongue. The dysarthria associated with lower motor neuron lesions has been classified as flaccid dysarthria (Table 25.2). It is a neuromuscular disorder due to weakness of the articulatory muscles. The most prominent feature is the nasality of the speech. Inhalation and exhalation are audible, giving speech a breathy quality. Air wastage produces short phrases. The articulation of vowels and consonants is imprecise, the lingual and labial consonants are not pronounced at all. Associated neurological signs are face, tongue, palatal weakness, wasting and fasciculations

Dysarthria

Table 25.2. Features of flaccid (lower motor neuron) dysarthria listed in order of importance, and associated neurological signs

Table 25.3. Features of combined spastic and flaccid dysarthria listed in order of importance, and associated neurological signs

Speech features Hypernasality Imprecise consonants Breathy voice Monopitch

Speech features Imprecise consonants Hypernasality Harsh voice Slow rate Monopitch Short phrases Distorted vowels Low pitch Monoloudness Excess and equal stress Prolonged intervals

Associated signs Face, tongue, palatal weakness Fasciculations Dysphagia Dysphonia Atrophy of the tongue Limb weakness, sensory loss Ataxia Extraocular movement abnormalities Source: Adapted from Darley et al. (1969a).

of the tongue, dysphonia, and dysphagia (Darley et al., 1969a; Adams & Victor, 1993). Other brainstem and long tract signs may also occur, due to the involvement of other brainstem structures. These signs include upper motor limb weakness and sensory loss, as well as extraocular movement abnormalities and cerebellar dysfunctions.

Combined upper and lower motor neuron lesions Ischemic lesions in the vertebrobasilar territory can result in both, upper and lower motor neuron involvement. In such instances the dysarthria has been classified as mixed, carrying the features of the spastic and flaccid types. Table 25.3 shows how mixed dysarthria not only combines the features of upper and lower motor neuron lesions, but also creates a unique pattern of motor speech dysfunction. The voice quality is harsh, the voice pitch is low and monotonous as in upper motor neuron disease, the speech is hypernasal; vowel and consonant articulation is imprecise as in lower motor neuron lesions. Overall the speech is poorly intelligible. Voice quality, articulation, prosody and the respiration are markedly altered, making it difficult for the patient to produce even short phrases. The associated neurological signs of mixed dysarthria include those discussed in the section on flaccid dysarthria, as the responsible lesions occur within the vertebrobasilar arterial territory.

Associated signs Tongue, face, hand weakness Atrophy Spasticity Hyporeflexia Hemianopia Fasciculations Dysphagia Dysphonia Extraocular abnormalities Source: Adapted from Darley et al. (1969a).

Cerebellar lesions Ataxic dysarthria is the result of lesions occurring in the territory of the superior cerebellar and posterior inferior cerebellar arteries. The paravermal zone of the rostral cerebellum (lobulus simplex and semilunaris superior), corresponding to the territory of the medial branch of the superior cerebellar artery, has been identified as the most frequently involved in cerebellar dysarthria. Therefore, dysarthria has been described as a characteristic sign of rostral cerebellar involvement, as vertigo is for caudal cerebellar involvement (Lechtenberg & Gilman, 1978). In some other reports, dysarthria has been observed in patients with small infarcts of the anterior part of the rostral cerebellum, the territory of the lateral branch of the superior cerebellar artery, and not the paravermal zone (Amarenco et al., 1991). The precise anatomic location of the lesions associated with cerebellar dysarthria is still controversial. The speech disorder related to cerebellar lesions may take one of two forms, it can be either a slow, slurring

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Table 25.4. Features of ataxic (cerebellar) dysarthria listed in order of importance, and associated neurological signs Speech features Imprecise consonants Excess and equal stress Irregular articulatory breaks Distorted vowels Harsh voice Associated signs Dysdiadochokinesia Dysmetria Nystagmus Hypotonia Gait or truncal ataxia Source: Adapted from Darley et al. (1969a).

Table 25.5. Features of hypokinetic (parkinsonian type) dysarthria listed in order of importance, and associated neurological signs Speech features Monopitch Reduced stress Monoloudness Imprecise consonants Inappropriate silence Short rushes Harsh voice Breathy voice Associated signs Resting tremor Masked face Paucity of movement

dysarthria, or a scanning, ataxic dysarthria, so called because the words are broken up into syllables (Table 25.4). Scanning dysarthria is uniquely cerebellar, the principal abnormalities being slowness of speech, slurring, monotony, and unnatural separation of the syllables of words (scanning). The coordination of speech and of respiration is disordered. There may not be enough breath to express certain words or syllables, and others are expressed with greater force than intended (explosive speech) (Adams & Victor, 1993). Speech proceeds at an artificial, measured pace. An alteration in the prosody places undue stress on words and syllables that usually are unstressed. The neuromuscular basis for this pattern of dysarthria is believed to include inaccurate direction and rhythm of movement, slow movement, ataxia, and flaccidity (Darley et al., 1969a). Neurological deficits associated with the dysarthria of cerebellar stroke include dysdiadochokinesia, dysmetria, nystagmus, hypotonia and gait or truncal ataxia (Adams & Victor, 1993).

Source: Adapted from Darley et al. (1969a).

Extrapyramidal lesions

Dysarthria resulting from a lesion in one of these structures is classified as either hypokinetic (Table 25.5) or hyperkinetic (Table 25.6) (Darley et al, 1969a; Espir & Rose, 1985). In hypokinetic dysarthria the voice is low pitched and monotonous. Loudness variation, from the explosive utterance of words to the point where speech is almost inaudible, is characteristic. Speech is short and rushed, with unclear articulation, followed by periods of inappropriate silence. The underlying neuromuscular dysfunction includes reduced range of individual and repetitive movements and weakness of movements (Darley et al., 1969a). An example of hypokinetic dysarthria is the speech distur-

Dysarthria can follow ischemic lesions of the extrapyramidal system occurring in the vascular territories of the deep penetrating branches of the anterior and middle cerebral arteries. The deep penetrator from the anterior cerebral artery is the medial striate artery, also known as Heubner’s artery. The penetrators from the middle cerebral artery are the lenticulostriate arteries. The grey nuclei of the extrapyramidal system, caudate nucleus, putamen, and globus pallidum, are believed to be the sites of lesions producing dysarthria (Adams & Victor, 1993).

Table 25.6. Features of hyperkinetic (choreic or dystonictype) dysarthria listed in order of importance, and associated neurological signs Speech features Imprecise consonants Distorted vowels Harsh voice Irregular articulatory breaks Strained voice Monopitch Monoloudness Associated signs Choreic: random, unsustained irregular movements Dystonic: distorted posturing of the head, neck, trunk, or proximal limbs Source: Adapted from Darley et al. (1969a).

Dysarthria

Table 25.7. Features of speech dysfunction seen in dysarthria Dimension

Description

Imprecise consonants

Consonants lack clarity and sharpness Monotone voice lacking inflectional changes Reduction of proper emphasis pattern Monotone of loudness Level of voice sound is low Speed of speech is low Excessively nasal-sounding voice Sounds pronounced with great effort Phrases shortened, as though speaker is out of breath Weak, continuous, breathy voice Nasal emission of air stream Excess stress on parts of speech that are not usually stressed Nonsystematic breakdown of articulation Vowels sound are distorted throughout their duration Rough, raspy voice Silent intervals occur inappropriately Short rushes of speech separated by pauses Rate alternates from fast to slow

Monopitch Reduced stress Monoloudness Low pitch Slow rate Hypernasality Strained voice Short phrases Breathy voice Nasal emission Excess and equal stress Irregular articulatory breaks Distorted vowels Harsh voice Inappropriate silence Short rushes Variable rate

Source: Adapted from Darley et al. (1969a).

bance found in Parkinson’s disease. The associated neurological findings are tremor, masked facies, and paucity of movements. In hyperkinetic dysarthria, speech is loud, poorly coordinated with respiration, and interrupted by anticipations and/or involuntary bodily and facial movements. This results in unpredictable voice halting, with disintegration of articulation and prosody (Table 25.7). There is excessive variation of loudness resulting from an altered breathing cycle. The neuromuscular basis includes inaccurate, unsustained, and irregular rhythm of movement, slowness of movement, reduced force of movement and sustained or spasmodic hypertonus (Darley et al., 1969a). The random, unsustained and irregular movements of chorea or the distorted posturing of the head, neck, trunk and proximal limbs of dystonia are the neurological findings associated with hyperkinetic dysarthria.

iReferencesi Adams, R. & Victor, M. (1993). Principles of Neurology, 5th edn. pp. 683–93. New York: McGraw-Hill. Amarenco, P., Roullet, E., Goujon, C., Cheron, F., Hauw, J-J. & Bousser, M.G.(1991). Infarction in anterior rostral cerebellum (the territory of the lateral branch of the superior cerebellar artery). Neurology, 41, 253–8. Arboix, A., Marti-Vilalta, J.L. & Garcia, J.H. (1990). Clinical study of 227 patients with lacunar infarcts. Stroke, 21, 842–7. Bogousslavsky, J. & Regli, F. (1990). Capsular genu syndrome. Neurology, 40, 1499–502. Caplan, L.R., Schmahmann, J.D., Kase, C.S. et al. (1990). Caudate infarcts. Archives of Neurology, 47, 133–43. Combarros, O., Diez, C., Cano, J. & Berciano, J. (1992). Ataxic hemiparesis with cheiro-oral syndrome in capsular infarction (Letter). Journal of Neurology, Neurosurgery and Psychiatry, 55, 859–60. Damasio, A.R., Damasio, H., Rizzo, M., Varney, N. & Gersh, F. (1982). Aphasia with nonhemorrhagic lesions in the basal ganglia and internal capsule. Archives of Neurology, 39, 15–20. Darley, F.L., Aronson, A.E. & Brown, J.R. (1969a). Differential diagnostic patterns of dysarthria. Journal of Speech and Hearing Research, 12, 246–69. Darley, F.L., Aronson, A.E. & Brown, J.R. (1969b). Cluster of deviant speech dimensions in the dysarthrias. Journal of Speech and Hearing Research, 12, 462–96. Decroix, J.P., Gravelau, P., Asson, M. & Cambier, J. (1986). Infarction in the territory of the anterior choroidal artery. Brain, 109, 1071–85. Espir, N.T. & Rose, F.C. (1985). The Basic Neurology of Speech and Language, 3rd edn, pp. 47–76. London: Blackwell. Fisher, C.M. (1967). A lacunar stroke. The dysarthria-clumsy hand syndrome. Neurology, 17, 614–17. Fisher, C.M. (1982). Lacunar strokes and infarcts: a review. Neurology, 32, 871–6. Ichikawa, K. & Yasutumi, K. (1991). Clinical anatomic study of pure dysarthria. Stroke, 22, 809–12. Kataoka, S., Hori, A., Shirakawa, T. & Hirose, G. (1997). Paramedian pontine infarction. Neurological/topographical correlation. Stroke, 28, 809–15. Kim, J.S. (1994). Pure dysarthria, isolated facial paresis, or dysarthria-facial paresis syndrome. Stroke, 25, 1994–8. Lechtenberg, R. & Gilman, S. (1978). Speech disorders in cerebellar disease. Annals of Neurology, 3, 285–90. Melo, T.P., Bogousslavsky, J., Van Melle, G. & Regli, F. (1992). Pure motor stroke: a reappraisal. Neurology, 42, 789–98. Ozaki, I., Baba, M., Narita, S., Mtsunaga, M. & Takebe, K. (1986). Pure dysarthria due to anterior internal capsule and/or corona radiata infarction. Journal of Neurology, Neurosurgery and Psychiatry, 49, 1453–7. Ropper, A.H. (1987). Severe dysarthria with right hemisphere stroke. Neurology, 37,1061–3. Schiff, H.B., Alexander, M.P., Naeser, M.A. & Galaburda, A.M. (1983). Aphemia: clinical–anatomic correlations. Archives of Neurology, 40, 720–7.

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Sohn, Y., Lee, B.I., Sunwoo, N., Kim, K. W. & Suh, J.H. (1990). Effect of capsular infarct size on clinical presentation of stroke. Stroke, 21, 1258–61. Urban, P.P., Hopf, H.C., Fleischer, S., Zorowka, P.G. & Müller-Forell, H. (1997). Impaired cortico-bulbar tract function in dysarthria due to hemispheric stroke. Functional testing using transcranial magnetic stimulation. Brain, 120, 1077–84.

Tonkonogy, J. & Goodglass, H. (1981). Language function, foot of the third frontal gyrus, and rolandic operculum. Archives of Neurology, 38, 486–90. Wanger, S. (1979). Lacunar strokes. Primary Care, 6(4), 757–69. Yorkston, K., Beukelman, D. & Beli, K. (1988). Clinical Management of the Dysarthric Speaker, p.63. Boston: College Hill Press.

26

Dysphagia and aspiration syndromes Mark J. Alberts1 and Jennifer Horner-Catt2 1 Department of Medicine, Duke University Medical Center, Durham NC, USA and 2Department of Speech and Language Therapy, University of Canterbury, Christchurch, New Zealand

Introduction Dysphagia (abnormal swallowing causing dysfunction) and aspiration (passage of material below the level of the true vocal folds) are being recognized as significant complications of several different stroke syndromes. According to a recent federal report, about 6.2 million Americans over age 60 have swallowing problems (AHCPR, 1999a), with stroke alone accounting for about 250 000 to 550 000 new cases of dysphagia each year (AHCPR, 1999b). When considering patients with dysphagia or aspiration, it is important to understand that, while many stroke patients may have oropharyngeal dysphagia, not all such patients aspirate. However, all patients who exhibit prandial aspiration have oropharyngeal dysphagia (by definition). This chapter will review the anatomy and physiology of normal and abnormal oropharyngeal swallowing, the occurrence of dysphagia/aspiration in various stroke syndromes, and the treatment of patients with dysphagia after an acute stroke.

Anatomy and physiology of swallowing Swallowing is a complex function, with both voluntary and reflexive components. Normal adults swallow 600–1000 times per day. Probably no more than 10% of all swallows are voluntary; the remainder are reflexive. Voluntary swallowing is initiated by activation of the cortical motor strip (probably in the area controlling pharyngeal function) or stimulation of the supplemental motor area (precentral gyrus) (Larson et al., 1980; Logemann, 1983). These cortical areas are bilaterally represented. The reflexive portion of a swallow is controlled by the bilateral ‘swallowing centres’ of the brainstem which encompass the nucleus solitarius and nucleus ambiguus (Miller, 1982; Miller, 1986). Several

Table 26.1. Cranial and spinal nerves involved in swallowing Cranial nerves

Spinal nerves

V VII IX X XI XII

C1 C2 C3 C4/diaphragm

Trigeminal Facial Glossopharnygeal Vagus Spinal accessory Hypoglossal

cranial nerves and spinal nerves are involved in oropharyngeal swallowing (see Table 26.1), in addition to over 100 muscles of the head and neck (Bosma et al., 1986). The pharyngeal structures involved in swallowing are depicted in Fig. 26.1. There are four phases or stages of swallowing: (i) oral preparatory, (ii) reflex initiation, (iii) pharyngeal–laryngeal, and (iv) esophageal. These phases are not distinct, but overlap and complement one another. Together, they effect a patterned (though not stereotyped) response to ingested material. The oral phase prepares food for swallowing by chewing, organizing, and propelling the bolus back into the pharynx. In the reflex initiation phase, the sensory stimulation of the bolus triggers the swallow reflex. The pharyngeal–laryngeal phase involves a complex series of motor events: closure of the vocal folds and larynx (to prevent aspiration), elevation of the larynx, downward propulsion of the bolus by the tongue, and relaxation of the upper esophageal sphincter. Lastly, the esophageal phase involves peristaltic movement of the bolus into the stomach (Kahrilas, 1993; Miller, 1986). This chapter does not address esophageal dysphagia (Castell & Donner, 1987; Perlman & Schulze-Delrieu, 1997; Zaino &

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Fig. 26.1. Line drawing showing some of the key structures involved in swallowing.

Beneventano, 1997), or the risks and complications of gastrostomy tubes (Cogen et al., 1991; Mitchell et al., 1997; Grant et al., 1998).

Pathophysiology of dysphagia and aspiration From an anatomic perspective, lesions of upper motor neurons, specific cranial or spinal nerves and muscles, various pharyngeal structures, or the esophagus can produce dysphagia, with or without aspiration. Because most of the structures described above subserve more than one function, lesions in them may produce findings in addition to dysphagia. Some typical findings include an absent or asymmetric gag reflex, abnormal palatal movement, dysarthria, dysphonia, oral apraxia, and a weak cough (Buchholz, 1987). Lingual discoordinaton has been reported in 19% of acute stroke patients and may cause abnormal bolus preparation (Daniels et al., 1999). Sensory input from the oral pharynx is probably very important for initiation of swallowing, and appears to be attenuated or delayed in many stroke patients (Miller, 1986). Recent work using an air pulse stimulus to the pharynx confirms laryn-

gopharyngeal sensory discrimination deficits in stroke patients with dysphagia. (Aviv et al., 1998). Aspiration is one of the most worrisome consequences of dysphagia, since it can lead to pneumonia, sepsis, asphyxiation, and death. Aspiration can occur before, during, or after swallowing. Severe dysphagia, even without aspiration, can lead to malnutrition. When aspiration occurs before swallowing, it is usually due to premature leakage of material from the mouth when the larynx is open. Aspiration during swallowing is often due to delayed or incomplete reflexive glottic or laryngeal closure. In cases of aspiration after swallowing, material is retained in the pharynx (often in the piriform sinuses) due to weakness of the pharyngeal constrictors. This material can be aspirated when the larynx opens immediately following a swallow (Jones & Donner, 1988). In some cases aspiration causes a reflexive cough, which serves as an indicator that aspiration is taking place (Castell & Donner, 1987). However, some severely affected patients (particularly those lethargic or sedated) may lack a protective cough reflex, and others may frequently aspirate small amounts of material without coughing. Such cases are termed ‘silent’ aspiration, since the absence of a cough or choking belies the occurrence of aspiration (Huxley et al., 1978; Linden & Siebens 1983). This is a dangerous scenario, as patients may silently aspirate large amounts of material, or repeatedly aspirate small amounts of material, potentially leading to pulmonary complications.

Diagnosis of dysphagia and aspiration Due to the occult nature of aspiration in some cases, a thorough and complete history and examination of the lower cranial nerves by an experienced clinician is mandatory in all stroke patients (see Table 26.2). Performance of Logemann’s four-point swallowing test may help identify abnormalities that increase the risk of aspiration (Logemann, 1983). DePippo and colleagues have advocated a 3 ounce swallowing test as a sensitive technique for detecting aspiration in stroke patients (DePippo et al., 1992). A low threshold for performing a videofluoroscopic swallowing (VFSS) examination (Jones & Donner, 1988; Logemann, 1985) is appropriate, since a high percentage of acute stroke patients will experience silent aspiration that can be confirmed only by radiologic study (see below) (Horner & Massey, 1988a). Figure 26.2 shows several radiographs from swallowing studies with various amounts of aspiration. Recently, many groups have begun using fibreoptic

Dysphagia and aspiration syndromes

Table 26.2. Bedside swallowing evaluation Historical data

Subjective symptoms

Objective findings

Dietary texture Feeding mode Dentition Respiratory status Gastrointestinal disease

Choking Strangling Coughing Sticking Poor initiation Drooling Congestion

Level of consciousness Cognitive status Speech function Oral apraxia Voice characteristics Laryngeal excursion Voluntary and reflexive cough Ability to swallow graduated liquid boluses Cranial nerve findings (motor and sensory) (V, VII, IX, X, XI, XII)

endoscopic evaluation of swallowing (FEES) as a noninvasive tool to assess swallowing function in stroke patients with dysphagia (Langmore & McCulloch, 1997). When used by well-trained health-care providers, the FEES technique can be used to detect aspiration. Its advantages over VFSS are that it can be performed at the bedside, avoids exposure to radiation, is well tolerated by patients, and can be repeated serially. (Leder et al., 1998) A large study of FEES in 400 patients found that it could be used reliably to determine aspiration risk and the need for dietary modifications. (Leder, 1998). Significantly, the Agency for Health Care Policy and Research concluded recently that neither videofluoroscopy nor fibreoptic endoscopy is a ‘gold standard’ for detection of aspiration. Furthermore, based on available evidence about acute poststroke dysphagia, the AHCPR observed that ‘[f]ull bedside exams can have sensitivities for aspiration near 80 percent – with specificities near 70 percent,’ indicating that ‘these exams are capable of detecting most aspiration, even silent aspiration.’ The AHCPR emphasized the need for further research. (AHCPR, 1999b). There has been much research to define clinical characteristics that can be used to identify patients likely to have dysphagia and aspiration. A study by Horner and colleagues (Horner et al., 1988b) found that 17 of 24 (71%) patients who aspirated had bilateral cranial nerve signs, while 7 of 24 (29%) patients with unilateral cranial nerve signs also aspirated. Barer (1989) found that aspiration was strongly correlated with language impairment and facial weakness. Gordon and colleagues (Gordon et al., 1987) reported that patients with dysphagia tended to have more severe strokes than patients without dysphagia, but there was significant heterogeneity between the two groups. More dysphagic patients had cranial nerve dysfunction or upper motor neuron facial weakness than non-dysphagic patients. In a study of patients with bilateral strokes, Horner and

colleagues (Horner et al., 1993) found that an abnormal cough and an abnormal gag were independently associated with aspiration. Using a logistic model, they reported that an abnormal cough and gag predicted an aspiration frequency of 85%, while a normal cough and gag reduced aspiration frequency to 14%. A study by Logemann failed to find a strong association between the presence or absence of a gag reflex and swallowing function (Logemann & Lazarus, 1987). Taken together, these studies show a general trend towards more frequent or severe dysphagia in patients with more cranial nerve abnormalities, although considerable overlap still exists between normal and dysphagic patients in this regard. In a large study of 128 hospital-referred patients with stroke, clinical and videofluoroscopic features that were predictors of severe dysphagia and complications were delayed oral transit, delayed or absent swallow reflex, and penetration (Mann et al., 1999). Other studies report changes in oropharyngeal function with advancing age that may contribute to dysphagia after stroke. (Tracy et al., 1989; Logemann, 1990; Robbins et al., 1992). Notably, Langmore and colleagues studied a large cohort of elderly subjects who were hospitalized or in nursing homes and found that feeding dependence, decayed teeth, more than one medical diagnosis, number of medications and smoking were predictors of aspiration pneumonia. Dysphagia was among the risk factors but was not sufficient to cause pneumonia unless other risk factors were present (Murray et al., 1996; Langmore et al., 1998) Therefore, the presence or absence of a particular clinical finding or isolated swallowing abnormality cannot be used as a definitive indicator of swallowing status or aspiration risk (AHCPR, 1999b). Instead, these findings should be used to estimate the risk of dysphagia and aspiration in populations of stroke patients. It is likely that cumulative deficits are more predictive of aspiration than any one particular deficit.

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(a )

(b)

(c)

(d ) Fig. 26.2. Pictures of videofluoroscopy swallowing studies, taken in the lateral projection. Radiopaque material appears dark in these pictures. (a) Barium is seen coating the epiglottis (small black arrow) and in the pyriform sinuses (white arrow). A trace amount of aspirated material is seen in the trachea (large black arrow). (b) Barium is seen in the vallecular space (white arrow) and in the subglottic space (small black arrow). A moderate amount of aspirated material is seen in the trachea (large black arrow). (c) The epiglottis is seen (white arrow) with barium above and below it. A large amount of aspirated material is seen in the trachea (black arrow). (d) A large piece of unmasticated, barium-coated cookie is seen in the vallecular space (large black arrow). Some material is seen in the pyriform sinuses (small black arrow). This is a dangerous scenario, as it can lead to aspiration of large amounts of food.

Incidence of dysphagia and aspiration Studies of the incidence of dysphagia and aspiration following stroke are highly dependent upon the methods of patient accrual, the population under study, and the use of a large barium bolus in the swallowing study. There are several large studies in the literature that prospectively investigated either consecutive or predefined groups of stroke patients who were not specifically referred for speech/ swallowing evaluations because of a suspected swallowing problem. Gordon and colleagues (Gordon et

al., 1987) found that 41 of 91 (45%) stroke patients had dysphagia on admission. A study by Wade and Hewer (1987) reported dysphagia in 194 of 452 (43%) stroke patients. These two studies used clinical, not radiologic assessments of swallowing function. Robbins and Levine (1988) noted dismotility or aspiration in 50% and 37% of stroke patients (respectively) with lesions in different hemispheres (location is discussed in more detail below). They used detailed radiologic techniques to identify and quantify dysphagia. Another large study by Barer (1989) examined 357 stroke patients and found dysphagia in

Dysphagia and aspiration syndromes

30%. In this study, dysphagia was defined as difficulty swallowing a mouthful of water; detailed radiologic evaluations were not performed. Among stroke patients with dysphagia, one study found mild dysfunction in 39%, moderate dysfunction in 50%, and severe dysphagia in 11% (Chen et al., 1990). Two additional large studies of dysphagia after stroke have been reported. In one study, 121 consecutive stroke patients admitted within 24 hours of onset were evaluated prospectively. This study found that 51% of patients had evidence of a dysphagia on admission (Smithard et. al., 1997). Another large study of 128 stroke patients also found that on admission 51% had some evidence of dysphagia (Mann et al., 1999). Considering all of these studies together, it seems reasonable to conclude that some degree of dysphagia will be present in approximately 50% of all stroke patients. This makes dysphagia a common as well as a significant abnormality. Since aspiration is the most serious acute complication of dysphagia, how frequent is aspiration after acute stroke? One detailed study by Robbins and colleagues (Robbins et al., 1993) found radiologic aspiration in 8 of 40 (20%) patients with middle cerebral artery territory strokes. Gordon and colleagues (Gordon et al., 1987) found evidence for a possible aspiration pneumonia in 11 of 86 (13%) patients with hemispheric stroke. Other studies have reported higher frequencies of aspiration, but most preselected patients on the basis of swallowing abnormality or pneumonia (Martin et al., 1994). The issue of silent aspiration is of interest, since these patients may be difficult to identify clinically. Using videofluoroscopic examinations, Horner and Massey (1988a) found that 8 of 21 (38%) patients with dysphagia had silent aspiration. Another study of 121 stroke patients found videofluoroscopic evidence of aspiration in 22% of cases (Smithard et al., 1997). Also of note in this study was the finding that a repeat examination at 1 month showed that eight additional patients had developed aspiration not previously identified. According to the Agency for Health Care Policy and Research in a 1999 evidence-based report, an estimated ‘43 to 54 percent of stroke patients with dysphagia experience aspiration, approximately 37 percent of these patients will develop pneumonia, and 3.8 percent of these patients will die of pneumonia if they are not part of a dysphagia diagnosis and treatment program.’ (AHCPR, 1999b). From these data it can be concluded that a significant minority of stroke patients with dysphagia will experience aspiration (symptomatic or silent), and a subset of those patients will develop aspiration pneumonia. A commonly asked question is ‘How much aspiration is significant?’ Although this issue has not been formally

studied, our clinical experience in acute stroke patients suggests that trace aspiration of liquids is rarely associated with aspiration pneumonia or other serious problems. However, aspiration of viscous or particulate food may have more serious consequences (Chokshi et al., 1986). Since stroke syndromes can be slowly progressive (particularly with brainstem strokes), the clinician should be alert to the possibility of worsening of a stable stroke with a concomitant increase in the frequency or severity of aspiration.

Dysphagia and lesion location There continues to be considerable debate in the literature concerning the location of strokes responsible for dysphagia. The key issues are (i) side of hemispheric lesion, (ii) unilateral hemispheric vs. bilateral hemispheric vs. brainstem, and (iii) radiologic lesions. Two studies by Robbins and colleagues (Robbins et al., 1993; Robbins & Levine, 1988) reported that left cortical strokes were associated with impaired oral stage function and apraxia, while right cortical strokes were characterized by more aspiration and pharyngeal abnormalities. These studies used small barium boluses, and the findings have not been replicated by other investigators. Gordon and colleagues (Gordon et al., 1987) did not find any significant difference in dysphagia frequency between right and left hemispheric strokes. Veis and Logemann (1985) did not find a significantly different rate of aspiration between right and left hemispheric strokes. Evatt et al. (1993) reported a non-significant difference in aspiration between 35 right and 35 left hemispheric stroke patients. Based on the available studies, there is no convincing clinical data to support the theory that aspiration or dysphagia are more likely to occur with right vs. left hemispheric strokes. A recent study used neurophysiologic tests to study the pathogenesis of dysphagia in patients with unilateral hemispheric lesions. The study investigated electromyographic responses after transcranial magneto-electric stimulation of affected and unaffected hemispheres in stroke patients. A surprising finding was that the presence of dysphagia was related to the magnitude of the pharyngeal motor response in the unaffected hemisphere. The stimulation of the unaffected hemisphere produced smaller pharyngeal responses in dysphagic patients than in nondysphagic patients. This study, if confirmed by additional ones, may provide important insights into the pathophysiology of dysphagia (Hamdy et al., 1997). It is commonly thought that patients with brainstem

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strokes are more likely to have dysphagia and aspiration than patients with hemispheric strokes. However, the literature supporting this association is quite limited. One prospective study has assessed the risk of aspiration in brainstem strokes, and found that four of five patients had dysphagia (Gordon et al., 1987). Most of the other prospective studies included patients with only hemispheric strokes. Horner and colleagues (Horner et al., 1991) reported 23 patients with brainstem strokes who had a brain CT or MRI, and a videofluoroscopic swallowing study. They found aspiration in 65% of these patients. There were no clear associations between stroke type (small vessel vs. large vessel) or stroke side (unilateral vs. bilateral) and the occurrence of aspiration. Two clinical findings, vocal fold paralysis and severe dysarthria, were strongly associated with aspiration in this group of patients (Horner et al., 1991). From these limited data it appears that dysphagia and aspiration are quite common with brainstem strokes. There are several studies in the literature that have attempted to correlate specific radiographic lesions with swallowing function after stroke. Since brain MRI is more sensitive than CT for detecting small lesions and brainstem strokes, we have chosen to review only those studies using MRI. All of these studies are retrospective, and patients were selected because they had both an MRI and swallowing evaluation. These studies did not distinguish between acute and chronic radiographic lesions. One study by Alberts et al. (1992) found that 21 of 38 (55%) stroke patients had aspiration. Patients with only small vessel strokes had a lower incidence of aspiration (3 of 14, 21%) than patients with large vessel strokes (3 of 4, 75%) or patients with both large and small vessel strokes (15 of 20, 75%). There was no clear association between aspiration status and lesion location. While this study showed significantly less frequent aspiration with only small vessel strokes, this group still had a significant (over 20%) occurrence of aspiration. A small study of four patients with unilateral cortical strokes found that three out of four patients with lesions in the anterior insular cortex had dysphagia (Daniels & Foundas, 1997). However with such small numbers in most studies, it is difficult to draw any meaningful conclusions. A larger study by the same group found that among 54 male stroke patients, aspiration was associated more with anterior and subcortical strokes than with posterior locations (Daniels & Foundas, 1999). One case report documents dysphagia as the sole manifestation of bilateral strokes (Celifarco et al., 1990). The patient had the acute onset of dysphagia. He had a normal cranial nerve examination. The past history was significant

for a left body stroke one year earlier, without any swallowing problems. An MRI showed an old stroke in the deep white-matter on the right, and an acute stroke in the left deep white-matter. A swallow study showed marked retention within the valleculae and piriform sinuses, and a pseudodiverticulum in the upper esophagus. Whether his dysphagia was due to the new stroke, or a combination of the new and chronic stroke, is unclear. A study by Levine and colleagues (Levine et al., 1992) found a correlation between periventricular white matter lesions and prolonged oropharyngeal swallowing in normal aged individuals. There was no indication that these individuals had symptomatic dysphagia or aspiration, however. On balance, there is little evidence to support a dogmatic conclusion that lesions of a certain size or location are always (or never) associated with the occurrence of dysphagia/aspiration in stroke patients. Some general trends can be identified: dysphagia and aspiration appear to be more frequent in large vessel strokes and brainstem strokes. However, these findings should not be substituted for a thorough clinical evaluation of swallowing function in stroke patients.

Treatment of dysphagia and prevention of aspiration The management of dysphagia in stroke patients is based in three principles: prevent aspiration, ensure good nutrition, and education. A broad outline of our approach can be seen in Table 26.3. The prevention of aspiration is possible in the vast majority of stroke patients. We recommend that acute stroke patients be NPO for 24 hours, followed by a detailed clinical speech/swallowing evaluation. Patients with gross dysphagia on bedside testing, or those with normal or near normal examinations probably do not require an instrumental swallowing examination. However, patients with some clinical swallowing abnormalities or with multiple risk factors for aspiration are advised to undergo a definitive instrumental swallowing study. For patients found to have some dysphagia or at high risk for aspiration, we recommend a modified diet of thickened liquids and soft solids – thin liquids are avoided. The diet is customized for the patient’s chewing and swallowing ability. If severe dysphagia is present, a Dubhoff feeding tube is placed temporarily. These tubes are dislodged frequently, often become plugged, and are generally poorly tolerated by patients and nurses. In general, we only use them for a maximum of 7–10 days. If, after that time, the patient has not exhibited significant improvement in swal-

Dysphagia and aspiration syndromes

Table 26.3. Principles of oropharyngeal dysphagia management Methods

Principles

Diagnostic evaluation

A thorough evaluation is prerequisite to effective care. The main components are a thorough oropharyngeal and esophageal history, a bedside examination using replicable and sensitive tests, and selective use of oropharyngeal videofluoroscopy. Aspiration prevention is vital to successful patient outcomes. These precautions include individualized oral feeding plans, pertaining either to conservative therapeutic feedings or to mealtime textural and postural compensations. In addition, the nursing staff is advised to monitor all dysphagic patients for signs of possible aspiration: excessive coughing during or between meals; wet-gurgly, congested voice or lungs during or between meals; temperature (fever spikes); decreased alertness; noncardiac chest pain; dehydration (input–output and blood tests); changes in vital signs; patient complaints. In the absence of food or saliva, the swallow reflex will be absent or profoundly diminished. Given ingestible stimuli, the swallow reflex will approximate its normal frequency. Therefore, direct treatment involves swallow stimulation with actual food and liquid as soon as possible after the stroke. Bolus texture and bolus size must be tailored to each individual patient to assure safety and comfort. In the acute phase of recovery, direct treatment is accompanied by the compensatory techniques when the latter have been shown to be both helpful and necessary. Indirect treatment may be beneficial for some patients. Indirect treatment involves sensorimotor stimulation of the jaw, lips, tongue, and the oropharyngeal port. Proponents of indirect treatments (e.g. thermal stimulation and oral exercises) assume that effects will generalize to naturalistic swallowing. Nonoral nutritional methods may be necessary on a temporary or permanent basis, as replacement for, or in addition to, oral feeding. Dubhoff or nasogastric tube feedings are temporary solutions, usually used for 7–10 days and never more than 30 days. Gastrostomy or jejunostomy, though not risk free, offer the advantage of optimal hydration, nutrition, and medication delivery during the recovery from poststroke dysphagia. Compensatory techniques seek to minimize the effects of oropharyngeal dysphagia while allowing the patient to eat. Postural compensation: compensatory techniques involve individualized changes in head and neck posture designed to improve efficiency and safety of bolus transit from the mouth through the upper esophageal sphincter, taking advantage of the effect of gravity on bolus movement. Bolus-size compensation: the pharyngeal spaces can hold ½ to 1 teaspoon of material. Maintaining small boluses helps patients minimize the potentially harmful effects of delayed swallowing and post-swallow residue. Textural compensation: use of ‘safe textures’ minimizes aspiration by tailoring the viscosity, evenness, and moistness of foods to the oropharyngeal speed, strength, and control parameters of each patient. Glottal closure and laryngeal excursion: This category of compensatory techniques focuses on laryngeal excursion and closure, e.g. Mendelsohn’s manoeuvre, supraglottic swallow, and super-supraglottic swallow.

Aspiration precautions

Direct treatment (oral feeding)

Indirect treatment

Parenteral nutrition

Compensatory techniques

lowing function, we recommend placement of a gastrostomy tube. The ‘G-tube’ tends to be better tolerated by patients, and allows for ease of feeding and medication delivery. Thermal stimulation has been advocated to improve swallowing function, although its efficacy is

unproven at present (Lama Lazzara et al., 1986; Rosenbek et al., 1991, 1996b, 1998). An expanded listing of these interventions and other useful techniques is provided in Table 26.4. Ensuring adequate nutrition is important for acutely ill,

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Table 26.4. Summary of techniques used for prandial aspiration and other poststroke swallowing disorders (in alphabetical order) Technique

References

Definition

Biofeedback

Bryant (1991; Huckabee & Cannito, 1999)

Use of electromyography as an adjunct to other procedures designed to improve swallowing speed and force.

Dietary texture modifications

Coster & Schwartz (1987), Curran & Groher (1990), Langmore (1991), Martin (1991), O’Gara (1990)

Aspiration-risk-reduction diets match dietary textures to the cause, pattern, and severity of the dysphagia. Modifications: oral diets are modified with regard to liquid viscosity and solid-food evenness, moistness, and ease of mastication. Close monitoring by a nutritional specialist is imperative to assure adequate hydration and nutrition. Upper motor neuron poststroke dysphagia: typically, the dysphagia diet will include thickened liquids and moist, evenly textured foods, gradually upgraded from puree to ground to soft/regular foods, with inclusion of thin liquids only after adequate recovery of the propulsive force of the tongue in concert with laryngeal closure. Lower motor neuron poststroke dysphagia: typically, the dysphagia diet begins with small boluses of iced, thin liquids and thickened liquids, with advancement of food textures only after recovery of a reliable swallow reflex and adequate pharyngeal peristalsis.

Laryngeal adduction exercises (effort-closure techniques)

Aronson (1990)

Designed for patients with vocal-fold paralysis, these exercises involve ‘capitalizing on the effort closure reflex by means of grunting, controlled coughing, laughing, pushing, and lifting’ (p. 340).

Mendelsohn’s manoeuvre

Lazarus et al. (1993), Logemann & Kahrilas (1990)

This manoeuvre is designed to increase the extent and duration of upper esophageal sphincter (UES) opening by prolonging maximal laryngeal elevation during the swallow.

Oral sensorimotor exercises

Logemann (1986)

These include, for example, ‘resistance exercises and range-ofmotion exercises to improve [tongue-to-palate] contact, anterior–posterior movement, and ability to lateralize material, or they may be designed to improve fine control in shaping of the tongue in order to hold the bolus together and prevent it from entering the pharynx’ (p. 36)

Postural modifications

Logemann et al. (1989), Logemann (1986), Logemann & Kahrilas (1990)

Postural modifications optimize the direction and speed of bolus transit. The timing of aspiration may suggest different postural manoeuvres: Aspiration before the swallow (due to oral weakness): neck flexion during oral preparation and then neck extension at the point of reflex initiation. Aspiration during the swallow (due to delayed swallow): forward neck flexion to enlarge the vallecular space and thereby slow the bolus transit. Aspiration after the swallow (due to pharyngeal residue): neck extension or supine position during swallowing (in select cases).

Super-supraglottic swallow

Lazarus et al. (1993)

‘This technique requires breath holding with increased effort, resulting in laryngeal vestibule closure and supraglottic airway protection by means of tilting the arytenoids to contact the epiglottic case’ (p. 419).

Supraglottic swallow

Lazarus et al. (1993), Logemann & Kahrilas (1990)

Also termed ‘voluntary airway protection’, the patient is instructed to: (a) inhale, (b) hold breath, (c) swallow, (d) cough.’

Dysphagia and aspiration syndromes

Table 26.4 (cont.) Technique

References

Definition

Surgical techniques

Baredes (1988), Butcher (1982), Sacks et al. (1988)

For chronic laryngeal paralysis causing dysphonia and aspiration and/or incomplete relaxation of the upper esophageal sphincter, techniques include (i) removal of tracheostomy, (ii) removal of tracheostomy plus myotomy, (iii) reinnervation of the vocal folds, (iv) in the most severe cases, epiglottic flap, vocal-fold suture, and tracheoesophageal bypass, (v) myotomy, and (vi) procedures for chronic glottic insufficiency (Teflon injection, arytenoid medialization, etc.).

Thermal stimulation

Lama Lazzara et al. (1986), Rosenbek et al. (1991), (1996b), (1998)

In this procedure, ‘the [dental] mirror is placed in ice in order to make it cold, and it is then put in contact in a stroking motion with the anterior faucial arch. After five or six contacts on each side of the oral cavity at the faucial arches, the patient is given a small amount of material, usualy a cold, carbonated beverage, and asked to swallow. The contact of the mirror to the faucial arch does not trigger a swallow. When the patient initiates the swallow after the stimulation, the reflex should trigger more rapidly’ (Logemann, 1986, p. 36).

Valsalva manoeuvre

Bryant (1991)

This technique is described as a ‘hard swallow’ and is used to increase strength of the pharyngeal swallow and to clear pharyngeal cavities of residual postswallow pooling.

hospitalized patients. Many stroke patients may be dehydrated or may not have eaten since the onset of their stroke. A variety of dietary supplements (e.g. Ensure, Jevity, Sustecal) along with specially formulated dysphagia diets can be used to provide adequate nutrition. Additional fluids, either IV or via tube, are often required to avoid dehydration. Education of the patient, family, and staff about methods to avoid aspiration is critical to a successful outcome. Instructional videotapes, printed material, and meetings with swallowing staff and dietary personnel can enhance compliance with a swallowing management plan. The efficacy of any of these interventions has not been firmly established (Langmore & Miller, 1994; Miller & Langmore, 1994). In a prospective study, DePippo et al. (1993) found no difference in the occurrence of medical complications among groups of stroke patients given different levels of dysphagia treatment. However, this study did not include a placebo group, and the median admission time was 4 weeks after stroke. The rate of aspiration pneumonia in this study was 7.8%. Using a multidisciplinary approach in a Stroke Unit, Alberts et al. (1991) reported that the incidence of aspiration pneumonia could be reduced to 3.5% in a group of acute stroke patients. The

rates of aspiration pneumonia in both the DePippo and Alberts studies are substantially lower than the 12–15% rate seen in other studies, suggesting some efficacy for these interventions. Another study by Odderson and colleagues (Odderson & McKenna, 1993) using a multidisciplinary team approach found a 38.7% reduction in the number of aspiration pneumonias, and reduced the length of stay from 17.5 to 12.8 days. Huckabee and Cannito (1999) included electromyography biofeedback in the treatment of ten patients with chronic dysphagia after brainstem stroke and reported significant improvement in eight patients. A modest sized prospective randomized trial of dysphagic stroke patients was reported several years ago. The trial consisted of 30 patients with persistent dysphagia 14 days after stroke onset. Sixteen were randomized to placement of a gastrostomy tube and 14 to feeding with a nasogastric tube. Mortality at 6 weeks was significantly lower in the gastrostomy tube group (12%) compared to the nasogastric group (57%). In addition, the group treated with a gastrostomy tube had increased feeding efficiency, increased serum albumin levels and earlier discharge from the hospital (Norton et al., 1996). While it is difficult to draw conclusions from a relatively small randomized trial, this

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does support the clinical practice at our medical center as well as others. Stroke patients with significant dysphagia persisting longer than 7–10 days after stroke onset are candidates for early gastrostomy placement, particularly if they have failed to show evidence of improvement during that time period. In considering interventions for dysphagia and aspiration after stroke, it is important to understand the natural history of these disorders. This has been addressed by several recent large studies. One study found that about half of the patients with dysphagia had essentially total resolution within the first seven days. Approximately 90% showed resolution over the first 6 months (Smithard et al., 1997). These findings were similar to those of another study of 128 stroke patients, which found that 87% of such patients were using a normal diet 6 months after stroke. However, approximately 50% of the patients who initially had dysphagia had persistent evidence of swallowing abnormalities by videofluoroscopic study at six months (Mann et al., 1999). Another study of 126 patients treated with a PEG after a stroke found that 28% died in hospital, most commonly due to aspiration pneumonia (James et al., 1998). So, while overall the prognosis is fairly good for such patients, continued vigilance is certainly required in a significant subset. These studies provide the basis for future prospective, randomized trials that can definitively address the issue of stroke outcomes with or without dysphagia treatment programs. In this era of cost-effective health-care delivery, a focus on efficacious preventative therapies seems justified.

Conclusion Dysphagia is a common and important consequence of stroke. It can occur in many different types of strokes, but appears most common with large vessel and brainstem strokes. An organized proactive routine for diagnosis, along with a multidisciplinary approach for treatment, are essential for successful care of the dysphagic stroke patient.

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Murray, J., Langmore, S.E., Ginsberg, S. & Dostie, A. (1996). The significance of accumulated oropharyngeal secretions and swallowing frequency in predicting aspiration. Dysphagia, 11, 99–103. Norton, B., Hamer-Ward, M., Donnelly, M.T. (1996). A randomized prospective comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding after acute dysphagic stroke. British Medical Journal, 312 (7022), 13–16. Odderson, I. & McKenna, B. (1993). A model for management of patients with stroke during the acute phase. Outcome and economic implications. Stroke, 24, 1823–7. O’Gara, J. (1990). Dietary adjustments and nutritional therapy during treatment for oral-pharyngeal dysphagia. Dysphagia, 4, 209–12. Perlman, A.L. & Schulze-Delrieu, K. (eds.) (1997). Deglutition and its Disorders: Anatomy, Physiology, Clinical Diagnosis, and Management. San Diego: Singular. Robbins, J. & Levine, R. (1988). Swallowing after unilateral stroke of the cerebral cortex: preliminary experience. Dysphagia, 3, 11–17. Robbins, J., Hamilton, J.W., Lof, G.L. & Kempster, G.B. (1992). Oropharyngeal swallowing in normal adults of different ages. Gastroenterology, 103, 823–9. Robbins, J., Levine, R.L., Maser, A., Rosenbek, J.C. & Kempster, G.B. (1993). Swallowing after unilateral stroke of the cerebral cortex. Archives of Physical Medicine and Rehabilitation, 74(12), 1295–300. Rosenbek, J., Robbins, J., Fishback, B. & Levine, R. (1991). Effects of thermal application on dysphagia after stroke. Journal of Speech and Hearing Research, 34, 1257–68.

Rosenbek, J.C., Robbins,J.A., Roecker, E.B., Coyle, J.L. & Wood, J.L. (1996a). A penetration–aspiration scale. Dysphagia, 11, 93–8. Rosenbek, J.C., Roecker, E.B., Wood, J.L. & Robbins, J. (1996b). Thermal application reduces the duration of stage transition in dysphagia after stroke. Dysphagia,11, 225–33. Rosenbek, J.C., Robbins, J., Willford, W.O. et al. (1998). Comparing treatment intensities of tactile–thermal application. Dysphagia, 13, 1–9. Sacks, S., Lawson, W. & Biller, H. (1988). Correction of late glottic insufficiency. In Aspiration and Swallowing Disorders. The Otolaryngology Clinics of North America, ed. Y. Krespi & A. Blitzer, pp. 761–9. Philadelphia: W.B. Saunders. Smithard, D.G., O’Neill, P.A., England, R.E. et al. (1997). The natural history of dysphagia following a stroke. Dysphagia, 12(4), 188–93. Tracy, J.F., Logemann, J.A., Kahrilas, P.J., Jacob, P., Kobara, M. & Krugler, C. (1989). Preliminary observations on the effects of age on oropharyngeal deglutition. Dysphagia, 4, 90–4. Veis, S. & Logemann, J. (1985). Swallowing disorders in persons with cerebrovascular accident. Archives of Physical Medicine and Rehabilitation, 66, 372–5. Wade, D. & Hewer, R. (1987). Motor loss and swallowing difficulty after stroke: frequency, recovery, and prognosis. Acta Neurologia Scandinavica, 76, 50–4. Zaino, C. & Beneventano, T.C. (1977). Mechanical factors affecting the contour of the orohypopharynx and the esophagus. Radiologic Examination of the Orohypopharynx and the Esophagus. pp. 107–140. New York: Springer-Verlag.

27

Respiratory dysfunction François Vingerhoets and Julien Bogousslavsky Department of Neurology, University of Lausanne, Switzerland

Introduction Voluntary, limbic, automatic and reflex respiratory functions depend on structures extending from the cerebral cortex to the pontomedullary nuclei. These different pathways appear to converge solely on the spinal level (Berger et al., 1977). The study of respiratory dysfunction following a cerebrovascular event may permit localization of the neuroanatomic lesion. In addition, some respiratory dysfunctions are related to the etiology and the prognosis of stroke. We will review current knowledge regarding these associations.

Central organization of respiration Since Lumsden’s work on anesthetized cats, the rostrocaudal organization of respiration has been recognized (Lumsden, 1923). The cortical areas are mainly inhibitory for respiration function (Fig. 27.1), except for the motor and premotor areas which slightly stimulate breathing (Plum, 1970). In humans, areas involved in respiration include the anterior hippocampal gyrus, ventral and medial surface of the temporal lobe and anterior portions of the insula (Plum, 1970; Simon, 1993). Cortical stimulation and seizures occurring in these areas have been reported to result in apnea that may be long-lasting (Coulter, 1984; Nelson & Ray, 1968). Total transection below the inferior colliculus, isolating the hindbrain, does not alter respiration, emphasizing that hemispherical effect on breathing is not prominent (Lumsden, 1923). In the brainstem, multiple interdependent centres, acting on breathing, have been recognized (Fig. 27.2). In the rostral pons lies the pneumotaxic centre. It includes the medial parabrachialis nucleus and the Kölliker–Fuse nucleus. This centre appears to be driven by the ventilatory

Fig. 27.1. Cortical areas of Macaca Mulata where electrical stimulation elicited inhibition of respiration. (Adapted from Kaada, B.R., 1951).

neuronal group in the medulla and may function as a relay, finely tuning the ventilatory pattern generator (Berger et al., 1977). A transection immediately superior to the rostral pons results in slow, deep breathing. An additional vagal lesion induces apneusis, which is defined as apnea during sustained inspiration (Lumsden, 1923). The medulla is crucial to respiratory function – as a

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(a )

(b)

(c )

Fig. 27.2. Brainstem respiratory organization: Different distribution for voluntary (shaded) and automatic (hatched) controls of respiration at upper pons (a), medulla (b), and spinal level (c). PNC: pneumotaxic center; PBm: nucleus parabriachialis medialis; KF Kölliker–Fuse nucleus; PCS: pedunculus cerebellaris superior; TS: tractus solitarius; DRG: dorsal respiratory group; VRG: ventral respiratory group; NA: nucleus ambiguus; NRA: nucleus retroambiguus; Insp: to inspiratory motoneurons; Exp: to expiratory motoneurons. (See text for details and references.)

transverse lesion above it does not alter respiration rhythm, whereas lesions below the medulla completely interrupt breathing (Lumsden, 1923). In the medulla lie two centres: the dorsal and the ventral respiratory groups. The dorsal respiratory group is stationed bilaterally in the

ventrolateral portion of the tractus solitarius and receives primary visceral afferents through the ninth and tenth cranial nerves. It may represent the initial processing station for visceral reflexes. The dorsal respiratory group is uniquely inspiratory and drives the contralateral spinal

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cord (supplying the phrenic motoneurons) and the ventral respiratory group (Berger et al., 1977). This last group is further divided into two columns of cells: one, lying in the nucleus ambiguus, includes the cell bodies of the respiratory units of the recurrent laryngeal nerve, the other, extending from the obex to the first cervical segment and laterally to the nucleus ambiguus, represents the nucleus retroambiguus. It contains inspiratory and expiratory neurons which project contralaterally to the spinal cord and represents the major drive to thoracic and auxiliary muscles innervated by the vagus nerve (Berger et al., 1977). Besides its rostro-caudal organization, respiration depends on parallel systems carrying voluntary, automatic and limbic control of breathing (Plum, 1970, 1992). Voluntary control originates at the cortical level, and its efferents appear to travel with the cortico-spinal tract. A topographical association with the oro-bucco-pharyngeal musculature representation is probable as impaired voluntary swallowing is always accompanied by voluntary breathing dysfunction. Automatic control centres are localized in the dorsal medulla (Plum, 1970). The efferents cross the midline at the level of the obex (Bianchi, 1971) and then travel in the reticulo-spinal tract. The presence of an independent limbic efferent pathway is suggested by: (i) the preservation of limbic respiration (e.g. capacity to increase breathing when laughing and crying), when voluntary corticospinal breathing pathway is completely interrupted (Munschauer et al., 1991), (ii) the emotional lability in pseudobulbar palsy (Besson et al., 1991), which may lead to prolonged periods of apneusis (Stewart et al., 1996) and (iii) the effect of limbic cortex stimulation and epileptic fits (Simon, 1993). A relay through the reticular formation has been postulated (Plum, 1992) but the actual pathways are unknown (Plum, 1992). These diverse controls on respiration appear to converge solely on the spinal level.

Hemispheric strokes Unilateral hemispheric ischemic strokes appear to affect respiratory function to a modest degree. Both reduced chest wall movement (Fluck, 1966) and reduced diaphragmatic excursion (Keltz et al., 1969) contralateral to the stroke have been reported. The latter association correlates well with the lateralization of diaphragmatic cortical representation found by transcranial magnetic stimulation (Maskill et al., 1991). Patients with hemiplegia following capsular lesions seem to be more prone to develop diaphragmatic asymmetric function than those with lesion of other localization (Similowski et al., 1996).

Bilateral hemispheric strokes may be associated with Cheyne–Stokes respiration (Heyman et al., 1958; Plum, 1970). Cheyne–Stokes breathing is alternating progressive hyperpnea and progressive hypoventilation ending in apnea. It is accompanied by respiratory alkalosis. This pattern may develop in the normal subject during sleep or at high altitude. Its association with bilateral strokes may result from an increased response to CO2 following interruption of normal cortical inhibition (Heyman et al., 1958). Such a response may persist months to years after the stroke. Cheyne–Stokes respiration has also been described in unilateral lesions in the presence of underlying cardiac or pulmonary dysfunction (Lee et al., 1974). As strokes can induce EKG anomalies (Vingerhoets et al., 1993), the significance of Cheyne–Stokes respiration in relation to unilateral strokes remains unclear. Pseudobulbar palsy is classically defined as faciopharyngo-glosso-masticatory diplegia resulting from the bilateral interruption of cortico-nuclear projections (Besson et al., 1991). In some cases accessory respiratory muscles, such as the trapezii and sternocleidomastoids and, rarely, the vocal cords, are paralyzed (Cambier et al., 1983). Usually these deficits do not result in dyspnea. Recently, periodic dyspnea has been reported in association with a biopercular stroke. This stroke resulted in very slow, periodic movements of the vocal cords, their position alternating, over a period of minutes, between extreme abduction and complete adduction (the latter inducing dyspnea). This syndrome may be related to decreased cortical inhibition restricted to the larynx, because of the small size of the lesion (Cambier et al., 1983). Multiple bilateral hemispheric strokes have been reported to impair voluntary breathing (Plum, 1970). Unfortunately, these reports have not been supported by anatomical correlation. In keeping with the anatomical organization of the control of respiration, hemispheric strokes do not directly impair automatic breathing. However, respiratory arrest represents the primary cause of death in the first days following acute hemispheric stroke (Oppenheimer & Hachinski, 1992). Such an alteration may indirectly occur when cerebral edema induces secondary brainstem shift and transtentorial herniation. As herniation progresses, the respiratory pattern changes successively from normal breathing to Cheyne–Stokes respiration, followed by hyperventilation, and eventually irregularly irregular breathing immediately prior to death (Plum & Posner, 1982). Other major causes of respiratory arrest include secondary ventricular hemorrhage, massive bronchoaspiration and pulmonary embolism (Oppenheimer & Hachinski, 1992).

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inducing lesions almost completely transected the pons, rostral to the trigeminal nerve level; nevertheless, apneusis developed despite the integrity of the vagus nuclei.

Autonomous breathing Any brainstem lesion sparing the medulla and more precisely its dorsolateral part (Plum, 1970), does not impair rhythmic, physiologically effective breathing (Fig. 27.3). Moreover, such lesions may lead to autonomous breathing where the patient is unable to modify breathing voluntarily, while the physiological control is preserved (Munschauer et al., 1991), and may allow extensive survival (Feldman, 1971). The most common cause is a midpontine lesion resulting in locked-in syndrome (Nordgren et al., 1971) (Feldman, 1971; Munschauer et al., 1991). Smaller lesions, limited to the upper part of the pontine corticospinal tract, may cause isolated inability to voluntarily breath and swallow (Plum, 1970) (Fig. 27.4). Besides the classical preservation of CO2 responsivity, the capacity to laugh, sob and cry, as well as respiratory responses to anxiety may be preserved in patients with autonomous breathing (Munschauer et al., 1991). As the corticospinal route is interrupted by the stroke, it has been deduced that the limbic efferent pathway bypasses the voluntary control system to affect respiration through the medullary respiratory centres. However, these centers may not represent the only limbic efferent pathway, as inability to cry, laugh or sob with emotional expression has never been reported in the carefully investigated Ondine’s curse cases.

Ondine’s syndrome Fig. 27.3. Extensive paramedian pontine infarct: no effect on respiratory rhythm (from Plum, F., 1970).

Brainstem strokes In contrast to cerebral hemispheric involvement, brainstem strokes may induce typical sydromes allowing neuroanatomical localization.

Apneusis Apneusis is an unusual feature following stroke. In 23 patients with brainstem infarct, specifically studied for respiratory dysfunction, none developed apneusis (Lee et al., 1975). However, it has been reported by Plum in two patients (Plum, 1964). In keeping with the experimental model, the

Stroke involving the lateral aspects of the tegmentum pontis and medulla, dramatically impairs automatic respiration (Bogousslavsky et al., 1990; Levin & Margolis, 1977; Khurana, 1982; Devereaux et al., 1973; Hunziker et al., 1964; Beal et al., 1983). Clinically, these patients may present with mild cyanosis when awake. They are not disturbed by their respiratory failure, which may be actively reversed on request (Devereaux et al., 1973). Despite their benign appearance, these patients have a life-threatening condition and may present with major impairment of respiration, leading to convulsions and even death, when asleep (Levin & Margolis, 1977). This clinical entity was named after a water nymph in the Jean Giraudoux adaptation of a German legend: Ondine. She cursed the knight, Hans, following his marital misconduct by revoking his automatic functions. He subsequently slept to death (Severinghaus & Mitchell, 1962).

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Fig. 27.4. Lacunar lesions leading to a selective inability to voluntarily breathe and swallow (from Plum, F., 1970).

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(a )

(b)

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Fig. 27.5. Left laterobulbar stroke leading to Ondine’s curse (from Bogousslavsky, J. et al., 1990).

Strokes complicated by Ondine’s curse usually result from a distal vertebral artery occlusion. The development of Ondine’s curse is a major determinant for poor outcome in this kind of stroke (Norrving & Cronqvist, 1991; Caplan et al., 1986). The majority of reported clinicopathological studies describe patients with unilateral lateral medullary infarction (Bogousslavsky et al., 1990; Levin & Margolis, 1977; Khurana, 1982) (Fig. 27.5). This probably reflects selection of strokes with unilateral vascular involvement as those allowing survival (Caplan et al., 1986; Levin & Margolis, 1977). A left-sided predomi-

nance may be proposed for central control of respiration function (three of four unilateral lesions were left-sided). An alternative explanation to lateralization of respiratory control is the possible interruption of contralateral decussating efferent pathways by an extensive unilateral lesion (Bogousslavsky et al., 1990). The smallest reported ischemic lesion leading to Ondine’s curse involved the nucleus ambiguus and adjacent medullary reticular formation, while sparing the nucleus tractus solitarius (Bogousslavsky et al., 1990).

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(c)

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Fig. 27.5 (cont.)

Sleep apnea syndromes Ondine’s syndrome represents the central type of sleep apnea syndrome (Guilleminault et al., 1976). It will be reflected in polysomnography by concomitant interruption of both thoracic and airflow movements. In contrast, obstructive type of sleep apnea demonstrates interrupted airflow (caused by obstruction), and increased thoracic movements. Obstructive sleep apnea syndrome (OSAS) is the most common form of sleep-disordered breathing in stroke patients affecting over 50% of the patients (Bassetti et al., 1997). OSAS prevalence is similar following stroke to

TIA suggesting that it represents a predisposing condition: OSAS and stroke share similar risk factors such as age, obesity and hypertension (Bassetti et al., 1997). However, presence of OSAS seems to worsen the prognosis of a stroke (Dyken et al., 1996; Good et al., 1996). Obstructive (Chaudhary et al., 1982) and mixed (Askenasy & Goldhammer, 1988) sleep apnea syndrome have also been reported in lateral medullary strokes. The suspected mechanism is pharyngeal obstruction caused by the paralysed soft palate. Careful examination is required to differentiate this condition from true Ondine’s curse. Obstructive sleep apnea is usually position dependent, increasing in the

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dorsal decubitus position and when lying on the paretic side. Increasing thoracic effort, resulting in snoring upon opening of the airway, may be present. The condition can be treated successfully with intubation (Chaudhary et al., 1982) or positive end expiratory pressure devices, while Ondine’s syndrome requires assisted ventilation (Bogousslavsky et al., 1990).

Hiccup Hiccup may be regarded as a failure of the usual alternative excitation–inhibition between glottis closure and inspiration. The coordinating centre is located in the brainstem reticular formation (Askenasy, 1992). Hiccup is one of the typical transient symptoms appearing at the onset of a lateral medullary stroke; it may become chronic (al Deeb et al., 1991). Stroke is an unusual cause of chronic hiccup: cerebrovascular pathology was implicated in only 5% of the largest study reported regarding intractable hiccups (Souadjian & Cain, 1968), intractable hiccups (lasting over 2 days) being found in 3 out of 270 consecutive admissions in a stroke rehabilitation unit (Kumar & Dromerick, 1998). Its persistence may favor respiratory complications and prevent proper feeding in these patients having already bulbar symptoms (Kumar & Dromerick, 1998).

Cough, yawn and sneeze The actual neurophysiology of these three involuntary respiratory functions is still poorly understood. They have not been described occuring secondary to stroke. The spinal efferent pathway leading to cough is distinct from the automatic breathing pathway, as cough may be preserved in Ondine’s curse (Simon, 1993). Coughing preceding stroke evokes a paradoxical embolism through a patent foramen ovale, particularly in the young patient (Lechat et al., 1988). The Valsalva manoeuvre, which induces intrathoracic hypertension, reverses the normal pressure gradient between the atria. This may lead to a right-to-left shunt through a patent foramen ovale with liberation of emboli into the cerebral arterial vasculature. Yawning depends mainly on midbrain structures and is typically preserved in anencephalic newborns. After strokes limited to the upper pons yawning may even be associated with automatic movements of otherwise plegic limbs (personal observations). Sneezing is rarely related to brain disease (Simon, 1993). However, a probable vertebral artery dissection has been described after sneezing (Gutowsky et al., 1992).

Hyperventilation: poor prognosis Prognosis of patients with stroke who need mechanical ventilation is poor with in-hospital mortality ranging from over 50% to as high as 90%, and survival at 2 years barely reaching 10–30%, most of them severely disabled (Ludwigs et al., 1991; el-Ad et al., 1996; Steiner et al., 1997). This led to questions about the use of mechanical ventilation in stroke patients (el-Ad et al., 1996) and to define prognostic factors: age above 65, Glasgow coma scale less than 10, atrial fibrillation, bilateral absence of corneal or pupillary reflexes, infratentorial strokes and bilateral Babinski’s signs carrying bad prognosis (Steiner et al., 1997). In these studies, prognosis of the various kinds of respiratory disturbances was not studied. Besides the poor prognosis of Ondine’s curse, central hyperventilation is the only respiratory dysfunction that has been recognized to have prognostic value in stroke (Rout et al., 1971; Lee et al., 1974, 1975) and other acute brain damage (North & Jennett, 1974). The presence of an associated hypocapnia reinforces the bad prognosis. The mechanism leading to the hyperventilation is still unclear and not related to specific stroke location (Lee et al., 1975). Even the central origin of the tachypnea has been questioned, as a majority of patients presenting with tachypnea also had concurrent metabolic acidosis or pulmonary dysfunction with a direct relationship between outcome and PO2 (Plum, 1972, 1982). Cases of central hyperpnea are unusual when the definition is confined to tachypnea with hypocapnia and normal PO2 (Plum, 1982). However, it has been more and more recognized that primary central nervous system lesions may lead to cardiac and pulmonary dysfunction (Simon, 1993; Yamour et al., 1980). In these instances, it may be difficult to differentiate peripheral from central tachypnea when both are diagnosed simultaneously. To complicate the issue, tachypnea with hypocapnia is a well-recognized sign of pulmonary embolism, itself a frequent complication of stroke and a major contributor to stroke-related mortality (Oppenheimer & Hachinski, 1992).

Conclusion Respiratory function depends on numerous neurological structures, extending from cerebral cortex to medulla. Besides voluntary, automatic and limbic pathways have been recognized. Hemispheric strokes have minimum effects on breathing, Cheyne–Stokes respiration being more frequent with bilateral involvement. Autonomous breathing suggests bilateral dysfunction of the corticospinal motor tract, usually in the ventral brainstem.

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Ondine’s curse may result from lateral medullary strokes; unilateral lesions here may lead to complete respiration failure resulting in death during sleep. Respiratory dysfunctions may also provide useful information on the etiology and prognosis of stroke.

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Clinical aspects and correlates of stroke recovery Marta Altieri, Vittorio Di Piero, Edoardo Vicenzini and Gian Luigi Lenzi Department of Neurological Sciences, University of Rome, Italy

Epidemiologic aspects of stroke-related disability At the dawn of the new Millennium, with specific effective therapies for the treatment of acute ischemic stroke still unavailable, we are witnessing in industrialized countries a significant decrease in stroke mortality accompanied by a rising total prevalence of this disease (Warlow, 1998). This observation may be related to an improved survival, rather than to the declining incidence of stroke. Accordingly, the number of patients with stroke-related disabilities may be twice as high as was previously thought (Geddes et al., 1996). Of all patients alive 6 months after an ischemic event, about 30% are dependent for their primary activities of daily living (ADL) (Bernspång et al., 1987; Ahlsïo et al., 1984; Warlow, 1998), while approximately 60% are expected to recover independence with self-care. Institutional care is common during the first months after stroke (around 20%), decreasing progressively because of high case fatality among the most severe patients (Jongbloed, 1986; Strand et al., 1985). Thus, most of the staggering economic costs related to stroke are not due to acute hospitalization, but to postacute rehabilitation and long-term care. Furthermore, many patients are already markedly impaired in their secondary ADL, such as mobility outdoors, cooking food and cleaning the house, before the stroke occurs (Åström et al., 1992). These activities are further reduced after the stroke, and only half of the patients, or fewer, are able to ride a bus, walk outdoors or clean the house when evaluated 1 to 3 years after stroke (Åström et al., 1992). Nowadays, much attention has been given in order to improve quality of life after stroke, with emphasis on continuing rehabilitation and longer-term support (Neau et al., 1998; Shin et al., 1997; de Haan et al., 1995). The major-

ity of patients who are afflicted by a stroke in their active years will never return to work (Fugl-Meyer & Jaasko, 1975); moreover, leisure time and social activities markedly decline in such patients, whether or not they have made a complete functional recovery (Sacco, 1995). Therefore, besides further improvements in prevention and the development of novel acute management strategies, new treatments designed to enhance poststroke recovery are of great clinical and economic importance.

Predictors of outcome In general, the entire process of restoration of activity may be due both to spontaneous natural improvement of brain function and to recovery attributable to rehabilitation treatment (de Pedro-Cuesta et al., 1992). At present, we cannot easily differentiate between the influence of specific interventions and the natural recovery process. Both the degree and the time course of functional recovery are closely related to the initial stroke severity. In the Copenhagen Stroke Study the highest degree of ADL function was reached within 3 weeks by patients with initially mild strokes, within 7 weeks by patients with moderate strokes, and within 11.5 weeks by patients with severe strokes (Jorgensen et al., 1995a). However, a valid prognosis of functional outcome can be made much earlier. Toni et al. (1997) found that, in approximately 40% of cases, the 30-day outcome could be predicted on the basis of the neurological course in the first 48 hours of hospitalization. Among predictors of outcome, depressed consciousness, severity of the neurological deficit and urinary incontinence have been reported as early clinical predictors (Chambers et al., 1987; Sacco, 1997; Heinsius et al., 1998).

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were younger than patients who died of other causes, probably because young brains are more prone to develop edema.

Severity of the neurological deficit

Fig. 28.1. CT scan and SPECT images of cerebellum in two stroke patients presenting with muscular spasticity (MSp) and prolonged muscular flaccidity (PMF) after an ischemic lesion involving the internal capsule. No cerebellar perfusion asymmetry is present in the first case, while crossed cerebellar diaschisis (CCD) is very clear in the second, emphasizing the link between functional cerebellar impairment and muscular hypotonia.

Depressed consciousness Depressed consciousness has been reported as an early clinical predictor of poor outcome; patients in coma seem to have the worst prognosis, with a greater likelihood of herniation from the mass effect of cerebral edema associated with larger infarcts (Sacco, 1998). In the ECASS II study, during the first 7 days, cerebral edema was the commonest cause of death in the placebo group (Hacke et al., 1998). Heinsius et al. (1998) found that nearly all the deaths due to large infarctions in the territory of the middle cerebral artery (MCA) could be attributed to brain edema. Patients who died because of brain edema

Motor weakness, the commonest complaint among stroke patients, is found in 80% to 90% of cases (Herman et al., 1982; Libman et al., 1996; Bogousslavsky et al., 1998). Hemiparesis with uniform weakness of the hand, foot, shoulder, and hip accounts for at least two-thirds of cases. The severity of early motor weakness is helpful not only in predicting stroke subtypes, but also stroke recovery. It has been observed that patients who can take a few steps with assistance at admission, have a 60% probability of being able to walk independently and nearly a 100% probability of being able to walk with assistance at discharge (Alexander, 1997). Those who are unable to walk on admission have only a 15% probability of being able to walk independently after rehabilitation (Jorgensen et al., 1995b). Similarly, no more that 2% of patients presenting with severe arm weakness at 1 to 2 weeks after stroke, recover completely at 3 months (Wade et al., 1983; Parker et al., 1986). Patients with persistently impaired balance and hypotonia due to a lesion involving the basal ganglia (particularly the lentiform nucleus or the striatum) and the internal capsule have a poorer functional outcome and a diminished response to rehabilitation (Aring, 1940; Fries et al., 1993; Baloh et al., 1995; Pantano et al., 1995; Miyai et al., 1997). Moreover, Pantano et al. (1995), found that a central hypotonia persisting for more than 2 months after stroke could be a clinical correlate of crossed cerebellar diaschisis (CCD) (see Fig. 28.1). Miyai et al. (1997), by comparing the admission and discharge functional outcome of patients with similar neurologic impairments (homonymous hemianopia, hemisensory loss and hemiparesis), found that patients with only cortical lesions had the least impairment and the best outcome when compared with patients who presented with lesions involving the deep territory of the MCA. This might be due to altered basal ganglia modulation of the cortex and thalamus (Albin et al., 1989). Moreover, clinical and experimental evidence suggest that direct damage to the basal ganglia–nigral network or the corticothalamic network initiates additional secondary damage to structures within that network, not damaged by the initial injury, that develops weeks after the stroke (Nakane et al., 1992). Inability to perform movement can also result from neuropsychological dysfunction. Patients with motor

Stroke recovery

neglect show a lack of initiative in moving the contralateral limbs, despite preserved muscular strength (Melo & Bogousslavsky, 1998). Injury to the right hemisphere causes behavioural abnormalities that include constructional apraxia, dressing apraxia, motor impersistence, anosognosia, neglect of left hemispace, extinction on double-simultaneous stimulation, prosopagnosia, and unilateral spatial neglect on drawing (Hier et al., 1993a). Neglect, which is present in up to 82% of patients with right-hemisphere strokes (Stone et al., 1993), represents the most important clinical factor in deterring recovery (Denes et al., 1982). Katz et al. (1999) observed that patients with neglect had the lowest scores on measures of impairment (sensory–motor and cognitive) and of disability in ADL. Levine et al. (1986) observed that patients with larger right-hemisphere lesions and greater premorbid cortical atrophy showed the least recovery from neglect. Hier et al. (1993b) found that, among all the patients presenting with neglect of the left hemispace and motor impersistence, those with hemorrhagic strokes recovered faster than those with infarcts; this observation is probably due to the fact that hemorrhages tend to occur deep in the whitematter and to dissect brain tissue without destroying it, while infarcts are frequently superficial. Among cognitive deficits, aphasia is one of the most frequent. Of patients with aphasia at 1 month postonset, 33% to 50% remain substantially aphasic at 6 months, and 25% at 1 year. Initial severity predicts long-term recovery (Knopman et al., 1984; Kertsz & McCabe, 1977). Patients with severe non-fluent aphasia at 1 month overwhelmingly remain severely non-fluent. Milder non-fluent patients become fluent, usually within a few weeks. Recovery of comprehension is fastest over the first few months, but may continue for at least 1 year (Demeurisse et al., 1980). Few previously employed patients with aphasia manage to return to work. Those who do depend, in part, on others, show a reduced capacity and are frequently socially isolated.

Urinary incontinence Urinary incontinence independently correlates with more severe deficits in the recovery phase, and negatively influences short- and long-term outcome after stroke (Wyman et al., 1990). By contrast, continence usually precedes functional independence. Incontinence occurs in up to 50–60% of patients at one week post onset (Barer, 1989; Gelber et al., 1993; Ween et al., 1996), declining to 35% after 1 month, and to 14% at 6 months (Brocklehurst et al., 1985). There are several factors that contribute to poststroke

incontinence: (i) impairment of neurologic micturition control mechanisms, resulting in hyperreflexic bladders or detrusor–sphincter dyssynergia; (ii) bladder hypotonia from ‘cerebral shock’, administration of anticholinergic drugs, premorbid neuropathic changes or early hospital bladder mismanagement; (iii) prestroke structural changes in the urinary tract; and (iv) poststroke impairments of mobility, communication and awareness (Khan et al., 1981; Gelber et al., 1994; Ween et al., 1996). Other factors such as neurologic impairments, mobility limitations and cognitive deficit are associated with persistent urinary incontinence (Ween et al., 1996). Patients who are incontinent at 1 week are much likelier to die or to be profoundly impaired in ADL at 6 months (Barer, 1989). The question remains whether urinary incontinence adds to a poor prognosis independently or is simply reflective of the poor prognosis already made by means of the severity measure (Ween et al., 1996). Fecal incontinence is present in 31% of patients with severe hemiparetic stroke in the first 2 weeks. Its persistence after this period is associated with a poor prognosis (Brocklehurst et al., 1985).

Therapeutic correlates of recovery The rehabilitation process involves three major areas of focus: (i) preventing and managing comorbid illness and medical complications; (ii) physical training for maximum independence; (iii) enhancing quality of life.

Preventing and managing comorbid illness and medical complications Stroke predisposes patients to a number of associated medical problems: the need for ventilatory support and airway protection, prophylaxis against pressure sores, dysphagia, urinary retention, agitation, seizures, deep venous thrombosis, pulmonary embolism, bladder and pulmonary infections, and so on. Attention must also be given to depression, stress-induced gastritis, and musculoskeletal back, hip, and knee pain secondary to prolonged sitting or traumatic hemiparetic ambulation. The recovery phase must thus start in the acute phase of stroke and be continued in a rehabilitation setting and requires a dedicated staff including physicians and nurses with a specific interest in stroke, physical and speech therapists, and psychologists. It has been widely accepted that specialist stroke intensive-care units are one of the key elements for successful and effective stroke care (Garraway et al., 1980;

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Stevens et al., 1984; Strand et al., 1985; Indredavik et al., 1998; Patel et al., 1998). The latest systematic review of all randomized trials that compared organized inpatient stroke care with contemporary conventional care showed a long-term reduction in deaths, and in the combined poor outcomes of death or dependency and death or institutionalization (The Stroke Unit Trialists’ Collaboration, 1997). The beneficial effects were independent both of the patient’s age, sex or stroke severity and of variations in stroke unit organization. The length of hospital stay is shorter than in conventional care, and patients seem to recover faster, as determined by their ADL score (Langhorne et al., 1993). Furthermore, the review suggested that patients in stroke units have more frequent contacts with nursing staff, which appears to be of therapeutic benefit (Lincoln et al., 1996). Despite these positive results in terms of stroke outcome, the reasons why organized stroke units ‘work’ remains largely undetermined (Jorgensen et al., 1995c). Stroke units provide complex and varied interventions comprising medical, nursing and remedial therapy. Indredavik et al. (1998) hypothesized that benefits were due to this more integrated approach, which links acute treatment to early mobilization and rehabilitation, an opinion supported by other authors (Jorgensen et al., 1995c). None of the acute stroke therapies (Langhorne et al., 1993) or treatment of medical complications (Indredavik et al., 1998) had a significant effect on mortality. This suggests that the positive effect of stroke units is related to the careful monitoring of clinical parameters and clinical emergencies, coupled with the possibility of early rehabilitation treatment and physical therapy. During the acute phase of stroke, it is also extremely important to control all the modifiable factors known to be related to a poor functional outcome. Among the abnormalities in blood tests at admission, the most frequently studied is hyperglycemia, which is thought to exert a harmful effect mainly by increasing local tissue acidosis, blood–brain barrier permeability and the risk of hemorrhagic transformation of the lesion (Venables et al., 1985; Prado et al., 1988; Woo et al., 1988; Toni et al., 1992; Weir et al., 1997; Bruno et al., 1999). Nevertheless, the authors found a varying effect of hyperglycemia depending on the type of stroke, with a worse outcome in non-lacunar strokes and a better outcome in lacunar ones (Toni et al., 1992; Bruno et al., 1999). Other serological abnormalities which have been found to predict a worse early outcome include reduced levels of protein C, high levels of white blood cells (WBC), and increases in the erythrocyte sedimentation rate (ESR). Elevated peripheral WBC soon after a cerebral infarction

reflects the degree of inflammatory response in the acute phase, and seems to be a directly related to the extent of local cerebral damage and to a poor neurological outcome (Pozzilli et al., 1985; Akopov et al., 1996). In a recent study, Silvestrini et al. (1998) found that WBC aggregation was able to determine the severity of neurological impairment in stroke patients, which suggests an involvement of altered WBC rheology in the development of cerebral ischemic injury. The association between ESR and functional stroke outcome has recently been evaluated by Vila et al. (1999). They found that dependent outcome was predicted by severe stroke at admission, non-lacunar infarct size and ESR, with a sensitivity of 76% and a specificity of 80%, respectively. High fibrinogen concentrations may aggravate a stroke owing to increased blood viscosity, which might reduce cerebral blood flow, and to higher platelet activation in the acute phase. It has been suggested that an immediate reduction in fibrinogen levels by heparin-induced extracorporeal low-density lipoprotein precipitation improves neurological function (Dávalos et al., 1997). Management of systolic blood pressure (BP) is still a matter of debate. There have been studies that discourage the use of antihypertensive drugs in the acute phase because these agents may reduce the pressure-dependent cerebral blood flow in the ischemic penumbra, thereby increasing cerebral damage (Yatsu & Zivin, 1985; Lavin, 1986; Strandgaard & Paulson, 1994). Conversely, it has been argued that poststroke hypertension could be deleterious, facilitating edema in the ischemic tissue (O’Brien et al., 1974; Hatashita et al., 1986). Carlberg et al. (1991) found BP admission to be unrelated to clinical outcome, except in patients with impaired levels of consciousness, in whom increased BP was associated with a worse prognosis. Others found that higher systolic BP at admission indicated a good outcome (Allen, 1984). In their recent study, Chamorro et al. (1998) found that complete recovery from ischemic stroke is facilitated by a moderate blood pressure reduction when brain edema is present, very likely as a result of more adequate cerebral perfusion pressure. Stroke worsening due to pharmacological hypoperfusion is exceptional. Hyperthermia has been found to be associated with the progression of symptoms and with a poor outcome in patients with acute stroke (Dávalos et al., 1997). Castillo et al. (1998) found that hyperthermia within the first 24 hours of stroke onset was independently related to larger infarct volume, higher neurological deficit and dependency at 3 months. This association was evident only when fever developed within the first 24 hours of stroke onset. This suggests that the relationship between brain damage

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and high temperature is greater the earlier the increase in temperature occurs (Castillo et al., 1998). This is not, however, in accordance with the results of other Authors who found that fever was an independent predictor of poor outcome even up to one week after the occurrence of stroke (Azzimondi et al., 1995).

Physical training At present, it has been widely accepted that physical therapy reduces the level of disability in stroke survivors, although its effectiveness is difficult to measure because of the multiplicity of factors that influence outcome and the difficulties in measuring impairment after stroke. There are numerous rehabilitation techniques that have been developed to optimize functional recovery following stroke, but there is no evidence that some are more effective than others. Traditional rehabilitation therapy attempts to mobilize patients using whatever devices or techniques are necessary. The proprioceptive neuromuscular facilitation approach is based on an assessment of functional joint movements and stresses the need for rehearsing ‘spiral and diagonal’ movement for the recovery of limb function. Weight-bearing through an extremity affected by hemiparesis has been purported to promote motor recovery, probably by enhancing the magnitude of cortical motor responses. Other treatments, including acupuncture, transcutaneous electrical nerve stimulation and electromyographic biofeedback, have also been used to improve motor recovery. During the early phase of recovery, the physical therapist assists patients in maintaining a joint range of motion and helps them relearn to turn in bed. Once the patient can tolerate the sitting position for prolonged periods the more active phase of his rehabilitation starts. Attention is then aimed at recovering the ability to perform stand–pivot transfers from bed to wheelchair and back, and at initiation of ambulation. The physical therapist is also trained to provide a number of treatment modalities that help reduce pain, spasticity and disuse muscle atrophy.

Enhancing quality of life The possible benefits of an integrated system of care should be considered not only in terms of greater independence, but also in terms of quality of life and return to social and hobby activities. A quality of life assessment should include at least four dimensions: physical, functional, psychological and social health. The physical health dimension refers primarily to disease-related symptoms

Fig. 28.2. PET–CBF study of a patient presenting with a chronic ischemic lesion of the right caudate (white spot) and depression, showing an area of hypoperfusion in the site of the lesion and in the right frontal lobe (diaschisis). (By courtesy of Professor R.S.J. Frackowiak.)

(de Haan et al., 1995). Functional health comprises selfcare and physical activity level. Cognitive functioning, emotional status and affective disorders are the components of the psychological life domain. Failure to maintain or re-establish social ties, except for those with close family members, is probably an important determinant of poor life satisfaction late after stroke. Åström et al. (1992) found that, 3 months after stroke, poor life satisfaction was associated with major depression and poor performance of ADL. Poststroke depression is a frequent affective disorder: its incidence ranges from 30% to 60% (Robinson & Price, 1982; Ng et al., 1995), while its prevalence is about 40% in the acute phase, and between 18% and 54% in the chronic phase (Ghika-Schmid & Bogousslavsky, 1997). When indicated, this number is approximately equally split between major and mild depression (Sinyor et al., 1986; Ebrahim et al., 1987). The frequency of this disorder is slightly higher in left-sided cases, particularly in those with deep frontal lesions (see Fig. 28.2). Poststroke depression can adversely affect resumption of social activities, short-term physical therapy outcome, and cognitive impairment (Robinson & Price, 1982; Herrmann et al., 1998). This adverse effect has been

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observed in patients with both major and minor depression and, in most cases of major depression, delayed recovery was apparent even after the depression had waned (Parikh et al., 1990). A reciprocal relationship between depression and impairment has been observed: it does not appear that impairment leads to depression but, rather, that existing depression and concomitant physical or intellectual impairments interact with each other, i.e. major depression seems to impair intellectual function even more than would be expected from the lesion alone, while physical impairment in the acute phase of stroke correlates significantly with severity of depression even at 6-month followup (Robinson et al., 1984). The consequences of depression on function strongly suggest that patients should be quickly referred for possible antidepressive treatment (Lipsy et al., 1984, Reding et al., 1986, Dam et al., 1996; Miyai & Reding, 1998). Noradrenergic and serotoninergic antidepressants seem to be equally effective as treatment, though noradrenergic reuptake inhibitors may be associated with worse self-care and ambulation outcome, perhaps due to presynaptic noradrenaline depletion (Miyai & Reding, 1998).

Drugs and recovery Several classes of drugs that may interfere with recovery are often used to treat concomitant medical problems in patients with stroke. These drugs include antihypertensive agents (clonidine and prazosin), anticonvulsants (phenytoin and phenobarbital), anxiolytics, neuroleptics and other dopamine receptor antagonists (Goldstein, 1998). It has been observed that motor recovery in patients who receive at least one of these ‘detrimental’ drugs in the acute phase is worse than in controls, regardless of the degree of the initial motor impairment, comorbid conditions and other prognostic factors (Goldstein, 1998). However, it remains uncertain whether the degree of recovery in such cases is due to the reason for the administration of a given drug or to the drug itself. Short-term administration of drugs increasing noradrenaline (NE) release, when combined with physical therapy, promote recovery. In rats, central infusion of NE hastens locomotor recovery, whereas the administration of DSP-4, a neurotoxin that leads to the depletion of NE in the central nervous system, delays it (Feeney et al, 1993). In this regard, the administration of dopaminergic and noradrenergic blockers is accompanied by the reoccurrence of the previously recovered motor deficit (Goldstein, 1998). In humans, the administration of the NE stimulant

Table 28.1. Effect of antidepressant drugs on stroke recovery Antidepressants Trazodone Fluoxetine Maprotiline Nortriptyline Desipramine Citalopram Venlafaxine

Recovery effect ⫹ ⫹ ⫺ ⫺ ⫺ ? ?

amphetamine combined with physical therapy seems to enhance motor recovery (Clark & Mankikar, 1979; Crisostomo et al., 1988; Walker-Batson et al., 1995), even by promoting neuronal reorganization processes in both the affected (Stroemer et al., 1998) and the unaffected hemisphere (Goldstein & Hulsebosch, 1999; Chollet et al., 1991). Miyai and Reding (1998) by comparing the effects of noradrenergic reuptake inhibitor (desipramine) with a relatively selective serotonin reuptake inhibitor (trazodone) and a super-selective serotonin reuptake inhibitor (fluoxetine), observed a clear-cut more positive effect of both the serotonin reuptake inhibitors in comparison with the noradrenergic agent. Dam et al., (1996) tested fluoxetine and maprotiline, selective inhibitors of serotonin reuptake, on functional recovery in hemiplegic patients. A markedly greater improvement was observed in the group treated with fluoxetine than in the placebo group. Long-term treatment with fluoxetine increases serotoninergic transmission through stimulation of motor function by enhancing regenerative processes after ischemic damage; serotonin induces synaptogenesis (Glanzman, 1994) and increases the excitability of spinal motoneurons (Elliot & Wallis, 1992). The effects of antidepressant drugs on stroke recovery are summarized in Table 28.1.

Concluding remarks Functional restoration is a complex phenomenon dependent on different clinical and physiological factors: the nature of the affected function, the residual viability of damaged brain structures, and the capability of other anatomic structures to assume the function of damaged brain regions. Physicians caring for patients recovering from stroke should also be aware of the potential negative effect of all the modifiable factors influencing recovery. In particular, some drugs commonly prescribed to treat other condi-

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tions may have adverse effects and should be avoided. As the basic neurobiological factors underlying recovery become better understood, drugs targeted at enhancing the recovery process may become part of the standard treatment of stroke.

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Vascular topographic syndromes

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Arterial territories of human brain Laurent Tatu1,3, Thierry Moulin1, Julien Bogousslavsky2 and Henri Duvernoy3 Neurology Services and 3Anatomy Laberators, Central University Hospital, Besançon, France 2 Department of Neurology, University of Lausanne, Switzerland

1

Introduction The advent of neuroimaging has allowed clinicians to improve clinico-anatomic correlations in patients with strokes. Anatomic structures are now well delineated on magnetic resonance imaging, and a knowledge of arterial territories is needed to achieve accurate localization of ischemic lesions. MRI studies have re-evaluated the clinical spectrum of both anterior and posterior circulation strokes. Because the topographic, etiologic, and clinical spectra vary, large prospective studies including well-documented patients are of upmost importance. Classical syndromes have been revisited and new clinical patterns highlighted. However, most of the recent studies are based on various anatomic support and sometimes even lack anatomic reference. In this latter case, MRI is sometimes even considered to be an effective means of identifying etiologies according to the location of the infarction. On the other hand, only scarce reports exist in which the arterial vascular territories are well identified by anatomic studies. This lack of standardization in both arterial territory localization and the planes used to identify them, mar totally the accuracy of such reports. This recent neuroimaging development necessitates a precise and standardized tool for anatomo-radioclinical correlations. However, a perfect knowledge in the general organization of brain arterial circulation is the first step needed for a good understanding in some particularities of brain arterial territories. The present chapter is designed to show precise brain arterial circulation organization and to depict brain arterial territories in a form directly applicable to neuroimaging slices in clinical practice.

General organization of brain arterial circulation Brainstem Arterial trunks supplying the brainstem include: vertebral artery, basilar artery, anterior and posterior spinal arteries, posterior inferior cerebellar artery, anterior inferior cerebellar artery, superior cerebellar artery, posterior cerebral artery, and anterior choroidal artery (Fig. 29.1). The collaterals of these arteries are divided into four arterial groups: anteromedial, anterolateral, lateral and posterior, according to their point of penetration into the parenchyma. This classification is that of Lazorthes (1976), who divided the superficial arteries into anterior, lateral and posterior. For the arteries of the anterior group, the subdivision is that proposed by Duvernoy (1978–1995) dividing anterior arteries into anteromedial and anterolateral arteries. Each of the anteromedial, anterolateral, lateral and posterior arterial groups supplies corresponding arterial territories in the brainstem. At each level of the brainstem, the origin of arterial supply of each territory varies. The arterial territories have a variable extension at different levels of the brainstem. For example, the posterior group disappears in the lower pons. Consequently, the nuclei and tracts that extend into the brainstem may be supplied by several arterial groups.

Cerebellum Cerebellum is supplied by the three long cerebellar arteries: the posterior inferior cerebellar artery, the anterior inferior cerebellar artery and the superior cerebellar artery. The posterior inferior and superior cerebellar arteries give rise to medial and lateral branches to vascularize the cortex

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Fig. 29.1. Anterior view showing the general arrangement of the brainstem and cerebellar arteries. A ⫽ medulla; B ⫽ pons; C ⫽ midbrain; D ⫽ Cerebellum. Main arterial trunks: 1 ⫽ vertebral artery; 2 ⫽ anterior spinal artery; 3 ⫽ posterior inferior cerebellar artery; 4 ⫽ basilar artery; 5 ⫽ anterior inferior cerebellar artery; 6 ⫽ superior cerebellar artery; 7 ⫽ posterior cerebral artery; 8 ⫽ collicular artery; 9 ⫽ posteromedial choroidal artery; 10 ⫽ anterior choroidal artery. Arteries of the anterior and lateral aspects of the brainstem: 11 ⫽ anteromedial group of medullary arteries; 12 ⫽ anterolateral group of medullary arteries; 13 ⫽ lateral group of medullary arteries (arteries of the lateral medullary fossa): a, inferior rami; b, middle rami; c, superior rami; 14 ⫽ anteromedial group of pontine arteries penetrating the basilar sulcus (14); penetrating the foramen caecum (14⬘); penetrating the interpeduncular fossa (inferior rami of the interpeduncular fossa) (14⬙); 15 ⫽ anterolateral group of pontine arteries; 16 ⫽ lateral group of pontine arteries originating from the superior lateral pontine artery (16⬘), from the inferior lateral pontine artery (16⬙); 16⬘ ⫽ lateral group of pontine arteries originating from the inferior lateral pontine artery; 17⫽anteromedial group of mesencephalic arteries (middle rami of the interpeduncular fossa); 18 ⫽ thalamoperforating arteries (superior rami of the interpeduncular fossa); 19 ⫽ anterolateral group of midbrain arteries. Arteries of the anterior aspect of the cerebellum: 20 ⫽ branches of the superior cerebellar artery; 21 ⫽ branches of the anterior inferior cerebellar artery; 22 ⫽ branches of the posterior inferior cerebellar artery.

Arterial territories of human brain

Fig. 29.2. Arterial circle of WILLIS: 1 ⫽ internal carotid artery; 2 ⫽ middle cerebral artery; 3 ⫽ anterior cerebral artery; 4 ⫽ anterior communicating artery; 5 ⫽ posterior communicating artery; 6 ⫽ anterior choroidal artery; 7 ⫽ posterior cerebral artery; 8 ⫽ basilar artery; 9 ⫽ superior cerebellar artery; 10 ⫽ recurrent artery of Heubner; 11 ⫽ middle cerebral artery perforating branches; 12 ⫽ internal carotid artery perforating branches; 13 ⫽ anterior choroidal artery perforating branches; 14 ⫽ posterior communicating artery perforating branches; 15 ⫽ posterior cerebral artery perforating branches; 16 ⫽ anterior perforated substance; 17 ⫽ lateral perforated substance.

and the central nuclei of the cerebellum. The three long cerebellar arteries also contribute to the blood supply of particular lateral or posterior arterial groups of the brainstem. Branches of the long cerebellar arteries develop a pial anastomotic network on the surface of the cerebellum.

Cerebral hemispheres Arterial circulation of the cerebral hemispheres is divided into two systems: the leptomeningeal arteries and the perforating arteries (Fig. 29.2). Nevertheless, perforating branches could arise from leptomeningeal arteries, and the origin of some leptomeningeal branches could be the large perforating arteries.

The leptomeningeal arteries (also known as superficial or pial), consist of the terminal branches of the anterior, middle and posterior arteries forming an anastomotic network on the surface of the hemispheres and yielding branches that penetrate the cortex and subjacent whitematter. The deepest ones form the medullary (or superficial perforating) arteries. The perforating arteries (or deep perforating arteries), arising from the arterial circle of Willis or from its immediate branches, perforate the brain parenchyma as direct penetrators (Fig. 29.3). The perforating arteries arising from the internal carotid artery, anterior cerebral artery, middle cerebral artery, and anterior communicating artery pass through the anterior perforated substance. Some

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For the brainstem, arterial territories are always divided into several territories: anteromedial, anterolateral, lateral and posterior. These territories are supplied by groups of arteries of various sources and rarely by only one source. Then, the delineation of a territory for a unique artery is not commonly possible. For each level of brainstem a short description of main arterial supply is given and, in addition, the details of each group of arteries supplying the different territories are defined according to the corresponding sections of the cartography. Accurate localization of ischemic lesions in the brainstem needs a knowledge of delineation of the four arterial territories: anteromedial, anterolateral, lateral and posterior. For cerebellum and cerebral hemispheres, arterial territories are usually supplied by a unique arterial source, and the territories are therefore, simply named in terms of the main supplying artery. A short description of main arterial branches and major structures supplied is given for each artery.

Arterial supply of brainstem Arterial groups to the medulla

Fig. 29.3. Coronal section of the brain showing the general arrangement of the hemispheric arteries. cc: corpus callosum, co: centrum ovale, cl: claustrum, c: caudate nucleus, fh: frontal horn of lateral ventricle, i: insula, ia: anterior limb of internal capsule, p: pallidum, gp: globus pallidus, aps: anterior perforated substance. 1 ⫽ middle cerebral artery; 2 ⫽ perforating arteries; 3 ⫽ medullary arteries; 4 ⫽ anterior cerebral artery; 5 ⫽ posterior cerebral artery.

perforating arteries arising from the posterior cerebral artery enter the brain through the posterior perforated substance forming the interpeduncular arteries. These latter arteries are classed in three rami: only the superior rami contribute to the blood supply of the thalamus, inferior rami vascularize the pons and middle rami the midbrain.

Details of arterial brain supply The organization of arterial brain supply for each territory is different in the brainstem from in the cerebellum and cerebral hemispheres (see above).

The arterial supply of medulla arises from vertebral arteries (giving the middle rami of the lateral medullary fossa), posterior inferior cerebellar artery (giving the inferior rami of the lateral medullary fossa), anterior and posterior spinal arteries. • Anteromedial group arises from: anterior spinal artery (sections I, II, III), anterior spinal and vertebral arteries (section IV). • Anterolateral group arises from: anterior spinal and vertebral arteries (section I), anterior spinal and posterior inferior cerebellar arteries (sections II, III), anterior spinal and vertebral arteries (section IV). • Lateral group arises from: posterior inferior cerebellar artery (inferior rami of the lateral medullary fossa) (sections I, II, III), vertebral artery (middle rami of the lateral medullary fossa) (section IV). • Posterior group arises from: posterior spinal artery (sections I, II), posterior inferior cerebellar artery (sections III, IV).

Arterial groups to the pons Different arterial trunks including vertebral arteries, anterior inferior cerebellar artery, superior cerebellar artery

Arterial territories of human brain

• Lateral group arises from: vertebral and anterior inferior cerebellar arteries (superior and posterior rami of the lateral medullary fossa)(section V), pontine arteries (sections IX, part b of sections VI and VII), anterior inferior cerebellar artery (part b’ of sections VI and VII), pontine arteries and anterior inferior cerebellar artery (sections VIII), superior cerebellar artery (section X). • Posterior group exists only in the upper part of the pons arises from: superior cerebellar artery (medial and lateral branches) (sections IX and X).

Arterial groups to the midbrain

Fig. 29.4. Sagittal section of the pons showing the paths of different pontine arteries arising from the basilar artery. A ⫽ ventral part of the pons; B ⫽ pontine tegmentum. 1 ⫽ arteries with a straight path supplying the middle part of the pontine tegmentum; 2 ⫽ arteries with a straight path supplying ventral part of the pons; 3 ⫽ descending arteries (inferior rami of the interpeduncular fossa) supplying the upper part of the pontine tegmentum; 4 ⫽ ascending arteries penetrating the foramen coecum and supplying the lower part of the pontine tegmentum.

and basilar artery supply the pons. The anterior inferior cerebellar artery enters the parenchyma in the pontomedullary sulcus and gives the superior and the posterior rami of the lateral medullary fossa. Different branches of the basilar artery entering the foramen coecum in the lower level (foramen coecum arteries), straighten the ventral part of the pons (anteromedial, anterolateral and lateral pontine arteries) or the interpeduncular fossa in the upper level (inferior rami of the interpeduncular arteries) (Fig. 29.4). • Anteromedial group arises from: foramen coecum arteries (section V, part a’ of sections VI and VII), pontine arteries (section VIII, part a of sections VI, VII, IX and X), interpeduncular fossa arteries (part a’ of sections IX and X). • Anterolateral group arises from: pontine arteries (sections V, VI, VII, VIII, IX, X).

Five arterial trunks supply the arterial midbrain groups, from below to above: the superior cerebellar artery (mainly the medial branch), the collicular artery, the posteromedial choroidal artery, the posterior cerebral artery (middle rami of the interpeduncular arteries) and the anterior choroidal artery. • Anteromedial group arises from: posterior cerebral artery (sections XI, XII). • Anterolateral group arises from: collicular and posteromedial choroidal arteries (section XI), collicular, posteromedial and anterior choroidal arteries (sections XII). • Lateral group arises from: collicular artery (section XI), collicular, posteromedial choroidal and posterior cerebral arteries (section XII). • Posterior group arises from: superior cerebellar and collicular arteries (section XI), collicular and posteromedial choroidal arteries (section XII).

Arterial supply of cerebellum The cerebellar arterial supply depends on three long arteries (Fig. 29.1).

The posterior inferior cerebellar artery This gives rise to two branches and vascularizes the inferior vermis and the inferior and posterior surfaces of the cerebellar hemispheres. The posterior inferior cerebellar artery also takes part in the lateral and posterior arterial groups of the medulla.

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The anterior inferior cerebellar artery This supplies the anterior surface of the simple, superior and inferior semilunar lobules as well as the flocculus and the middle cerebellar peduncle. The anterior inferior cerebellar artery supplies the middle cerebellar peduncle and often the lower part of the pontine tegmentum.

The superior cerebellar artery This divides into medial and lateral branches and vascularizes the superior half of the cerebellar hemisphere and vermis as well as the dentate nucleus. The territory of superior cerebellar artery often includes the upper part of the pontine tegmentum.

Arterial supply of cerebral hemispheres Perforating branches of the cerebral arteries Internal carotid artery perforating branches Arising from the supraclinoid portion of the internal carotid artery, near the origin of the anterior choroidal artery, some perforating branches pass through the anterior perforated substance to enter the brain. These branches supply the genu of the internal capsule, the adjacent part of the globus pallidus and the contiguous posterior limb of the internal capsule. In the absence of a strong uncal branch from the anterior choroidal artery, the perforating branches of the internal carotid artery could supply the uncus.

Anterior choroidal artery The anterior choroidal artery usually arises from the supraclinoid portion of the internal carotid artery. The superficial territory includes the amygdaloid nucleus, the lateral part of the lateral geniculate body, a part of the uncus and of the head of the hippocampus. The perforating territory includes the lower part of the posterior twothirds and the retro-lenticular part of the internal capsule, the adjacent optic radiations and acoustic radiations, the medial globus pallidus, the tail of the caudate nucleus. The contribution of the anterior choroidal artery to the arterial supply of the lateral thalamus is still debated.

fornix, the paraterminal gyrus including the septal nuclei and occasionally the subcallosal region, the anterior part of the corpus callosum and the cingulate gyrus.

Anterior cerebral artery perforating branches The anterior cerebral artery perforating branches are divided into two groups: the anterior cerebral artery direct perforators (usually arise from the proximal segment, before the junction with anterior communicating artery) and the recurrent artery of Heubner (arising from the segment distal to the anterior communicating artery). These arteries supply the anterior and inferior part of the head of the caudate nucleus, the anterior and inferior portion of the anterior limb of the internal capsule, the adjacent part of the putamen and globus pallidus, the caudal rectus gyrus, the subcallosal gyrus and a medial part of the anterior commissure.

Middle cerebral artery perforating branches The perforating branches of the middle cerebral artery usually originate from the sphenoidal segment of this artery. They are usually classified into two groups: the medial and the lateral arteries. However, this disposition is inconstant and a common stem could also be present. These perforating branches supply the superior part of the head and the body of the caudate nucleus, the lateral segment of the globus pallidus, the putamen, the dorsal half of the internal capsule and the lateral half of the anterior commissure.

Posterior communicating artery perforating branches The posterior communicating artery arises from the supraclinoid portion of the internal carotid artery and passes posteromedially to join the posterior cerebral artery. The largest perforating branch of the posterior communicating artery is termed the premamillary artery (anterior thalamoperforating artery or tuberothalamic artery). The posterior communicating artery perforators vascularize the posterior portion of the optic chiasm and optic tract and the posterior part of the hypothalamus and mamillary body. The thalamic territory of the posterior communicating artery includes the nucleus anterior and the polar part of the nucleus ventralis anterior and of the nucleus reticularis.

Anterior communicating artery The perforating branches of the anterior communicating artery originate directly from the anterior communicating artery or from the junctional site of the anterior communicating and anterior cerebral arteries. The anterior communicating artery gives rise to perforating branches supplying the lamina terminalis, anterior hypothalamus, septum pellucidum, a part of the anterior commissure and of the

Thalamoperforating branches The thalamoperforating (or paramedian thalamic) arteries are a part of the interpeduncular arteries penetrating the posterior perforating substance. The middle and superior rami of interpeduncular arteries arise as single or common trunks from the proximal segment (up to the posterior communicating artery) of the posterior cerebral artery.

Arterial territories of human brain

Only the superior rami corresponding to the thalamoperforating arteries contribute to the vascularization of the thalamus. They supply the medial nuclei, the intralaminar nuclei, a part of the dorsomedial nucleus, the posteromedial portion of the lateral nuclei and the ventromedial pulvinar. If the posterior communicating artery is hypoplastic, its perforators have a reduced territory and the thalamoperforating arteries have a more extended territory.

Thalamogeniculate branches The thalamogeniculate arteries (inferolateral thalamic arteries) usually arise as individual vessels from the distal segment (between the posterior communicating artery and the posterior aspect of the midbrain) of the posterior cerebral artery. They supply the major part of the lateral side of the caudal thalamus including the rostrolateral part of the pulvinar, the posterior part of the lateral nuclei and lateral dorsal nucleus and the ventral posterior and ventral lateral nuclei.

Posterior choroidal arteries The posterior choroid group usually includes one or two medial and one to six lateral posterior choroidal arteries. The medial posterior choroidal artery usually arises from the proximal segment of the posterior cerebral artery. The lateral posterior choroidal artery arises directly from the distal segment of the posterior cerebral artery. The posterior choroidal arteries supply the medial and lateral geniculate body, the posterior part of the medial nucleus and of the dorsomedial nucleus of the thalamus, the posterior part of the pulvinar.

Leptomeningeal branches of the cerebral arteries Anterior cerebral artery The distal segment of the anterior cerebral artery, the pericallosal artery, gives rise to the cortical and the callosal branches. The callosal branches supply the rostrum, genu and body of the corpus callosum. These branches are joined posteriorly by the splenial branches of the posterior cerebral artery. In the most frequent disposition, the cortical area of supply of the anterior cerebral artery is the medial surface of the hemisphere extending to the superior frontal sulcus and the parieto-occipital sulcus. On the orbitofrontal surface, the arterial territory includes the medial orbital gyri. At most, the cortical anterior cerebral artery territory reaches the inferior frontal sulcus and, at least, it includes only the anterior part of the frontal lobe.

Middle cerebral artery The middle cerebral artery begins its division into cortical arteries at the base of the sylvian fissure, extends over the

surface of the hemisphere and forms the distal segment of the artery. The most frequent area of supply of the middle cerebral artery extends, on the lateral surface of the hemisphere, to the superior frontal sulcus, the intraparietal sulcus and the inferior temporal gyrus. On the orbitofrontal surface, the arterial territory includes the lateral orbital gyri. The maximum area covers the whole lateral surface of the hemisphere, reaching the interhemispheric fissure. The minimum territory is confined between inferior frontal and superior temporal sulci.

Posterior cerebral artery As the posterior cerebral artery approaches the dorsal surface of the midbrain, it gives rise to cortical branches. These branches include the hippocampal arteries and the splenial artery which anastomose with the distal part of the pericallosal artery to supply the splenium of the corpus callosum. The most frequent cortical distribution of the posterior cerebral artery includes the infero-medial surfaces of the temporal and the occipital lobe extended to the parieto-occipital fissure. At most, cortical supply can extend as far as the superior temporal sulcus and the upper part of the precentral sulcus, and at least, only as far as the medial face of the occipital lobe limited by the parietooccipital fissure.

Brain arterial cartography This cartography is presented by 24 serial sections, which are based on a bicommissural plane passing through the centre of the anterior and posterior commissures (Fig. 29.5(a)). This centre-to-centre bicommissural line is easier to find on MRI sagittal views than is Talairach’s line, which is drawn through the superior edge of the anterior commissure and the inferior edge of the posterior commissure (Talairach & Tournoux, 1988). On CT, the external reference of the centre-to-centre bicommissural plane is the suborbitomeatal line, which passes at the lower margin of the orbital opening and in the centre of the external acoustic meatus (Duvernoy, 1995) (Fig. 29.5(b)). The sections concerning the brainstem and cerebellum are 4 millimetres thick (sections I to XII). They are presented in Fig. 29.6 (brainstem) and in Fig. 29.7 (cerebellum). The sections XII to XXIV concerning cerebral hemispheres are 8 millimetres thick (Fig. 29.8). These sections are modified views from brain anatomic atlases by Duvernoy (1995, 1991). The right side of the sections shows the anatomic structures and Brodmann’s areas for cerebral hemispheres. The legend of anatomic structures is mentioned in Table 29.1 for brainstem and cerebellum and in Table 29.2 for cerebral hemispheres (with colouring

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(b) Fig. 29.5. (a) Lateral view of the brain showing the bicommissural plane passing through the centre of the anterior and posterior commissures. (b) Lateral view of the skull showing the suborbitocentromeatal line. This external reference corresponds to the centre-to-centre bicommissural plane. The suborbitocentromeatal line passes at the lower margin of the orbital opening and the centre of the external acoustic meatus.

system). The arterial territories appear in the left-hand side of the sections. The arterial territories of brainstem have been drawn using the anatomic work of Duvernoy (1978, 1999). The details of the arterial groups supplying these territories are given above in the chapter details of arterial supply. For the cerebellum we used the pathologic work of Amarenco and

Hauw (1990a,b) and Amarenco (1991) and the injection studies of Marinkovic et al. (1995) (For more details, see Tatu et al., 1996). Table 29.3 indicates the colour legend for the cerebellum territories. The arterial territories of cerebral hemispheres were drawn, based on an extensive overview of anatomic studies of cerebral vascularization. This overview included either vascular injection studies or microanatomic studies of the cerebral arteries (for more details, see reference Tatu et al. 1998). Table 29.4 gives the colour legend for the territories of the arteries supplying the cerebral hemispheres. The cortical territory includes both the cortex and U-fibres. The latter are supplied by cortical branches, in this case, terminal twigs of the longest cortical arterioles and first collaterals of long medullary arterioles (Duvernoy et al., 1981). The arterial territory of each cortical branch of the anterior, middle and posterior cerebral arteries has not been detailed, because of the numerous variations in the branching patterns. However, the variability of the cortical territories of these arteries is presented, using the results of the study by Van der Zwann et al. (1992) to designate the minimal and maximal cortical supply areas of the anterior, middle and posterior cerebral arteries (this is indicated by coloured arrows). Nevertheless, several aspects of hemispheric vascularization have not voluntarily been detailed because of a lack of clear anatomic studies, or a too-complicated vascular organization, or individual particularities. The vascularization of the centrum ovale is still debated. It includes transcortical arterioles having exclusive territory as well as terminal ramifications of some perforating branches. The lack of specific anatomic studies on the origin of blood supply of the centrum ovale leads us not to consider its vascularization on the cartographies. The arterial supply of the external capsule/claustrum/extreme capsule area, called the insular zone in the sections, is more complex. According to Moody et al. (1990), this area has a triple blood supply: a double cortical supply, like the U-fibres, and lateral rami of the lateral striate arteries. The arterial territories represented in the sections are a model of dominant vascularization and cannot account for individual variations. In brainstem and cerebellum territories, some variations are not uncommon, such as an anterior inferior cerebellar artery replacing a hypoplasic posterior inferior cerebellar artery and taking over most of the anterior and inferior part of the cerebellar hemisphere. For cerebral hemispheres, the variations depend on the variable arrangement of the arterial circle of Willis or its immediate branches. For example, the posterior communicating artery/posterior cerebral artery system could stay of fetal type with a posterior communicating artery remaining the source of the posterior cerebral artery.

Fig. 29.6. Arterial territories of brainstem.

Fig. 29.6. (cont.)

Fig. 29.7. Arterial territories of cerebellum.

Fig. 29.7 (cont.)

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Fig. 29.8. Arterial territories of cerebral hemispheres.

Arterial territories of human brain

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Table 29.1. Anatomic structures of brainstem and cerebellum (sections I to XII) 1 2 2′ 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

Corticospinal tract Medial lemniscus Medial longitudinal fasciculus Spinothalamic tract Spinal trigeminal tract and nuclei Gracile and cuneate nuclei Nucleus of the solitary tract Dorsal motor vagal nucleus Hypoglossal nucleus Inferior olivary nucleus Inferior cerebellar peduncle Vestibular nucleus Nucleus prepositus Facial nucleus Superior olivary nucleus Abducens nucleus Pontine nuclei Motor trigeminal nucleus Principal sensory trigeminal nucleus Nucleus coeruleus Superior cerebellar peduncle Sustantia nigra Inferior colliculus Trochlear nucleus Superior colliculus Oculomotor nucleus Red nucleus Mamillary body Optic tract Lateral geniculate body

30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 V VII VIII IX

Medial geniculate body Pulvinar Mamillothalamic tract Column of fornix Caudate nucleus Putamen Anterior commissure Tonsil Biventer lobule Inferior semilunar lobule Pyramid of vermis Uvula Superior semilunar lobule Tuber of vermis Middle cerebellar peduncle Dentate nucleus Folium of vermis Nodulus Flocculus Declive Simple lobule Culmen Quadrangular lobule Central lobule Ala of the central lobule Trigeminal nerve Facial nerve Vestibulocochlear nerve Glossopharyngeal nerve

Arterial territories of human brain

Table 29.2. Anatomic structures of cerebral hemispheres (sections XII to XXIV) Gyri (Purple) CG Cingulate gyrus F1 Superior frontal gyrus F2 Middle frontal gyrus F3 Inferior frontal gyrus F3op Inferior frontal gyrus pars opercularis F3or Inferior frontal gyrus pars orbitalis F3t Inferior frontal gyrus pars triangularis FMG Frontomarginal gyrus GR Gyrus rectus LOG Lateral orbital gyrus MOG Medial orbital gyrus PCu Precuneus POG Posterior orbital gyrus SCG Subcallosal gyrus PCL Paracentral lobule PoCG Postcentral gyrus PrCG Precentral gyrus Sulci (Brown) AOS Anterior occipital sulcus CaS Calcarine sulcus CiS Cingulate sulcus CoS Collateral sulcus CS Central sulcus IFS Inferior frontal sulcus IOS Intra-occipital sulcus (superior occipital sulcus) IPS Intraparietal sulcus LF Lateral fissure LS Lingual sulcus OS Olfactory sulcus PCS Paracentral sulcus PoCS Postcentral sulcus POF Parieto-occipital sulcus PrCS Precentral sulcus RCS Retrocalcarine sulcus SFS Superior frontal sulcus SPS Subparietal sulcus STS Superior temporal sulcus (parallel sulcus) TOS Transverse occipital sulcus Internal structures (Green) CN Caudate nucleus CNh Caudate nucleus, head CNt Caudate nucleus, tail IA Internal capsule, anterior limb IG Internal capsule, genu IP Internal capsule, posterior limb NA Nucleus accumbens P Putamen PL Globus pallidus, pars lateralis PM Globus pallidus, pars medialis SN Septal nuclei

AG P1 P2 SMG T1 T2 T3 T4 T5 TTG O1 O2 O3 O4 O5 O6 GD RSG

Angular gyrus Superior parietal gyrus Inferior parietal gyrus Supramarginalis gyrus Superior temporal gyrus Middle temporal gyrus Inferior temporal gyrus Fusiform gyrus Parahippocampal gyrus Transverse temporal gyrus Superior occipital gyrus Middle occipital gyrus Inferior occipital gyrus Fusiform gyrus Lingual gyrus Cuneus Gyrus descendens (Ecker) Retrosplenial gyrus

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Table 29.2. Anatomic structures of cerebral hemispheres (sections XII to XXIV) A CM DM LD LP Pu VA VL VPL C CR IN LI CC F Hb Hh Ht AC Amg APS CrC GA H LB M MB MT OR OT ST T

Anterior thalamic nucleus Centromedian thalamic nucleus Dorsomedial thalamic nucleus Lateral dorsal thalamic nucleus Lateral posterior thalamic nucleus Pulvinar Ventral anterior thalamic nucleus Ventral lateral thalamic nucleus Ventral posterolateral thalamic nucleus Claustrum Corona radiata Insula Limen insulae Corpus Callosum Fornix Hippocampus, body Hippocampus, head Hippocampus, tail Anterior commissure Amygdala Anterior perforated substance Crus cerebri Gyrus ambiens Hypothalamus Lateral geniculate body Mamillary body Medial geniculate body Mamillo-thalamic tract Optic radiations Olfactory tract Subthalamic nucleus Tuber

Table 29.3. Cerebellar territories

Arterial territories of human brain

Table 29.4. Arterial territories of cerebral hemispheres

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iReferencesi Amarenco, P. & Hauw, J.J. (1990a). Cerebellar infarction in the territory of the superior cerebellar artery: a clinicopathologic study of 33 cases. Neurology, 40, 1383–90. Amarenco, P. & Hauw, J.J. (1990b). Cerebellar infarction in the territory of the anterior and inferior cerebellar artery. A clinicopathological study of 20 cases. Brain, 113, 139–55. Amarenco, P. (1991). The spectrum of cerebellar infarctions. Neurology, 41, 973–9. Duvernoy, H.M. (1978). Human Brain Stem Vessels. 2nd edn 1999. Berlin, Heidelberg, New York: Springer-Verlag. Duvernoy, H.M. (1991). The Human Brain. Surface Threedimensional Sectional Anatomy and MRI. 2nd edn. 1999. Wien, New York: Springer-Verlag. Duvernoy, H.M. (1995). The Human Brainstem and Cerebellum. Surface, Structure, Vascularization and Three Dimensional Sectional Anatomy with MRI. Wien, New York: Springer-Verlag. Duvernoy, H.M., Delon, S. & Vannson, J.L. (1981). Cortical blood vessels of the human brain. Brain Research Bulletin, 7, 519–79.

Lazorthes, G. (1976). Vascularisation et Circulation de l’Encéphale Humain. Paris: Masson. Marinkovic, S., Kovacevic, M., Gibo, H. et al. (1995). The anatomical basis for the cerebellar infarcts. Surgical Neurology, 44, 450–61. Moody, D.M., Bell, M.A. & Challa, V.R. (1990). Features of the cerebral vascular pattern that predict vulnerability to perfusion or oxygenation deficiency: an anatomic study. American Journal of Neuroradiology, 11, 431–9. Talairach, J. & Tournoux, P. (1988). Co-planar Stereotaxic Atlas of the Human Brain. 3-Dimensional Proportional System: An Approach to Cerebral Imaging. Stuttgart: Thieme. Tatu, L., Moulin, T., Bogousslavsky, J. & Duvernoy, H.M. (1996). Arterial vascular territories of human brain: brainstem and cerebellum. Neurology, 47, 1125–34. Tatu, L., Moulin, T., Bogousslavsky, J. & Duvernoy, H.M. (1998). Arterial vascular territories of human brain: hemispheres. Neurology, 50, 1699–708. Van der Zwann, A., Hillen, B., Tulleken, C.A.F., Dujovny, M. & Dragovic, L. (1992). Variability of the territories of the major cerebral arteries. Journal of Neurosurgery, 77, 927–40.

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Superficial middle cerebral artery syndromes Jean-Philippe Neau1 and Julien Bogousslavsky2 1

Clinical Neurology Services, Jean Bernard Hospital, Poitiers, France 2 Department of Neurology, University of Lausanne, Switzerland

Introduction The middle cerebral artery (MCA) and its branches are the most commonly affected brain vessels in cerebral infarction. The MCA territory was involved in more than twothirds of all cerebral infarcts in 891 patients with first stroke in the Lausanne Stroke Registry; the remainder affecting the posterior circulation (26%), and more rarely the anterior cerebral artery (2%). Among MCA infarcts, the superficial MCA territory was involved in more than half the patients, the deep MCA territory in one-third and the deep plus superficial MCA territory in one-tenth (Bogousslavsky et al., 1988a). Superficial MCA territory infarcts can be large when the occlusion of the MCA trunk is proximal, at the level of the bior trifurcation just after the origin of the lenticulostriate arteries, mainly in the absence of an efficient collateral system. However, superficial MCA territory infarcts can also be partial if a distal branch is occluded (Bogousslavsky, 1991b). In the Lausanne Stroke Registry, superficial MCA infarct was observed in nearly one-third of all first strokes, and in more than half the carotid territory infarcts (anterior superficial in 31%; posterior superficial in 20%) (Bogousslavsky et al., 1988a). Complete superficial territory infarcts may occur in 3% of the patients, whereas upper division and lower division MCA infarcts occur, respectively, in 18% and 14% (Bogousslavsky, 1991b), especially on the left side (Bogousslavsky et al., 1989; Mohr et al., 1978). Because most of the frontal, temporal, and parietal lobes are supplied by MCA pial branches, the neurologic picture is highly variable and follows the location of infarct. A few clinical syndromes are strongly suggestive of a MCA branch territory infarct, which can be recognized before CT or MRI. In addition, some topographic patterns of infarct may be preferentially associated with specific underlying mechanisms of stroke, which may be of great

help in establishing the etiologic diagnosis strategies in individual patients (Bogousslavsky, 1991a). Before delineating the different clinical syndromes, a good knowledge of the anatomy of the territory of the MCA and its branches, and of its anastomoses with pial vessels from the anterior and posterior cerebral artery, is necessary in order to understand the clinical and the neuroradiological findings of MCA territory infarction.

Anatomy and vascular territory Anatomy of the middle cerebral artery The MCA is the largest and probably the most complex of the six major cerebral arteries. Its anatomy and its territory have been studied by macroscopic examination using an injection of coloured mixtures (Van Der Zwan et al., 1992), dissecting microcospy (Gibo et al., 1981; Marinkovic et al., 1985), angiography, computed tomography with adapted techniques (Berman et al., 1984; Takahashi et al., 1985), and, more recently, magnetic resonance imaging, magnetic resonance angiography and computer-assisted 3D reconstruction (Gloger et al., 1994). The MCA is compared to a tree with a trunk and several branches. It originates as a single stem from the internal carotid artery at the medial end of the sylvian fissure, below the anterior perforated substance, lateral to the optic chiasm, and posterior to the olfactory tract. The main horizontal stem has variable parameters with a diameter ranging from 2.4 to 4.6 mm and a length ranging from 18 to 25 mm (Gibo et al., 1981; Grand, 1980; Grellier et al., 1978; Jain, 1964; Lazorthes et al., 1976). From 5 to 17 penetrating lenticulostriate arteries branch off this MCA trunk, most commonly from its dorsal surface. They are classified into medial and lateral branches; the latter being

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Fig. 30.1.Selective injection of the middle cerebral artery. Lateral view. 1: orbitofrontal (laterofronto basal) artery; 2: prefrontal artery; 3: precentral (prerolandic or precentral sulcus) artery; 4: central (rolandic or central sulcus) artery; 5: anterior parietal (postcentral sulcus) artery; 6: posterior parietal artery; 7: angular artery; 8: temporo-occipital artery; 9: posterior temporal (posterotemporal) artery; 10: middle (intermedial) temporal artery; 11: anterior temporal artery; 12: temporo-polar artery (from Salamon, 1973, with permission).

approximatively twice as large as the former (Marinkovic et al., 1985). They enter the anterior perforated substance and supply the body and the head of the caudate nucleus, the upper part of the anterior limb, the genu and the anterior part of the posterior limb of the internal capsule, and the putamen and lateral pallidum. However, these lenticulostriate branches can originate from the secondary trunks (15.3%), mainly the upper division of the MCA, and in 5.7% from the early branches, more usually temporal branches. After its horizontal segment, on entering the insular region, the MCA stem divides in one of three ways: (i) bifurcation into an inferior and a superior trunk (78%); (ii) trifurcation into an inferior, a middle, and an superior trunk (12%), or (iii) continuation into multiple smaller divisions with no major trunk (10%) (Gibo et al., 1981; Lazorthes et al., 1976). Twelve unequal branches subsequently originate (Salamon, 1973) and emerge from the lateral sulcus to supply the lateral surface of the hemisphere (frontal and parietal lobes, and the superior portion of the temporal

lobe), white-matter, claustrum and extreme capsule (Fig. 30.1). They distribute in a ‘fanlike’ fashion over the lateral convexity (Carpenter & Sutin, 1983). In the bifurcation pattern, the superior division almost invariably gives rise to the orbitofrontal, prefrontal, precentral, and usually the central sulcus (rolandic) branches, whereas the inferior division always gives rise to the posterior temporal, middle temporal, anterior temporal, temporopolar, and usually the temporo-occipital branches. The posterior parietal, anterior parietal, and angular branches originate from either division. In the trifurcation pattern, the superior division gives rise to the orbitofrontal, prefrontal, and precentral branches; the middle division gives rise to the central and the anterior parietal branches, and less often to the precentral, posterior parietal, angular, and temporooccipital branches; and the inferior division gives rise to the temporopolar, posterior, anterior, and middle temporal branches, and sometimes to the posterior parietal, angular and temporo-occipital branches (Fig. 30.2).

Superficial middle cerebral artery syndromes

Fig. 30.2. Branching patterns of the middle cerebral artery. Upper left: bifurcation into equal trunks (18%). Upper right: bifurcation into dominant inferior trunk (32%). Centre left: bifurcation into dominant superior trunk (28%). Center right: trifurcation pattern (12%). Lower: multiple trunks (10%). Main Tr. (main trunk); Sup. Tr. (superior trunk); Inf. Tr. (inferior trunk); Mid. Tr. (middle trunk); Len. Str. A (lenticulostriate arteries); Orb. Fr. A. (orbitofrontal artery); Pre. Fr. A. (prefrontal artery); Pre. Cent. A. (precentral artery); Cent. A. (central artery); Ant. Par. A. (anterior parietal artery); Post. Par. A. (posterior parietal artery); Ang. A. (angular artery); Temp. Occ. A. (temporo-occipital artery); Post. Temp. A. (posterior temporal artery); Mid. Temp. A. (middle temporal artery); Ant. Temp. A. (anterior temporal artery); Temp. Pol. A. (temporo-polar artery) (from Gibo et al., 1981, with permission).

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These cortical arteries give no significant branches to one another and end in a dense network of small arteries and arterioles that anastomose with terminal end-to-end pial vessels of the posterior (PCA) and anterior cerebral artery (ACA) in hemispheral borderzones (Duvernois et al., 1981). The superficial branches of the MCA supply most of the hemispheral white-matter through their medullary arteries, which perforate the centrum ovale and lead toward the upper part of the lateral ventricles (De Reuck, 1971). These medullary branches usually have single territories, do not anastomose to one another (Moore et al., 1991) and tend to form a borderzone with the deep perforating branches (lenticulostriate branches of Duret) of the MCA and of the anterior choroidal artery at the level of the deeper part of the corona radiata. This borderzone cannot be called ‘watershed’ because the medullary arteries are terminal and do not anastomose with the deep perforators of the lenticulostriate arteries. This is in contrast with the numerous anastomoses between the pial vessels, which form another type of borderzone, called watershed. Anatomic variants and anomalies of the MCA have been described in less than 3% of people (Umansky et al., 1988). MCA duplication (Vincentelli et al., 1970) is the most common; the duplicate vessel arises from the internal carotid artery and supplies the temporopolar, middle temporal, and anterior temporal territory. The absence of a MCA with an accessory MCA arising from the anterior cerebral artery and supplying the frontopolar territory is extremely rare. Exceptionally, the ACA (Goldberg, 1974; Rhoton et al., 1979) and the tuberothalamic artery may originate from the MCA. Furthermore, seventeen different variations of the intracerebral distribution of the MCA have been observed (Van Der Zwan et al., 1992).

Radiological description of the middle cerebral artery The MCA is classically divided into four segments. The M1 or sphenoidal segment is horizontal, begins at the origin of the MCA, and terminates just after the bifurcation. It provides the lenticulostriate arteries and small early cortical branches distributed to the frontal and temporal lobes (Gibo et al., 1981), then turns 90° at the genu of the MCA.The M2 or insular segment runs over the insula, terminates at the circular sulcus of the insula, and provides most cortical arteries. The M3 or opercular segment ends at the surface of the sylvian fissure after two 180° turns (Lazorthes et al., 1976). The branches of the M4 or cortical segment emerge from the sylvian fissure, follow along the sulci and gyri and extend over the cortical surface of the cerebral hemisphere.

Superfical arterial territory of the middle cerebral artery. This MCA arterial territory presents three main particularities: (i) a large cortical and subcortical territory, (ii) extensive borderzones with the anterior and posterior cerebral arteries, and (iii) its own subcortical borderzone between its superficial and deep branches. The cortical territory is supplied by the twelve pial branches including four-fifths of the convexity of the hemisphere, with the lateral part of the orbital surface of the frontal lobe, the parietal lobe, and the lateral part of the temporal lobe (Gibo et al., 1981). Table 30.1 and Fig. 30.3 show the classification proposed by Salamon (1973), which is widely used. Furthermore, in order to help clinicians localize the territory involved by infarcts, the CT and MRI templates of the superficial MCA territory (Fig. 30.4; Bogousslavsky et al., 1993a,b; Tatu et al., 1998), and the centrum ovale were carried out (Bogousslavsky et al., 1993a,b; Damasio, 1983), but they represent only dominant patterns of vascularization (Damasio, 1983).

Superficial middle cerebral artery syndromes First described in detail by Foix and Lévy in 1927, the varied clinical patterns of MCA territory infarcts depend on the location, size, and side of the infarct. While some clinical syndromes are highly suggestive of an infarct in the territory of one of the MCA branches, other infarcts are associated with non-characteristic features.

Complete MCA pial territory infarction Complete MCA pial territory infarct is relatively rare (Bogousslavsky, 1991a,b), without any specific study devoted to this type of infarct (Saver & Biller, 1995). Involvement of the territory of the superior division of the MCA is often prominent, with the territory of the orbitofrontal and anterior temporal branches often being spared, because these branches originate more proximally or in isolation (Foix & Lévy, 1927). Complete MCA pial territory infarct is usually due to distal occlusion of the MCA trunk, mainly attributable to cardiac or artery-to-artery embolism (Saito et al., 1987), but may result, although much more rarely, from in situ atherosclerosis (Fig. 30.5(a) and (b); Ueda et al., 1992). The typical, but non-specific, clinical picture of superficial MCA territory infarcts includes sudden onset of an isolated faciobrachial sensorimotor deficit with partial sensory loss associated with aphasia in left-sided lesions

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Table 30.1. Cortical territories of the middle cererbal artery Artery

Other names of the nomenclature

Vascular territory

Orbito frontal

Lateral frontobasal Frontobasalis lateralis

Orbital portion of the middle and the inferior frontal gyri Inferior pars orbitalis

Prefrontal artery

Candelabra Prefrontalis

Superior pars orbitalis; pars triangularis Anterior pars opercularis; middle frontal gyrus Inferior part of superior frontal gyrus

Precentral artery

Perolandic Precentral sulcus Sulci precentralis

Posterior pars opercularis; posterior middle frontal gyrus Anterior and middle part of precentral gyrus

Central artery

Rolandic Central sulcus Sulci centralis

Posterior precentral gyrus; anterior half of postcentral gyrus

Anterior parietal artery

Parietalis anterior Sulci postcentralis

Posterior postcentral gyrus; parasagittal portion of central sulcus Anterior part of inferior parietal lobule Anterior part of superior parietal lobule

Posterior parietal artery

Parietalis posterior

Posterior part of superior and inferior parietal lobules (including supramarginal gyrus)

Angular artery

Angular gyrus Gyri angularis

Posterior part of superior temporal gyrus Variable portion of supramarginal and angular gyri Superior part of lateral occipital gyrus

Temporo-occipital artery

Temporo-occipitalis

Inferior part of the lateral occipital gyrus Posterior half of the superior temporal gyrus Posterior extreme of the middle and inferior gyri

Posterior temporal artery

Posterotemporal Temporalis posterior

Middle and posterior parts of the superior temporal gyrus Posterior third of the middle temporal gyrus Posterior extreme of the inferior temporal gyrus

Middle temporal artery

Intermedial temporal Temporalis intermedia

Superior temporal gyrus; middle part of the middle temporal gyrus Middle and posterior parts of the inferior temporal gyrus

Anterior temporal artery

Anterotemporal Temporalis anterior

Anterior portion of the superior, middle and inferior temporal gyri

Temporopolar artery

Temporopolaris

Anterior pole of the superior, middle and inferior temporal gyri

and visuospatial impairment in right-sided lesions (Blecic et al., 1993). Hemiparesis usually has a brachiofacial distribution (Foix & Lévy, 1927; Lascelles & Burrows, 1965), but a distal predominance (Moody et al., 1990) or a severe hemiplegia (Mohr et al., 1993) can be found. Hemisensory loss, involving mainly tactile and discriminative modalities, usually exhibits the same distribution, but often spares the face (Foix & Lévy, 1927). Contralateral homonymous hemianopia or upper quadrantanopia, and transient conjugate deviation of eye and head toward the lesion, are also common. The neuropsychological disturbances associate global or Broca’s aphasia and ideomotor apraxia in leftsided lesions, and contralateral visuospatial neglect, anosodiaphoria, motor impersistence (De Renzi et al., 1986;

Fisher, 1956; Hier et al., 1983a,b), denial of illness (Hier et al., 1983a), inability to maintain eye closure (De Renzi et al., 1986), dressing and constructional apraxia (Hier et al., 1983a,b), acute confusional state (Mori & Yamadori, 1987), or, more rarely, sensory aprosodia (Darby, 1993) in rightsided lesions.

MCA superior or anterior division territory infarct MCA superior (anterior) division territory infarct is uncommon (Foix & Lévy, 1927; Mohr et al., 1978), because the superior trunk is very short (20 to 50 mm) (Foix & Lévy, 1927). The superior trunk supplies a large cortical and subcortical area, including the anterior parietal lobe and most

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Fig. 30.3. Cortical territories of the 12 branches of the middle cerebral artery: Orb.Fr. (orbitofrontal); Pre.Fr. (prefrontal); Pre.Cen. (precentral); Cen. (central); Ant.Par. (anterior parietal); Post.Par. (posterior parietal); Ang. (angular); Temp.Occ. (temporo-occipital); Post.Temp. (posterior temporal); Mid.Temp. (middle temporal); Ant. Temp. (anterior temporal); Temp.Pol. (temporo-polar) (from Gibo et al., 1981, with permission).

of the convexity of the frontal lobe, with involvement of the precentral and postcentral gyri (Fig. 30.6(a) and (b)). This territory infarct is not the consequence of a specific stroke mechanism and associates sensorimotor and neuropsychological disturbances. A contralateral hemiparesis with prominent faciobrachial deficit (sometimes associated with a mild lower limb deficit), and hemisensory loss with the same distribution are usually encountered. Conjugate eye deviation toward the lesion or a decreased exploration towards the opposite side with head and eyes remaining in the midline may be observed. Visual field defect is usually absent, observed in only 2% of patients with posterior extension towards the optic radiations (Bogousslavsky et al., 1989). Neuropsychological dysfunction is the rule (Heilman & Valenstein, 1972). In left-sided infarcts, mutism (aphemia) may sometimes be observed at stroke onset, evolving over a few days toward Broca’s aphasia frequently accompanied with buccolinguofacial apraxia (Tognola & Vignolo, 1980). Speech disturbances may be absent or may surprisingly correspond to those ofWernicke’s aphasia in 2% of the cases (Bogousslavsky et al., 1989). Poststroke depression seems to be particularly frequent after anterior left infarct (Robinson & Starkstein, 1990) and may be correlated with non-fluent aphasia (Astrom et al., 1993; Robinson, 1981;

Signer et al., 1989), although this remains controversial. In right-sided infarcts, variable degrees of hemi-inattention or hemispatial neglect associated with dysarthria or dysprosodia (monotonous speech without melodic and emotional inflections) (Ross, 1981) are common. Denial of hemiplegia (Cutting, 1978) and denial of eye closure with confabulations about what they claim they see through their closed eyes (Ellis & Small, 1994), may be present. Acute confusional state (failure to maintain a coherent stream of thought or action with inattention and distractibility) may be encountered in more than two-thirds of MCA superior division territory infarcts (Mori & Yamadori, 1987).

MCA inferior or posterior division territory infarct MCA inferior or posterior division territory infarct represents 14% of 2000 patients of the Lausanne Stroke Registry (Bogousslavsky, 1991b) with damage to the superior and inferior parietal and temporal gyri (Fig. 30.7). The neurologic picture is different from what is found in MCA superior territory infarct and associates visual field and neuropsychological disturbances. Motor weakness has a faciobrachial distribution, and is typically mild or transient and never isolated. Impairment of touch and pain sensation is often associated with extinction contra-

Superficial middle cerebral artery syndromes

lateral to the lesion on bilateral tactile stimuli. Visual field disturbances are common with contralateral homonymous hemianopia or upper quadrantanopia (Caplan et al., 1986). In left-sided infarcts, Wernicke’s aphasia (Fisher, 1970; Ross, 1993), and conduction aphasia, but usually as an evolutive pattern of Wernicke’s aphasia, are frequently encountered. More rarely, the initial speech disturbance is suggestive of a global aphasia within the first few hours of stroke, but rapidly evolving toward a Wernicke’s aphasia (Bogousslavsky et al., 1989; Vignolo et al., 1986). Exceptionally (1%), a Broca-type aphasia can be encounterd in posterior MCA infarcts (Bogousslavsky et al., 1989). In right-sided infarcts, left hemineglect, constructional dyspraxia resulting from involvement of the inferior parietal lobe, and behavioural changes are frequently observed. In half the patients, behavioural changes (Caplan et al., 1986; Mohr et al., 1978) are the most striking pattern of this type of infarct on the right side. Acute confusional state may be observed in right MCA inferior division territory infarct in nearly half the patients (Caplan et al., 1986; Mori & Yamadori, 1987). However, acute agitated delirium is more suggestive of this topography, although it occurs in 33% of cases. It includes vivid hallucinations, delusions and affective and autonomic excitement (Mori & Yamadori, 1987) and patients are agitated, restless, inappropriately unconcerned, jocular, and insomniac, and may produce continuous moaning-like utterances (Grafman et al., 1986). Acute agitated delirium is not observed in MCA superior division territory infarct, but may occur with posterior cerebral artery territory infarct. Acute agitated delirium is probably a result of damage to the right middle temporal gyrus and inferior parietal lobule. Sensory aprosody seems an acute marker of right inferior division territory MCA infarcts, but may be occasionally observed in right total MCA infarct, right MCA superior division territory infarct (Darby, 1993), and right large subcortical infarct (Wolfe & Ross, 1987). It is a disorder of emotional speech with impairment of prosodoaffective comprehension and repetition and identification of emotional gesturing, and relatively spared expression (Cancelliere & Kertesz, 1990; Darby, 1993; Gorelick & Ross, 1983; Hughes et al., 1983; Ross, 1981). Sensory aprosody is probably the result of damage to the right posterosuperior temporal lobe (Darby, 1993). An asymmetrical catalepsy with perseveration of posture more prominent in left extremities has rarely been reported (Saver et al., 1993). This unusual symptom may be viewed as the mirror image of ‘motor impersistence’ and is associated with severe left hemispatial neglect and hemisensory loss. Delayed poststroke depression may be more common with right than with left posterior infarct (Finset, 1988).

The stroke mechanisms of MCA superior and inferior division territory infarcts are different (Bogousslavsky et al., 1989). Large-artery disease may be the presumed cause of both infarct types in 34% of the patients, but severe ipsilateral disease (⬎90% ICA or MCA stenosis or occlusion) is more common in patients with anterior infarcts (26.5%) than in patients with posterior infarcts (17.5%).The much higher prevalence of cardioembolism in patients with posterior infarcts (34%) than in those with anterior infarcts (19%) is the most striking feature (Bogousslavsky et al., 1989; Caplan et al., 1986). In left temporal or temporo-occipital branches territory infarct, Wernicke’s aphasia with or without right hemianopia is suggestive of cardiac or artery-to-artery embolism (Bogousslavsky et al., 1989; Harrison & Marshall, 1987; Mohr et al., 1978; Zaraspe Yoo et al., 1982), whereas intrinsic occlusive disease of the MCA inferior division remains rare (Caplan et al., 1985). The explanation of the higher prevalence of cardioembolism in patients with posterior infarcts than in those with anterior infarcts remains unclear, but it has been suggested that hemodynamic channels in the carotid system may favour the progression of small thrombi along the inferior division of the MCA when the carotid artery is not stenosed or occluded (Caplan et al., 1985; Harrison & Marshall, 1987).

Orbitofrontal (or lateral frontobasal (Gloger et al., 1994) artery territory infarct The orbitofrontal branch supplies the orbital portion of the middle and inferior frontal gyri and the inferior orbital part of the frontal lobe (Gloger et al., 1994; Salamon, 1973). Isolated unilateral infarct of the orbitofrontal artery is exceptional, and prefrontral and central artery territory infarct is usually associated (Derouesné, 1973). To our knowledge, only one case has been reported in a series of 42 MCA occlusions diagnosed angiographically (Waddington & Ring, 1968). The clinical pattern is poorly delineated, but may include a ‘frontal syndrome’ with senseless joking, inappropriate playfulness and desinhibition, deterioration of thinking and behaviour’ associated with contralateral forced grasping and conjugate deviation of the eyes (Waddington & Ring, 1968).

Prefrontal artery territory infarct The prefrontal arteries are numerous with a common stem that branches off in a candelabra form and supplies the middle frontal gyrus and the superior orbital triangular and anterior opercular parts of the frontal lobe (Gloger

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(a )

Fig. 30.4(a) and (b). Template map of arterial territories of the cerebral hemispheres. The left side of the sections shows the territories of the cerebral arteries. The right side of the sections shows the anatomic structures (gyri in purple and sulci in green) and Brodmann’s areas (in blue) (from Tatu et al., 1998, with permission). Gyri (red): CG: cingulate gyrus, F1 superior frontal gyrus; F2: middle frontal gyrus; F3: inferior frontal gyrus; F3op: inferior frontal gyrus pars opercularis; F3or: inferior frontal gyrus pars oralis; F3t: inferior frontal gyrus pars triangularis; FMG: frontomarginal gyrus; GR: gyrus rectus; LOG: lateral orbital gyrus; MOG: medial orbital gyrus; PCu: precuneus; POG posterior orbital gyrus; SCG: subcallosal gyrus; PCL: paracentral lobule; PoCG: postcentral gyrus; PrCG: precentral gyrus; AG: angular gyrus; P1: superior parietal gyrus; P2: inferior parietal gyrus; SMG: supramarginalis gyrus; T1: superior temporal gyrus; T2: middle temporal gyrus; T3: inferior temporal gyrus; T4: fusiform gyrus; T5: parahippocampal gyrus; TTG: transverse temporal gyrus; O1: superior occipital gyrus; O2: middle occipital gyrus; O3: inferior occipital gyrus; O4: fusiform gyrus; O5: lingual gyrus; O6: cuneus; GD: gyrus descendens (Ecker); RSG: retrosplenial gyrus.

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(b)

Fig. 30.4(a) and (b) (cont.) Sulci (blue): AOS: anterior occipital sulcus; CaS: calcarine sulcus; Cis: cingulate sulcus; Cos: collateral sulcus; CS: central sulcus; IFS: inferior fronta sulcus; IOS: intraoccipital sulcus (superior occipital sulcus); IPS: intraparietal sulcus; LF: lateral fissure; LS: lingual sulcus; OS: olfactory sulcus; PCS: paracentral sulcus; PoCS: postcentral sulcus; POF: parieto-occipital fissure; PrCS: precentral sulcus; RCS: retrocalcarine sulcus; SFS: superior frontal sulcus; SPS: subparietal sulcus; STS superior temporal sulcus; TOS: transverse occipital sulcus. Brodmann’s areas (shaded)

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ites, utilization and imitation behaviors (Lhermitte, 1983; Lhermitte et al., 1986; Mori & Yamadori, 1982; Saver & Biller, 1995), grasp reflex (De Renzi & Barbieri, 1992), perseverations, with poor abstraction and categorization, impairment of mental flexibility, apathy and abulia. Delusions (false convictions not corrected by experience or reason), involve orientation in time and place, past events or identify of familiar individuals. They have been reported in dorsolateral prefrontal infarcts, more often right-sided than left-sided and usually need pre-existing cerebral atrophy to develop (Levine & Grek, 1984). In leftsided lesions, transcortical motor aphasia with diminished verbal fluency is common, especially in the acute stage of infarct, while right-sided infarct may induce motor neglect.

(a )

Precentral (prerolandic or precentral sulcus) artery territory infarct

(b)

Fig. 30.5. Magnetic resonance imaging scan of a bilateral superficial middle cerebral artery territory infarct (Fig. 30.5(a)) in a 39-year-old man with left stenosis of the MCA trunk after the origin of lenticulostriate arteries (arrow) on carotid angiogram (Fig. 30. 5(b)).

et al., 1994). The lack of sensorimotor disturbances and neuropsychological abnormalities (‘prefrontal syndrome’ of Luria) are the most prominent features of this infarct territory (Bogousslavsky & Regli, 1992). It includes cognitive and behavioural deficits with loss of programmation abil-

The precentral arteries (candelabra, operculofrontal, and prerolandic arteries) have several branches that supply primarily the anterior and middle parts of the precentral gyrus, the posterior middle frontal gyrus, and the superior orbital part of the frontal lobe. This territory infarct is not associated with a specific stroke mechanism (Bogousslavsky et al., 1989) and associates motor and often neuropsychological disturbances. The paresis is usually more prominent in the arm than in the leg, with involvement of the abduction, adduction, elevation, flexion, and extension of the proximal upper limb (Freund & Hummelshein, 1985). A right proximal upper limb weakness associated with transcortical motor aphasia and inability to perform successive motor sequences smoothly (premotor syndrome of Luria) is strongly suggestive of left precentral artery territory infarct (Bogousslavsky et al., 1989). However, a predominantly distal brachiofacial paresis may also be observed. In contrast to the motor impairment, sensory disturbances are absent or slight, resulting from damage to the anterior part of the parietal cortex when the precentral artery contributes to its supply (Kunesch et al., 1995). The neuropsychological disturbance is the second striking feature of the precentral territory infarct. ‘Premotor syndrome’ or loss of kinetic melody (limb kinetic apraxia), as first described by Luria (1969), is characterized by difficulties in smoothly switching from one motor act to another, whereas each act can be easily and normally performed in isolation (Freund & Hummelshein, 1985). This inability is manifested by motor perseverations, interruption of motor sequences, and decomposition of acts into elementary motor patterns (Bogousslavsky, 1992). ‘Motor

Superficial middle cerebral artery syndromes

Fig. 30.6. Magnetic resonance imaging scan of a left middle cerebral artery territory superior (or anterior) division territory infarct (Fig. 30.6(a)) and left carotid angiogram (Fig. 30.6(b)) showing occlusion (emboli) of the left anterior secondary MCA bifurcation (arrow).

impersistence’, described by Fisher 1956, designates the impossibility for the subject to sustain simple acts (keeping the mouth open, protruding the tongue, holding the breath (Kertesz et al., 1985) or holding the eyelids shut more than ten seconds (apraxia of lid closure of Lewandowsky (1907)). Its mirror syndrome, called ‘motor persistence’ (Bogousslavsky, 1991d), seems not so rare in the acute course of stroke and is characterized by abnormal maintenance of a peculiar and often uncomfortable position, and encountered mainly in right-sided infarct, sometimes following motor impersistence within a few days. Hemineglect is observed usually in retrorolandic lesions (Vallar & Perani, 1986), but it can also be observed in rightsided premotor lesions (Castaigne et al., 1972) with difficulties in the coordination of motor programmes for exploration, lack of spontaneous placing reaction, delayed and insufficient assumption of correct postures, impaired automatic withdrawal reaction to pain (Mohr et al., 1993) with prolonged reaction times for movements directed contralaterally (Heilman et al., 1985). This frontal neglect can be clinically distinguished from parietal neglect by an abnormal cancellation test associated with a normal line bisection test (Binder et al., 1992). Different types of aphasia may be encountered in left-sided precentral artery territory infarct. Transcortical motor aphasia is the most common type, with delayed initiation of speech, laconic, grammatical, sentence-length utterances with semantic paraphasias and preserved repetition and comprehension (Alexander et al., 1992). In a few cases, other types of aphasia can be observed: (i) global aphasia without hemiparesis, classically caused by two remote lesions in the dominant hemisphere (one affecting the posterior, and the other the anterior language areas) (Tranel et al., 1987; Van Horn & Hawes, 1982) or more rarely by a single left temporoparietal infarct (Bogousslavsky, 1988); (ii) aphemia or pure apraxia of speech with dysarthric spoken output not facilitated by reading, repetition, recitation, or naming but without aphasia (Schiff et al., 1983; (iii) pure anarthria of Pierre Marie; (iv) transcortical sensory aphasia (Otsuki et al., 1998). In a few cases, marked alexia (Foix & Lévy, 1927); agraphia with (Tohgi et al., 1995) or without (Rapcsak et al., 1988) acalculia, sometimes limited to alphabetical paragraphia (50); and even comprehension disturbances (Tramo et al., 1988), have been reported.

(a )

(b)

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Fig. 30.7. Computed tomography scan of a left middle cerebral artery territory inferior (or posterior) division territory infarct in 68-year-old woman with non-valvular atrial fibrillation.

Central sulcus (central or rolandic) artery territory infarct The vascular territory of the central sulcus arteries includes the posterior precentral gyrus (which could also be supplied, in half the patients, by an accessory branch coming from the precentral artery), and the anterior half of the postcentral gyrus. This vascular territory can be supplied by two central sulcus arteries or only one with two branches that run in parallel, one anterior supplying the motor strip and one posterior supplying the sensory strip (Gloger et al., 1994). Isolated central sulcus artery territory infarct, first thought to be rare (Foix & Lévy, 1927), may not be uncommon (Géraud et al., 1970; Waddington & Ring, 1968), consistent with small infarcts and is not associated with a specific stroke mechanism (Bogousslavsky et al., 1989). In proximal occlusion, the motor deficit is severe and affects the face and arm more than the leg, with hemisensory loss in the same distribution (Géraud et al., 1970; Waddington & Ring, 1968). In distal occlusion, motor weakness is usually limited to the arm or to the distal upper extremity with only mild hemisensory loss. Isolated cheiro-oral sensory loss may be also observed with occlusion of the posterior branch of the central sulcus artery, with infarction limited to the parietal operculum (posterior operculum syndrome of Bruyn) (Bruyn & Gathier,

1969). On the other hand, pure motor hemiparesis involving the face, arm, and leg (Bogousslavsky et al., 1989) or only fingers (Lee et al., 1998; Terao et al., 1993) may also be the sole manifestation of central sulcus artery territory infarct (Bogousslavsky et al., 1989). Unilateral upper limb ataxia with asterixis but no hemisensory disturbances (Nighoghossian et al., 1995; Waddington & Ring, 1968), writing tremor (Kim & Lee, 1994) or segmental action myoclonus (Manai et al., 1998) are unusual. In bilateral damage to the primary motor cortex in the frontal operculum, the cortical form of the anterior opercular syndrome (Foix–Chavany–Marie syndrome) could be observed and is characterized by loss of voluntary control of facial, pharyngeal, lingual, and masticatory muscles, preserved reflexive and automatic functions, and anarthria or severe dysarthria (Alajouanine & Thurel, 1932; Alajouanine et al., 1959; Besson et al., 1991; Foix et al., 1926; Levine & Mohr, 1979; Mao et al., 1989; Weller, 1992, 1993). In exceptional cases, a bilateral anterior opercular syndrome may be secondary to unilateral infarct (Berthier et al., 1986; Pertuiset & Perrier, 1960). In left-sided infarcts, mild Broca’s aphasia is usual, whereas in right-sided infarcts, dysarthria may be encountered. The association of dysarthria or mild Broca’s aphasia with right faciobrachial weakness and rapidly improving (within a few days) tongue, palatal, and trapezius weakness on the right side is suggestive of central sulcus artery territory infarct (Bogousslavsky et al., 1989), whereas dysarthria with the same motor deficit is found in right-sided infarct.

Anterior parietal (or postcentral sulcus) artery territory infarct The vascular territory of the anterior parietal artery includes the posterior postcentral gyrus and frequently the parasagittal part of the central sulcus, the anterior part of the inferior parietal gyrus, the supramarginal gyrus and parts of the upper and middle temporal gyri (Fig. 30.8). The anterior parietal artery territory infarct is relatively rare, identified in only 18 patients (5 right-sided and 13 leftsided) from more than 2500 patients with first ever stroke of the Lausanne Stroke Registry (Bogousslavsky, 1992). It does not imply a particular cause of stroke (Bogousslavsky et al., 1989). Neuropsychological disturbances (acute conduction aphasia or acute hemiconcern) and hemisensory dysfunction (pseudothalamic sensory syndrome or opercular cheiro-oral syndrome) are the most striking features of the anterior parietal territory infarct. The pseudothalamic syndrome, first reported by Roussy (Roussy & Foix, 1910) and by Foix (Foix et al., 1927),

Superficial middle cerebral artery syndromes

includes involvement of elementary modalities of sensation (touch, pain, temperature and vibration) typically affecting face, arm, and leg, and often the trunk, but usually predominating in the upper limb (Bassetti et al., 1993; Bogousslavsky et al., 1989; Foix et al., 1927; Lhermitte et al., 1990; Masson et al., 1991). The infarction always involves the posterior insula, the parietal operculum, the anterior part of the supramarginal gyrus, and the underlying white-matter (Bassetti et al., 1993; Pause et al., 1989). The clinical differentiation between thalamic and parietal strokes may be suspected, before CT or MRI, when neuropsychological dysfunctions (language impairment or visuospatial disturbances) are associated, because this distinction cannot be made on the basis of sensory deficits alone (Marie & Bouttier, 1922). Asymbolia for pain (Berthier et al., 1988; Masson et al., 1991), probably due to damage to the insula, induced or spontaneous pain (burning, icelike or constrictive pain) (Schmahmann & Leifer, 1992), summation hyperpathia, allodynia, essentially in right-sided infarct and developing in the acute stage of infarct or after a few months (Michel et al., 1990), are rarely observed. A parietal ataxia, with or without severe hemisensory loss (Appenzeller & Hanson, 1966), a slight motor weakness (lower facial assymmetry or decreased fine motility distally in the hand) or more rarely ataxia and dystonic postures of the hand (Bassetti et al., 1993) may be associated with this pseudothalamic syndrome. The rarity of the opercular cheiro-oral syndrome is probably due to the double vascularization to the parietal opercular area through branches of the temporal and anterior parietal arteries (Bogousslavsky, 1991c; Mrabet et al., 1993). It is characterized by objective or subjective sensory abnormalities in the face with severe hypoesthesia in the distal upper limb, involving mainly position sense, stereognosia and graphesthesia (Verger–Déjerine cortical hypoesthesia) and less frequently temperature and pain sensations (Bogousslavsky et al., 1991c; Mrabet et al., 1993). However, the cheiro-oral syndrome is more commonly described in thalamic involvement (Garcin & Laspresle, 1954; 1960; Kawakami et al., 1989) as emphasized by the review of literature of Haguenau (Haguenau, 1965) and more rarely among patients with pontine infarct (Kawakami et al., 1989), pontine hemorrhage (Araga et al., 1987; Iwasaki et al., 1989; Yasuda et al., 1988), and midbrain hemorrhage (Ono & Inoue, 1985). In left-sided infarcts, acute conduction aphasia, characterized by fluent speech, with normal comprehension, phonemic paraphasias, and impaired repetition, is usually observed and may be associated with ideomotor apraxia (Bogousslavsky et al., 1989), anomia, acalculia or agraphia

Fig. 30.8. 3D Magnetic resonance imaging of a left anterior parietal artery territory infarct (large arrow) in a 49-year-old man with dilated cardiomyopathy.

(Bassetti et al., 1993). This aphasia has also been earlier called ‘afferent motor aphasia’ of Luria or ‘kinesthetic aphasia’ (Lhermitte et al., 1990) and usually has an excellent recovery (Hyman & Tranel, 1989). It must be emphasized that, although conduction aphasia in stroke patients is a common evolutive pattern of Wernicke’s aphasia secondary to temporo-parietal lesion, acute conduction aphasia is unusual and specifically indicates a left anterior parietal artery territory infarct (Bogousslavsky et al., 1982) which represents a unique case of posterior aphasia due to an infarction of the MCA anterior division territory. In right-sided infarcts, hemisensory neglect or visuospatial and visuoconstructive abnormalities are common, mainly with involvement of the right inferior parietal lobule (Vallar & Perani, 1986). In the absence of spatial hemineglect, a particular motor and visual behavior, called ‘acute hemiconcern’ can be encountered in at least half the patients with right anterior parietal artery territory infarct (Bogousslavsky et al., 1995). This rare pattern, observed in less than 0.2% of acute stroke patients, is strongly suggestive of a right anterior parietal artery territory infarct, because it is not encountered in other infarcts with acute hemisensory loss (thalamic, capsular, brainstem). All patients presented severe loss of sensation. The patients concentrated on the left side of their bodies, looking at themselves for long periods and relentlessly rubbing, touching, pinching, pressing, lifting, and manipulating parts of their left arm, trunk, and leg with their right hand

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or foot. Their interest and activity are limited to the left side of their own body and were not associated with overinterest in the left hemispace. Neuropsychological testing in the acute phase fails to demonstatre any appreciable dysfunction. Acute hemiconcern is transient and lasts no more than a few days, disappearing with the improvement of the left-sided sensory disturbances (Bogousslavsky, 1992), and this may explain, in part, why it seems to have been commonly overlooked.

Posterior parietal artery territory infarct Isolated posterior parietal artery territory infarct is unusual (Géraud et al., 1970; Waddington & Ring, 1968), because it is more frequently observed in association with angular artery territory infarct (Derouesné, 1973; Foix & Lévy, 1927; Géraud et al., 1970); and only a few cases have been reported. The vascular territory of the posterior parietal artery includes the posterior parts of the superior and inferior parietal lobules with the supramarginal gyrus. Hemisensory disturbances with impairment of discriminative modalities in one or two parts of the body are observed. It corresponds to the cortical sensory syndrome, reported by Verger (1900) and by Déjerine and Mouzon (1914). It spares touch, vibration, pain, and temperature sensations and affects graphesthesia, usually associated with astereognosis and position sensory loss (Bassetti et al., 1993; Kim, 1992). Some numbness of the upper limb is always reported, but the face, arm, leg, and trunk are never involved together. It is sometimes associated with slight and transient motor weakness, usually faciobrachial, more rarely with ataxia or dystonia of the upper limb (Bassetti et al., 1993). A pseudothalamic syndrome (Jeannerod et al., 1984), a visual-field deficit (contralateral homonymous hemianopia or lower quadrantanopia) (Saver & Biller, 1995), or a parietal kinetic ataxia without proprioceptive deficit (Ghika et al., 1995) are exceptional. Neuropsychological aspects represent the second most common feature of the posterior parietal artery territory infarct with hemiextinction on bilateral simultaneous stimulation and visuospatial and visuoconstructive dysfunction in right-sided lesion (Bassetti et al., 1993). Wernicke’s aphasia; Gerstmann’s syndrome (Gerstmann, 1940) including right-left disorientation, finger agnosia, acalculia, and dysgraphia (Bassetti et al., 1993; Roeltgen et al., 1983; Waddington & Ring, 1968); ideomotor apraxia (Alexander et al., 1990; Bassetti et al., 1993; Rothi et al., 1985; Waddington & Ring, 1968); anomic aphasia; and phonologic agraphia and alexia may be observed in leftsided lesions.

Angular artery territory infarct Angular artery may be regarded as the main end-branch of the middle cerebral artery (Gibo et al., 1981) and its vascular territory usually includes the posterior portions of the superior and inferior parietal lobules, the inferior portion of the lateral occipital gyrus, and variable portions of the supramarginal and angular gyri. Isolated angular artery territory infarct is rare, because this artery is frequently occluded together with the parietal posterior artery (parieto-angular infarct of Foix and Lévy (1927) or with the posterior temporal artery (temporo-angular infarct of Foix and Lévy (1927). A few observations of isolated occlusion of angular arteries, without any particular causes, allow delineation of two clinical patterns of angular artery territory infarct (Géraud et al., 1970; Moore et al., 1991; Waddington & Ring, 1968) depending on the level of occlusion (Géraud et al., 1970). In distal occlusion, visual field abnormalities (contralateral hemianopia or lower quadrantanopia) may be the sole manifestation, without neuropsychological impairment whatever the side of the infarct (Géraud et al., 1970). Impaired tracking of visual targets directed toward the infarct side (Larmande et al., 1980), or optic ataxia, may be observed (Bogousslavsky et al., 1993). In proximal occlusion, the clinical pattern is more severe. A transient motor weakness may be associated with the visual field disturbances and prevalent neuropsychological impairments (Géraud et al., 1970; Waddington & Ring, 1968). Gerstmann’s syndrome (right-left disorientation, finger agnosia, acalculia, and dysgraphia) or angular gyrus syndrome (Benton, 1961, 1992) is usually encountered in leftsided lesions, but can also be produced by lesions in other areas of the brain (Santos et al., 1991). Its four components may be isolated (Strub & Geschwind, 1983) or accompanied by transcortical sensory aphasia, anomic aphasia (Bogousslavsky et al., 1993), Wernicke’s aphasia (Benson et al., 1982; Moore et al., 1991), alexia, or constructional disturbances (Benson et al., 1982). In rightsided lesions, hemispatial neglect with sensory predominance, hemiextinction on bilateral simultaneous stimulation, asomatognosia, visuoconstructive and visuospatial disturbances, and constructional apraxia are frequent; but Gerstmann’s syndrome is exceptional (Moore et al., 1991). In bilateral posterior parietal and angular artery territory infarcts, Balint’s syndrome (Balint, 1909) (psychic gaze paralysis, visual inattention, and optic ataxia) may be encountered, sometimes associated with anterograde and partially retrograde amnesia (Rousseaux et al., 1986).

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Temporal arteries territory infarct There are usually five temporal arteries: (i) the temporooccipital artery supplies the inferior part of the lateral occipital gyrus, the posterior half of the superior temporal gyrus, and the posterior extremes of the middle and inferior gyri; (ii) the posterior temporal artery supplies the middle and posterior part of the superior temporal gyrus, the posterior third of the middle temporal gyrus and the posterior extremes of the inferior temporal gyrus; (iii) the middle temporal artery supplies the superior temporal gyrus, the middle part of the middle temporal gyrus, and the middle and posterior parts of the inferior temporal gyrus; (iv) the anterior temporal artery supplies the anterior portions of the superior, middle, and inferior temporal gyri; (v) the temporopolar artery supplies the anterior poles of the superior, middle and inferior temporal gyri. Specific neurologic features of isolated temporal branch territory infarct have never been clearly delineated, and temporal arteries territory infarction is usually associated with coexisting damage to the inferior territory of the posterior parietal artery. The clinical feature associates neuropsychological and visual field disturbances (contralateral homonymous hemianopia or superior quadrantanopia) (Derouesné, 1973; Foix & Lévy, 1927) with sometimes slight and transient motor weakness and sensory dysfunction may be found (Caplan et al., 1986). A rotational vertigo with involvement of the posterior insula, the long insula and the transverse temporal (Heschl’s) gyrus has been described (Brandt et al., 1995). In left-sided lesions, isolated Wernicke’s aphasia or Wernicke’s aphasia with right hemianopia is the striking feature and is strongly suggestive of stroke in the left temporal or temporo-occipital artery territory (Bogousslavsky et al., 1989) with involvement of the posterior part of the superior temporal gyrus. Wernicke’ s aphasia is almost always associated with cardiac or artery-to-artery embolism as the cause of the infarct (Bogousslavsky et al., 1989). However, CT should be performed before anticoagulation, because Wernicke’s aphasia secondary to stroke may be associated with intracerebral hemorrhage in up to 10% of the patients (Knepper et al., 1989; Mohr et al., 1978). In right-sided lesions, left visual neglect, micropsia without spatial neglect (Ceriani et al., 1998), left-sided extinction on bilateral tactile stimuli, and constructional apraxia are the most common findings (Caplan et al., 1986). Acute agitated delirium (AAD) (Mori & Yamadori, 1982), and agitated confusional state (ACS), observed in half of the patients, with hyperactivity, hallucinations (Peroutka et

al., 1982), restlessness and distractibility (Awada et al., 1984; Boudin et al., 1963; Caplan et al., 1986), are the leading features. ACS could be caused by disruption of limbic structures (Caplan et al., 1986) and AAD by damage to the right middle temporal gyrus (Mori & Yamadori, 1987). In a recent prospective series, ACS occurs in one fourth of stroke patients over 40 years, is often associated with pre-existing cognive decline, metabolic or infectious disorders, and seems to be more frequent in right superficial infarcts (Hénon et al., 1999). However, ACS is also observed in left-sided infarcts (Gustafson et al., 1991) and in other locations such as right thalamic (Bogousslavsky et al., 1988b; Riedman, 1985; Santamaria et al., 1984), right ACA lesions, and left PCA territory infarcts (Devinsky et al., 1988). Secondary manic symptoms with elation, pressured speech and grandiose delusions, flight of ideas, hypersexuality, hyperactivity, irritability, and insomnia can be encountered in right temporobasal infarct (Starkstein et al., 1990), but they have also been observed after paramedian infarct of the right thalamus (Bogousslavsky et al., 1988b; Bogousslavsky, 1993), right caudate or anterior limb of the internal capsule infarcts (Starkstein et al., 1990). Unilateral cortical deafness or hemianacusia is rare. Expressive instrumental amusia (McFarland & Fortin, 1982), or difficulties with musical perception (Mazzuchi et al., 1982) independent of musical knowledge or training (Damasio & Damasio, 1977), can be present. Conversely, left temporoparietal lesions may not produce amusia (Signoret et al., 1987). Assal reported a pianist who had Wernicke’s aphasia and word deafness without any disturbance in his musical ability (Assal, 1973). However, difficulties in identification of melodies (Lechevalier et al., 1984; Souques & Baruk, 1930) or rhythm perception (Peretz, 1990) are usually present with damage to the left temporal lobe (Lechevalier et al., 1985) In bilateral lesions (Fig. 30.9), cortical deafness with complete (Barraquet-Bordas et al., 1980) or partial (Michel et al., 1980) deafness to all sounds may be observed, secondary to bilateral damage of the superior temporal gyri (Khurana et al., 1981). Cortical deafness may be associated with delusion characterized by time disorientation with a constant day’s advance (Assal & Bindschaedler, 1990), when the left parietal lobe, and temporal and insular areas in both hemispheres are involved. Pure word deafness with associated selective impairment of auditory verbal comprehension but without abnormalities of spontaneous speech, reading comprehension, and writing, may be observed after left temporal (Schuster & Taterka, 1926) or bilateral parietotemporal infarctions, mainly following Wernicke’s aphasia (Praamstra et al., 1991).

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Fig. 30.9. Computed tomography scan of a bilateral temporal artery territory infarct as the consequence of a non-valvular atrial fibrillation in a 78-year-old man with a cortical deafness.

Centrum ovale infarcts The centrum ovale (or centrum semiovale) of Vieussens comprises the central white-matter of the cerebral hemispheres, including the most superficial part of the corona radiata and the long association bundles (Fig. 30.10) (Bogousslavsky & Regli, 1992). Long perforating medullary arteries (2–5 cm) originated from the superficial (pial) MCA supply the centrum ovale and usually have a single territory without interdigitating. Centrum ovale infarcts account for only 1.2 (Read et al., 1998) to 2% of all strokes (Bogousslavsky & Regli, 1992) and two different subtypes may be distinguished because they differ by clinical, radiologic, and etiologic features,: (i) large centrum ovale infarct (maximum diameter greater than1.5 cm) and (ii) small centrum ovale infarct (maximum diameter of 1.5 cm or less) (Bogousslavsky & Regli, 1992). However, some discrepencies were recently reported concerning the incidence and the clinical patterns of these infarcts. The incidence seems much higher from 7% in the ECST series (Boiten et al., 1997) to 22% in the Lille series (Leys et al., 1994), which also includes silent centre ovale infarcts and associated infarcts outside the centrum ovale. Furthermore, the clinical patterns did not differ significantly between the two subtypes of centrum ovale infarcts (Read et al., 1988).

The large infarcts (Fig. 30.11) are the less frequent, representing less than one-quarter of the centrum ovale infarcts (Read et al., 1988). The stroke onset is usually acute and stabilizes within a few minutes. The neurologic picture is similar to that found in large superficial or extended MCA territory infarcts, including neuropsychological impairment (dysphasia, visuospatial dysfunction, and hemineglect) and motor, sensory, or visual field dysfunction (Bogousslavsky & Regli, 1992). On CT or MRI, large infarcts usually have irregular shapes with geographic margins often following the inner border of the cortex (Bogousslavsky & Regli, 1992). The mechanism of large infarcts is not clear and still discussed. Hemodynamic failure associated with severe ipsilateral carotid disease may be the main mechanism in up to three-quarters of the patients (Bogousslavsky & Regli, 1992), but artery-to-artery or cardiac embolisms can be found in some patients (Read et al., 1988). Small infarcts may often be silent (Leys et al., 1994) and they are more frequent than large infarcts (Read et al., 1988). In symptomatic patients, the neurologic deficit develops over several hours in at least one-half of the patients (Bogousslavsky & Regli, 1992). In 85% of the cases, the neurologic picture is compatible with a socalled lacunar syndrome, although the motor or sensory distribution pattern is more often partial (affecting mainly the upper limb (Read et al., 1988)) than (face, arm, and leg; Bogousslavsky & Regli, 1992; Gutmann & Scherer, 1989). Pure motor stroke is the most frequent pattern (Read et al., 1988), but pure sensory, sensorimotor stroke and ataxic hemiparesis can be observed (Bogousslavsky & Regli, 1992; Gutmann & Scherer, 1989). Movement disorders such as choreoathetosis (Barinagarrementeria et al., 1989) or neuropsychological impairment (dysphasia) are also uncommon. On CT or MRI, small infarcts are frequently round or ovoid (Bogousslavsky & Regli, 1992). They are usually associated with hypertension or diabetes, suggesting a mechanism similar to lacunar infarction in the territory of deep perforators of the MCA. Although most patients have risk factors for small-vessel disease, a complete diagnostic work-up is usually necessary, because the cause of small centrum ovale infarcts may be artery-toartery (Read et al., 1988) or cardiac embolism in one-third of the cases (Bogousslavsky & Regli, 1992; Leys et al., 1994).

Double infarction in one cerebral hemisphere Double infarct in one cerebral hemisphere is rare, representing less than 2% of first-ever acute strokes

Superficial middle cerebral artery syndromes

Fig. 30.10. White-matter medullary arteries territory (from Bogousslavsky & Regli, 1992, with permission).

(Bogousslavsky, 1991b). The most common combination involves territories of the anterior superficial middle cerebral artery plus the posterior superficial middle cerebral artery (Fig. 30.12); however, watershed infarct (usually anterior superficial MCA infarct associated with posterior watershed infarct) represents one-third of double infarcts. The most common mechanism of these infarcts is tight stenosis or occlusion of the ipsilateral internal carotid artery (Bogousslavsky, 1991b); contrasting with what is found in patients with a single infarct in the carotid system, where the prevalence of more than 50% stenosis or occlusion of ipsilateral ICA is about one-third (Bogousslavsky et al., 1988a). On the other hand, about 5% of first strokes with ICA occlusion may correspond to double infarct in one cerebral hemisphere. The prevalence of potential cardiac sources of embolism is similar to what is found in stroke in general (Bogousslavsky, 1991b). The most common neurological picture is similar to large infarction in the middle cerebral artery territory with

hemiparesis and hemihypesthesia, hemianopia, and aphasia or marked hemispatial neglect. However, more than 40% of the patients with double infarct in one cerebral hemisphere have a specific clinical syndrome, essentially in patients with left-sided infarcts (Bogousslavsky, 1991b).

Hemianopia–hemiplegia Homonymous hemianopia is usually congruent and complete, sometimes sparing part of the upper quadrant. Hemiparesis involves the face, arm and leg, or may have a brachiofacial distribution. There is no sensory dysfunction or speech disturbance. Hemispatial neglect may be found in right-sided infarcts.

Acute conduction aphasia with hemiparesis Hemiparesis has a brachiofacial distribution without sensory or visual field disturbances and is associated with a conduction aphasia.

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Fig. 30.11. Magnetic resonance imaging scan showing right large centrum ovale infarct (arrow) in a 58-year-old patient with right carotid artery dissection.

Fig. 30.12. Computed tomography scan of a double infarct in one cerebral hemisphere with involvement of the anterior superficial middle cerebral artery (arrows) and the posterior superficial middle cerebral artery (arrow heads) in a 78-year-old man with non-valvular atrial fibrillation.

Acute mixed transcortical aphasia This syndrome is uncommon, occuring mainly in the acute phase, and associates reduced speech, impaired naming, semantic paraphasias, echolalia, and impaired comprehension, but good repetition, reading, and writing on dictation. It may be associated with mild hemiparesis, usually predominating in the upper limb, slight hemisensory disturbances, or lower quadrantanopia. This particular type of aphasia has also be described in a patient with a left anterior capsular infarct followed two months later by a second stroke with extension of the first lesion (striatocapsular infarct) and a posterior watershed infarct (Cambier et al., 1980).

Acute multiple infarction in the anterior circulation Acute multiple infarction in the anterior circulation represents more than 5% of the ischemic strokes in the anterior circulation. Global aphasia with hemianopia, hemisensory loss or hemipareris, transcortical mixed aphasia with hemianopia, and acute pure cognitive impairment (‘dementia’) are three specific clinical pictures, found in up to 20% of the patients, and allowing diagnosis of acute multiple infarction in the anterior circulation before brain imaging. They are commonly caused by bilateral carotid atheroma or cardioembolism (Bogousslavsky et al., 1996).

Conclusions Although most neurologic patterns of MCA territory infarcts are less specific, and sometimes misleading, several clinical syndromes are highly suggestive of infarction in a specific superficial MCA territory. A good knowledge of these different patterns allows early clinical diagnosis of stroke topography and stroke etiology in over 95% of the patients with MCA territory infarction, in which final diagnoses could be made using delayed CT or MRI (Bogousslavsky et al., 1993b). Early identification of MCA territory infarct and suspicion of its mechanism is of utmost importance, since it leads to appropriate investigations and immediate treatment.

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Lenticulostriate arteries Patrick Pullicino Department of Neurology, Buffalo General Hospital, NY, USA

Anatomy There are usually two medial and four or five lateral lenticulostriate arteries (Rosner et al., 1984) (Fig. 31.1). and these divide to give an average of 26 branches on penetrating the brain (Marinkovic et al., 1985a) (Fig. 31.2).The lateral lenticulostriates are twice the diameter of the medial ones and are longer.The medial lenticulostriates supply the more medial deep MCA territory (lateral globus pallidus, medial putamen, whereas the lateral lenticulostriates supply the lateral putamen and external capsule, and the upper internal capsule (Herman et al., 1963) up to the white matter of the corona radiata (De Reuck, 1969; Donzelli et al., 1998). Up to 50% of penetrating arteries arise from a common stem (Fig. 31.3), and occasionally a single common stem gives rise to all lenticulostriates (Umansky et al., 1985;Vincentelli et al., 1990). The ramification zone of the lenticulostriates has been measured on a methacrylic resin cast of the perforating arteries (Marinkovic et al., 1985b). On the basis of these measurements, occlusion of a medial lenticulostriate or of the distal branches of a lateral lenticulostriate artery is likely to give an infarct within the accepted limit of a lacunar infarct (15mm diameter). Occlusion of a single lateral lenticulostriate proximally however, or of a common stem giving rise to two or more lenticulostriates, is likely to give an infarct considerably larger than the accepted dimensions of a lacunar infarct. Injection studies show that the territory supplied by all the lenticulostriates together has a typical comma shape on axial images (Rossberg et al., 1995) (Fig. 31.4), and an onion skin shape on coronal images (Fig. 31.5).

Pathology/pathogenesis The pathogenesis of occlusion of single lenticulostriate arteries differs from the pathogenesis when multiple

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lenticulostriates are occluded simultaneously. Cardioembolism and artery-to-artery embolism are significantly more frequent in striatocapsular infarcts (caused by occlusion of multiple lenticulostriates) than in lacunar infarcts due to single lenticulostriate artery occlusions (Nicolai et al., 1996). There is however, much overlap in the pathogenesis between striatocapsular infarcts and lacunar infarcts. The lenticulostriate arteries have been examined by serial sectioning in eight patients with lacunar infarcts in the lentiform nucleus or high internal capsule (Fisher, 1979). Fisher found an atheromatous stenosis in the lenticulostriate artery near its origin in five of these patients (Fig. 31.6). Atherosclerotic disease in the middle cerebral artery at the origin of the lenticulostriates may give rise to small deep infarcts (Bogousslavsky et al., 1991), as well as to striatocapsular infarcts (Bladin & Berkovic, 1984; Levine et al., 1988; Donnan et al., 1991) (Fig. 31.7), although it only accounts for about 20% of striatocapsular infarcts (see Table 31.1). The most frequent causes of striatocapsular infarcts are artery-to-artery embolism (causing 38% of striatocapsular infarcts) and cardiogenic embolism (causing 37% of striatocapsular infarcts) (see Table 31.1). Embolism may, however, occasionally also cause smaller lenticulostriate territory infarcts (Nicolai et al., 1996) (Fig. 31.8). The lenticulostriate arteries are susceptible to hypertensive change and are a frequent site of microaneurysms (Russell, 1963; Cole & Yates, 1967) or tortuosity (Challa et al., 1992), and these changes may be related to hypertensive hemorrhage which is frequent in this location (see Chapter 46: ‘Putaminal hemorrhages’). Enlarged perivascular spaces (Pullicino et al., 1998) and état criblé (Fenelon et al., 1995) are characteristic degenerative changes seen in the distal area of supply of the lenticulostriate arteries, although the clinical counterpart of these is unclear.

Lenticulostriate arteries

Fig. 31.1. The perforating arteries arising from the Circle of Willis. 1: head of caudate, 2: putamen, 3,4: globus pallidus, 6: lateral lenticulostriates, 7: intermediate lenticulostriates, 8: medial lenticulostriates (From Nieuwenhuys et al. (1981) with permission.)

Lacunes, giant lacunes or striatocapsular infarcts? The fundamental difference between a lenticulostriate lacunar infarct and a striatocapsular infarct is that a lacunar infarct is defined as an infarct caused by the occlusion of a single penetrating artery and a striatocapsular infarct results from occlusion of multiple lenticulostriate arteries on one side. Since it is not possible to image the lenticulostriates reliably in vivo, lacunar infarcts are differentiated from striatocapsular infarcts on the basis of their size on axial brain images. The usual accepted size of a lacunar infarct is ⱕ15 mm in diameter and striatocapsular infarcts are more than 20 mm in maximum diameter (Weiller, 1995; Nicolai et al., 1996). The size of an infarct on imaging does not reliably predict whether single or multi-

ple lenticulostriates have been occluded, however. In cases 1 and 3 from Fisher’s paper on capsular infarcts (Fisher, 1979) ischemia in the territory of a single lenticulostriate produced infarcts with diameters of greater than 15 mm, and he called these ‘giant’ lacunes. Occlusion of a common stem may give an infarct the size of a striatocapsular infarct: an infarct with dimensions of 25 mm⫻20 mm⫻ 12 mm was produced by ischemia arising in a stem that gave rise to two lenticulostriates (case 4 in Fisher’s paper) (Fisher, 1979). Since 50% of lenticulostriates arise from a common stem, this may, in part, explain an overlap in pathogenesis found between lacunes and striatocapsular infarcts. The pathogenesis of striatocapsular infarcts of ⬍50 mm diameter is, however, closer to that of striatocapsular infarcts of ⬎50 mm than to the pathogenesis of lacunar infarcts (Nicolai et al., 1996).

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Although the differences between striatocapsular infarcts and lacunar infarcts have been stressed (Bladin & Berkovic, 1984; Weiller et al., 1990) the clinical features overlap and striatocapsular infarcts may give rise to the ‘lacunar’ syndromes of pure motor hemiparesis and sensorimotor stroke. The differences in clinical features between striatocapsular infarcts and lacunes are likely to be due to the size of the infarct. Neuropsychological disorders, particularly aphasia or neglect, are only seen more frequently than in striatocapsular infarcts ⬎50 mm in diameter lacunar infarcts not in smaller striatocapsular infarcts (Nicolai et al., 1996). Subtle neuropsychological findings may, but be missed in smaller infarcts (Pullicino et al., 1994).

Clinical effects of small deep infarcts in specific sites The main anatomical sites that are supplied by the lenticulostriate arteries include: (i) the upper part of the anterior limb of the internal capsule, (ii) the whole upper part of the internal capsule and corona radiata lateral to the lateral ventricle, (iii) the external capsule, (iv) the lentiform nucleus, (v) the body and the upper half of the head of the caudate nucleus. Fig. 31.2. Drawing of a cast of lenticulostriate arteries showing diameters in micrometers. (From Marinkovic et al., (1985b) with permission.)

(a )

(b)

(c )

Fig. 31.3. Intraoperative observations of the variations in the origin of the lenticulostriate arteries in 60 patients. In 52% of cases, multiple lenticulostriates arose from a large trunk (a). In 35% multiple lenticulostriates arose from two large trunks (b). In 13% of cases all lenticulostriates arose separately. (From Aydin et al., 1994, with permission.)

Internal capsule, anterior limb Pure motor hemiparesis has been described secondary to infarcts in the anterior limb of the internal capsule. Pitres (1893) reported a case of brachiocrural deficit due to an anterior limb internal capsule lacunar infarct confirmed at autopsy. Manelfe et al. (1981) reported three patients with infarcts in the anterior limb of the internal capsule, giving faciobrachial weakness in two and hemihypesthesia in one. The case illustrated, however, showed a striatocapsular infarct affecting the putamen and caudate nucleus as well as the anterior limb of the internal capsule. Of eight patients with CT lesions ‘around the anterior limb of the internal capsule’ (Kashihara & Matsumoto, 1985), four had a slow parkinsonian gait, one had recent transient incontinence and three in whom the infarct extended up to the corona radiata had a mild hemiparesis. Four patients have been described with pure dysarthria secondary to infarcts in the anterior limb of the internal capsule (Ichikawa & Kageyama, 1991). Although the pyramidal tract is not involved in infarcts of the anterior limb of the internal capsule, there is a separate corticoreticulospinal motor system that projects from the premotor cortex via corticopontine fibres in the anterior

Lenticulostriate arteries

(a )

(b)

(c )

Fig. 31.4. Microangiogram (a), corresponding brain slice (b) and anatomical diagram (c) showing the typical ‘comma-shape’ of the lenticulostriate territory in an axial plane. (From Weiller (1995) with permission.)

limb of the internal capsule (Freund & Hummelsheim, 1985). Lesions of this pathway may result in a proximal hemiparesis. The anterior limb of the internal capsule also contains the anterior thalamic peduncle, which connects the thalamus to the frontal lobe. Infarcts affecting the anterior thalamic peduncle may, in this way, give rise to frontal lobe signs and motor neglect may result from an infarct in the anterior limb of the internal capsule (Viader et al., 1982). Akinetic mutism has been ascribed to bilateral infarcts of the anterior limb of the internal capsule (DeSmet et al., 1990).

seen with these infarcts arise from interruption of the pyramidal tracts: pure motor hemiparesis (Weiller et al., 1991) with or without involvement of the thalamocortical radiations (sensorimotor stroke, brachiofacial sensorimotor deficit, dysarthria-clumsy hand syndrome (Bladin & Chambers, 1993) dysarthria–facial paresis syndrome (Kim, 1994)). These infarcts may be associated with aphasia, hemineglect or constructional apraxia in addition to the sensorimotor deficit. There is still some dispute as to the origin of these ‘cortical’ features and this is discussed more fully below.

The region of the external capsule The upper part of the internal capsule and corona radiata adjacent to the lateral ventricle This area is supplied by the lateral lenticulostriates (Donzelli et al., 1998). Infarcts restricted to the paraventricular region are called internal watershed infarcts (Fig. 31.9) in contradistinction to lacunar infarcts which extend up from the lentiform nucleus into the paraventricular region (Fig. 31.6). Internal watershed infarcts (Weiller et al., 1991; Bladin & Chambers, 1993) are small focal or confluent (⬎15 mm diameter) infarcts that are associated with severe ipsilateral occlusive carotid disease and are of presumed hypoperfusion etiology. Internal watershed infarcts are located in the terminal ramifications of the lenticulostriate arteries or between the terminal branches of the lenticulostriates and those of the long medullary white-matter penetrating arteries (Fig. 31.10). The most frequent clinical features

This is also usually supplied by the lateral lenticulostriates. Infarcts involving this region (the subinsular region) are infrequent (Cobb et al., 1987), and their clinical features poorly documented. We have seen a patient with bilateral subinsular infarcts who had the anterior opercular syndrome (Pullicino et al., 1992) (bilateral palsy of facial, masticatory, lingual, and swallowing muscles). We have also seen a series of eight patients with ‘giant’ internal watershed infarcts that extended from the typical paraventricular location of internal watershed infarcts to the subinsular region without obvious involvement of the insular cortex (Fig. 31.11). In addition to hemiparesis, five (63%) of these patients had elements of the opercular syndrome (dysarthria and dysphagia or a complete unilateral (1) or bilateral (1) opercular syndrome) and three (37%) had aphasia. These findings suggest that subinsular infarcts may give

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similar clinical deficits to insular cortical infarcts. Subinsular infarcts are located in the borderzone between the lenticulostriate arteries and the short insular penetrating branches of the middle cerebral artery (Fig. 31.10). Subinsular infarcts and giant internal watershed infarcts are located just lateral to the typical location of lenticulostriate infarcts and this may explain their slightly different clinical picture.

Lentiform nucleus

Fig. 31.5. Diagram of sequential coronal brain slices showing the ‘onion-skin’ arrangement of the territories of the lateral (vertical lines) and medial (interrupted cross-hatch) lenticulostriates.

There are few reports of infarcts restricted to the lentiform nucleus because the adjacent internal capsule and caudate are often involved by ischemia that affects the lentiform nucleus. Micrographia is a known feature of putaminal infarcts (Yoshida et al., 1989) and mild deficits in expressive language and verbal memory have also been noted in association with micrographia secondary to an infarct restricted to the putamen (Pullicino et al., 1994). Aphasia and agraphia have been noted with lesions of the posterior putamen (Tanridag & Kirshner, 1985), and a patient with a putaminal infarct presented with postural deficits, causing him to fall to one side (Labadie et al., 1989). Bilateral putaminal infarction has been reported to produce parkinsonism (Friedman et al., 1986). The cause of many of these features of putaminal infarction appears to be a partial frontal ‘deafferentation’ via the striato-pallido-thalamo-cortical loop (Pullicino et al., 1994; Mega & Alexander, 1994).

The head of the caudate nucleus Caudate infarcts produce abulia, psychic akinesia, frontal lobe deficits and aphasia with left sided lesions and neglect syndromes with right sided lesions (Caplan et al., 1990; Kumral et al., 1999). Frontal deficits in caudate infarcts are probably due to interruption of frontal–subcortical circuits (Mega & Cummings, 1994). Chorea (Saris, 1983; Kawamura et al., 1988), may occur secondary to an infarct in the head of the caudate nucleus. A full discussion of caudate infarcts is found in Chapter 35.

Striatocapsular infarcts

Fig. 31.6. Diagram showing sites of obstruction of lenticulostriate arteries giving rise to infarcts. (From Fisher, (1979) with permission.)

Occlusion of all lenticulostriates on one side gives rise to a typical comma-shaped infarct appearance on axial images taken through the striatum (Fig. 31.7), which is similar to the appearance of the lenticulostriate territory on injected specimens (Donzelli et al., 1998) (Fig. 31.4). Striatocapsular infarcts have been defined as infarcts

Lenticulostriate arteries

(a )

(b)

greater than 20 mm (Weiller, 1995) or ⱖ30 mm (Bladin & Berkovic, 1984) in diameter in the territory of the lenticulostriate arteries. Demographic, clinical, outcome and pathogenesis data from the main published studies on striatocapsular infarction (Santamaria et al., 1983; Bladin & Berkovic, 1984; Levine et al., 1988; Weiller et al., 1990; Donnan et al., 1991; Boiten & Lodder, 1992; Weiller, 1995; Nicolai et al., 1996) are reviewed in the table. Men are about 1.5 times more frequently affected than women. The mean age is between 48 and 68. Hemiparesis is almost always present (97%), and this may be because hemiparesis can be caused both by involvement of the anterior limb of the internal capsule and by paraventricular extension of the infarct to affect the corticospinal tract. Hemiparesis is severe in 59%, moderate in 15% and mild in 23%. Hemisensory loss is probably also due to paraventricular extension of the infarct more posteriorly, to affect the thalamocortical radiations and occurs in 54% of patients (Weiller, 1995). Aphasia with left sided infarcts and neglect with right sided infarcts occur in 60% of patients. Recovery is full in 38%, moderate in 28% and absent in 29%. Pathogenesis is artery-to-artery embolism from carotid disease in 38%, cardiogenic embolism in 33% and secondary to middle cerebral artery disease in 20%. Patients with striatocapsular infarcts have also presented with visual hallucinations in the affected hemifield of vision (Martin et al., 1992) and also with absence of alcoholinduced hallucinations in the neglected hemifield of

(c )

(d )

Fig. 31.7. 76-year-old hypertensive woman with mild left hemiparesis. (a), (b), (c): Proton density MRI showing striatocapsular infarct. (d ) Magnetic resonance angiogram showing right middle cerebral artery stenosis (arrow).

vision (Chamorro et al., 1990). A patient has also presented with pathological laughter at the onset of the stroke (Carel et al., 1997). The cause of aphasia or neglect is debated. Patients with neglect or aphasia have larger infarcts than those without but no specific structure is involved in patients with these signs (Weiller et al., 1993). Patients with aphasia or neglect had significantly longer duration of middle cerebral artery

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Table 31.1. Published series of patients with striato-capsular infarction Rascol

Santamaria

Bladin &

Levine

Weiller

Donnan

Boiten

Weiller

et al.

et al.

Berkovic

et al.

et al.

et al.

& Lodder

et al.

Nicolai et al.

1982

1983

1984

1988

1990

1991

1992

1993

1996

Total (%)

11

24

29

50

15

57

56

265 (100)

18/6

20/9

27/23

10/5

31/26

30/26

Demographic data No. of patients

15

M/F ratio

8 1/7

5/6

Mean years (years)

48

63

59

55

63

53

68

Age range (years)

34–65

50–84

26–88

22–86

24–88

16–89

35–89

Clinical data Lacunar syndromes

15

1

2

5

6

Hemiparesis

15

8

11

24

29

Severe

9

18

13

10

29

79/135 (59)

Moderate

0

4

12

4

0

20/135 (15)

Mild

49

3

19

11

62/186 (33)

14

57

51

218/225 (97)

2

2

4

22

31/135 (23)

Hemi-hypoesthesia

0

6

0

15

23

30

10

1 40

20

121/225 (54)

Aphasia/neglect

0

4

8

17

8

35

11

26

34

127/225 (56)

No recovery

5/13

2

6

6

9

12

22

46/156 (29)

Moderate recovery

0/13

4

3

4

4

23

12

44/156 (28)

Complete recovery

8/13

2

2

14

11

15

19

60/156 (38)

Prognosis

Pathogenesis Cardiac source of embolism

2

8

5

7

25

29

83/225 (37)

ICA

0/6

0

6/8

17

5

9

12/27

4

17

20

76/198 (38)

MCA

2/6

0

2/8

5

15

3/27

0

25

4

39/198 (20)

occlusion than those without. This led the authors to conclude that selective neuronal loss in the cerebral cortex, secondary to prolonged reduced blood flow, was the cause of the aphasia or neglect (Weiller et al., 1993). In a series of ten patients, MRI frequently revealed a cortical infarct not seen on CT in patients with neuropsychological or frontal lobe signs (Godefroy et al., 1992). This supports cortical involvement as the cause for aphasia and neglect. On the other hand, there is increasing evidence to support that cortical involvement is not necessary to produce neuropsychological signs. Involvement of the anterior limb of the internal capsule or of the striatum is more frequent in patients with subcortical infarcts and aphasia (Damasio et al., 1982). Injury to the dominant striatum, or to the whitematter connections in the anterior limb of the internal capsule, could thus be responsible for the aphasia. Involvement of white-matter connections to the frontal lobe are likely responsible for a ‘core’ aphasia in patients with subcortical infarcts (Mega & Alexander, 1994). In a series of 14 patients with aphasia secondary to subcortical infarcts, the severity of the aphasia varied in proportion to

14/24

7

lesion size. Strong support for the production of neuropsychological disorders secondary to subcortical damage comes from a recent series of 56 patients with striatocapsular infarcts who had no evidence of cortical damage. Neuropsychological deficits were significantly more frequent in 31 patients with striatocapsular infarcts ⬎50 mm in diameter than in 25 patients with striatocapsular infarcts ⬍50 mm in diameter (Nicolai et al., 1996).

iReferencesi Bladin, P.F. & Berkovic, S.F. (1984). Striatocapsular infarction: Large infarcts in the lenticulostriate arterial territory. Neurology, 34, 1423–30. Bladin, C.F. & Chambers, B.R. (1993). Clinical features, pathogenesis, and computed tomographic characteristics of internal watershed infarction. Stroke, 24, 1925–32. Bogousslavsky, J., Regli, F. & Maeder, P. (1991). Intracranial largeartery disease and ‘lacunar’ infarction. Cerebrovascular Diseases, 1, 154–9.

Lenticulostriate arteries

(a )

(b)

Fig. 31.8. 29-year-old man with sudden left pure motor hemiparesis following a drinking binge. Transient cardiac murmur noted. (a) Right posterior lentiform nucleus infarct on T2 MRI. (b) Focal signal loss in right middle cerebral artery due to probable embolus.

Boiten, J. & Lodder, J. (1992). Large striatocapsular infarcts: clinical presentation and pathogenesis in comparison with lacunar and cortical infarcts. Acta Neurologica Scandinavica, 86, 298–303. Caplan, L.R., Schmahmann, J.D., Kase, C.S. et al. (1990). Caudate infarcts. Archives of Neurology, 47, 133–43. Carel, C., Albucher, J.F., Manelfe, C., Guiraud-Chaumeil, B. & Chollet, F. (1997). Fou rire prodromique heralding a left internal carotid artery occlusion. Stroke, 28, 2081–3. Challa, V.R., Moody, D.M. & Bell, M.A. (1992). The Charcot– Bouchard aneurysm controversy: impact of a new histologic technique. Journal of Neuropathology and Experimental Neurology, 51, 264–71. Chamorro, A., Sacco, R.L., Ciecierski, K., Binder, J.R., Tatemichi, T.K. & Mohr, J.P. (1990). Visual hemineglect and hemihallucinations in a patient with a subcortical infarction. Neurology, 40, 1463–4. Cobb, S.R., Mehringer, C.M., Itabashi, H.H. & Pribram, H. (1987). CT of subinsular infarction and ischemia. American Journal of Neuroradiology, 8, 221–7. Cole, F.M. & Yates, P.O. (1967). The occurrence and significance of intracerebral micro-aneurysms. Journal of Pathology and Bacteriology, 93, 393–411.

Damasio, A.R., Damasio, H., Rizzo, M., Varney, N. & Gersh, F. (1982). Aphasia with nonhemorrhagic lesions in the basal ganglia and internal capsule. Archives of Neurology, 39, 15–20. De Reuck, J. (1969). La limite du territoire profond de l’artere Sylvienne chez l’homme. Acta Anatomica, 74, 30–5. Desmet, Y., Rousseau, J.J. & Brucher, J.M. (1990). Infarctus putamino-capsulo-caudes bilateraux, symetriques et simultanes. Revue Neurologique, 146, 415–19. Donnan, G.A., Bladin, P.F., Berkovic, S.F., Longley, W.A. & Saling, M.M. (1991). The stroke syndrome of striatocapsular infarction. Brain, 114, 51–70. Donzelli, R., Marinkovic, S., Brigante, L. et al. (1998). Territories of the perforating (lenticulostriate). Branches of the middle cerebral artery. Surgical and Radiologic Anatomy, 20, 393–8. Fenelon, G., Gray, F., Wallays, C., Poirier, J. & Guillard, A. (1995). Parkinsonism and dilatation of the perivascular spaces (Etat crible) of the striatum: a clinical, magnetic resonance imaging, and pathological study. Movement Disorders, 10, 754–60. Fisher, C.M. (1979). Capsular infarcts. The underlying vascular lesions. Archives of Neurology, 36, 65–73. Freund, H-J. & Hummelsheim, H. (1985). Lesions of the premotor cortex in man. Brain, 108, 697–733. Friedman, A., Kang, U.J., Tatemichi, T.K. & Burke, R.E.(1986). A case

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Fig. 31.9. T2 MRI showing two partial internal watershed infarcts (arrows).

of Parkinsonism following striatal lacunar infarction. Journal of Neurology, Neurosurgery and Psychiatry, 49, 1087–8. Godefroy, O., Rousseaux, M., Leys, D., Destée, A., Scheltens, P. & Pruvo, J.P. (1992). Frontal lobe dysfunction in unilateral lenticulostriate infarcts. Prominent role of cortical lesions. Archives of Neurology, 49, 1285–9. Herman, L.H. Ostrowski, A.Z. & Gurdjian, E.S. (1963). Perforating branches of the middle cerebral artery. Archives of Neurology, 1, 32–4. Ichikawa, K. & Kageyama, Y. (1991). Clinical anatomic study of pure dysarthria. Stroke, 22, 809–12. Kashihara, M. & Matsumoto, K. (1985). Acute capsular infarction. Location of lesions and the clinical features. Neuroradiology, 27, 248–53. Kawamura, M., Takahashi, N. & Hirayama, K. (1988). Hemichorea and its denial in a case of caudate infarction diagnosed by magnetic resonance imaging. Journal of Neurology, Neurosurgery and Psychiatry, 51, 590–1. Kim, J.S. (1994). Pure dysarthria, isolated facial paresis, or dysarthria–facial paresis syndrome. Stroke, 25, 1994–8. Kumral, E., Evyapan, D. & Balkir, K. (1999). Acute caudate vascular lesions. Stroke, 30, 100–8. Labadie, E.L., Awerbuch, G.I., Hamilton, R.H. & Rapcsak, S.Z.

(1989). Falling and postural deficits due to acute unilateral basal ganglia lesions. Archives of Neurology, 46, 492–6. Levine, R.L., Lagreze, H.L., Dobkin, J.A. & Turski, P.A. (1988). Large subcortical hemispheric infarctions: presentation and prognosis. Archives of Neurology, 45, 1074–7. Manelfe, C., Clanet, M., Gigaud, M., Bonafe, A., Guiraud, B. & Rascol, A. (1981). Internal capsule: normal anatomy and ischemic changes demonstrated by computed tomography. American Journal of Neuroradiology, 2, 149–55. Marinkovic, S.V., Kovacevic, M.S. & Marinkovic, J.M. (1985a). Perforating branches of the middle cerebral artery. Journal of Neurosurgery, 63, 266–71. Marinkovic, S.V., Milisavljevic, M.M., Kovacevic, M.S. & Stevic, Z.D. (1985b). Perforating branches of the middle cerebral artery. Stroke, 16, 1022–9. Martin, R., Bogousslavsky, J. & Regli, F. (1992). Striatocapsular infarction and ‘release’ visual hallucinations. Cerebrovascular Diseases, 2, 111–13. Mega, M.S. & Alexander, M.P. (1994). Subcortical aphasia: The core profile of capsulostriatal infarction. Neurology, 44, 1824–9. Mega, M.S. & Cummings, J.L. (1994). Frontal–subcortical circuits and neuropsychiatric disorders. Journal of Neuropsychiatry and Clinical Neurosciences, 6, 358–70. Nicolai, A., Lazzarino, L.G. & Biasutti, E. (1996). Large striatocapsular infarcts: clinical features and risk factors. Journal of Neurology, 243, 44–50. Nieuwenhuys, R., Voogd, J. & Van Huijsen, C. (1981). The Human Central Nervous System. A Synopsis and Atlas. Berlin: SpringerVerlag. Pitres, A. (1893). A propos d’un cas de monoplégie persistante du membre inférieur gauche causée par une lésion trés limitée de la capsule interne droite. Archives Clinics Bordeaux, 1–14. Pullicino, P., Miller, L.L., Munschauer, F.E. & Ostrow, P.T. (1992). Linear subinsular MR hyperintensities. Annals of Neurology, 32, 267–8 (Abstract). Pullicino, P., Lichter, D. & Benedict, R.H.B. (1994). Micrographia with cognitive dysfunction: ‘Minimal’ sequelae of a putaminal infarct. Movement Disorders, 9, 371–3. Pullicino, P.M., Ostrow, P.T., Stone, A.D. & Chakravorty, S.S. (1998). Striato-thalamic ischemic rarefaction: the basal penetrating artery counterpart of hemispheric white matter ischemic rarefaction. Stroke, 29, 306(Abstract). Rascol, A., Clanet, M., Manelfe, C., Guiraud, B. & Bonafe, A. (1982). Pure motor hemiplegia: CT study of 30 cases. Stroke, 13, 11–17. Rosner, S.S., Rhoton, A.L. Jr, Ono, M. & Barry, M. (1984). Microsurgical anatomy of the anterior perforating arteries. Journal of Neurosurgery, 61, 468–85. Rossberg, C., Boccalini, P. & Wagner, H.J. (1995). Über Infarkte im Versorgungsgebiet der arteriae lenticulstriatae. Eine neuropathologische und postmortal-neuroradiologische Analyse. Cited in Weiller, C. (1995). Russell, R.W.R. (1963). Observations on intracerebral aneurysms. Brain, 86, 425–40. Santamaria, J., Graus, F., Rubio, F., Arbizu, T. & Peres, J. (1983).

Lenticulostriate arteries

Fig. 31.10. Coronal postmortem microangiogram showing paraventricular zone where internal watershed infarcts are located (circular dotted area) and the borderzone between the lenticulostriates and short insular penetrating branches (line of dots).

Cerebral infarction of the basal ganglia due to embolism from the heart. Stroke, 14, 911–14. Saris, S. (1983). Chorea caused by caudate infarction. Archives of Neurology, 40, 590–1. Tanridag, O. & Kirshner, S. (1985). Aphasia and agraphia in lesions of the posterior internal capsule and putamen. Neurology, 35, 1797–801. Umansky, F., Gomes, F.B., Dujovny, M. et al. (1985). The perforating branches of the middle cerebral artery. Journal of Neurosurgery, 62, 261–8. Viader, F. Cambier, J. & Pariser, P. (1982). Phénomene d’extinction motrice gauche. Revue Neurologique, 138, 213–17. Vincentelli, F., Caruso, G., Andriamamonjy, C. et al. (1990). Étude micro-anatomique des branches collatérales perforantes de l’artère cérébrale moyenne. Neurochirurgie, 36, 3–15.

Weiller, C. (1995). Striatocapsular infarcts. In Lacunar and other Subcortical Infarctions, ed. G.A. Donnan, B. Norrving, J.M. Bamford & J. Bogousslavsky. pp. 103–16. Oxford: Oxford University Press. Weiller, C., Ringelstein, E.B., Reiche, W., Thron, A. & Buell, U. (1990). The large striatocapsular infarct. A clinical and pathophysiological entity. Archives of Neurology, 47, 1085–91. Weiller, C., Ringelstein, E.B., Reiche, W. & Buell, U. (1991). Clinical and hemodynamic aspects of low-flow infarcts. Stroke, 22, 1117–23. Weiller, C., Willmes, K., Reiche, W. et al. (1993). The case of aphasia or neglect after striatocapsular infarction. Brain, 116, 1509–25. Yoshida, T., Yamadori, A. & Mori, E. (1989). [A case of micrographia with the right hand due to left putaminal infarction]. Rinsho Shinkeigaku, 29, 1149–51.

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(b) (a )

Fig. 31.11. 49-year-old man with right hemiparesis, hemianopia, aphasia and dysphagia after temporary clipping of left middle cerebral artery during aneurysm surgery. CT shows a ‘giant’ internal watershed infarct extending from the periventricular (a) to the subinsular (b) region.

32

Anterior cerebral artery John C.M. Brust1, Tohru Sawada2 and Seiji Kazui2 1 Harlem Hospital Center, New York, USA National Cardiovascular Center, Osaka, Japan

2

Anatomy

A1 segment

The anterior cerebral artery (ACA) arises as the medial branch of the bifurcation of the internal carotid artery (ICA) at the level of the anterior clinoid process. The ACA supplies the whole of the medial surfaces of the frontal and parietal lobes, the anterior four-fifths of the corpus callosum, the frontobasal cerebral cortex, the anterior diencephalon, and other deep structures. The posterior extent of the ACA depends on the extent of the supply of the posterior cerebral artery and its splenial branches. The band of lateral cortex supplied by the ACA is wider anteriorly, often extending beyond the superior frontal sulcus, and is narrowed progressively posteriorly. The ACA can be divided into five segments (A1–A5) (Fischer, 1938). The A1 segment, also called the proximal ACA, is the part between the internal carotid bifurcation and the anterior communicating artery (ACoA). The postcommunicating part of the ACA comprises the segments A2, A3, A4, and A5, which are generally designated the distal ACA. The A2 and A3 segments together are referred to as the ascending segment, with inferior forward convexity (A2) and superior forward convexity (A3). The A4 and A5 segments form the horizontal segment, extending posteriorly to the coronal suture (A4) and from there to the artery’s termination.

Above the anterior clinoid process the A1 segment curves medially and forward, crossing over the optic chiasm or the optic nerve. It turns a right angle between the optic chiasm and olfactory trigone and enters the interhemispheric fissure to join the ACoA. The A1 segment varies in length from 7.2 to 18.0 mm (average 12.7 mm), and its diameter is approximately half that of the middle cerebral artery (MCA), ranging from 0.9 to 4.0 mm (average 2.6 mm). From 2 to 15 basal perforating branches (average of 8), exclusive of Heubner’s artery, arise from each A1 segment (Perlmutter & Rhoton, 1976). The proximal (lateral) half of the A1 is a richer source of branches than is the distal (medial) half. The proximal vessels penetrate the brain by way of the anterior perforate substance, lateral chiasm, and optic tracts. Branches that originate from the A1 segment at the internal carotid bifurcation perfuse the genu, the contiguous posterior limb of the internal capsule, and the rostral thalamus. Proximal 4 mm branches of the A1 segment supply the anterior limb of the internal capsule, the neighbouring hypothalamus, the anteroventral putamen, and the pallidum. Branches arising from the distal A1 segment are small and contribute only to the arterial plexus of the optic nerve, chiasm, and tract (Dunker & Harris, 1976).

Basal arteries and their perforating branches

Anterior communicating artery

Many perforating branches arise from the anterior circle of Willis (Table 32.1, Fig. 32.1). Most of them are thin, and only the recurrent artery of Heubner can be easily identified by means of angiography. As with other penetrating arteries supplying the diencephalon and basal ganglia, those originating from the ACA and ACoA have sparse anastomoses (‘end-zone arteries’).

The mean outer diameter of the ACoA is 1.4 mm, and the total length is 3.3 mm. The perforating branches of this communicating artery originate mainly from the superoposterior portion and penetrate the brain at the lamina terminalis, anterior perforating substance, and medial chiasm. These perforating branches perfuse the most anterior hypothalamus, mesial anterior commissure, lamina

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Table 32.1. Characteristics of basal perforating branches arising from the anterior circle of Willis Branch

Number (average)

Site of penetration

Areas of supply

A1 segment Proximal Distal ACoA A2 segment Heubner’s artery

1–11 (4.2–5.3) 0–6 (1.1–3.2) 0–13 (2.0–3.9) 0–10 (1.2–4.8) 1–12 (4.2–6.5)

APS, OC, OT ON, OC, OT LT, APS, OC GR, OS, OC, LT APS, SF, OFL

ICG, ICP, RT, HT, PT, PL ON, OC, OT HT, AC, LT, Fo, BF, CC, Ci GR, IFA, SA, AD, CC HC, ICAI, PL, PT, HT

Note: AC, anterior commissure; AD, anterior diencephalon; APS, anterior perforate substance; BF, midline and paramedial basal forebrain; CC, corpus callosum; Ci, cingulum; Fo, fornix; GR, gyrus rectus; HC, head of caudate; HT, hypothalamus; ICAI, anterior inferior internal capsule; ICG, genu of internal capsule; ICP, posterior limb of internal capsule; IFA, inferior frontal area; LT, lamina terminalis; OC, optic chiasm; OFL, orbital frontal lobe; ON, optic nerve; OS, olfactory sulcus; OT, optic tracts; RT, rostral thalamus; PL, pallidum; PT, putamen; SA, suprachiasmatic area; SF, sylvian fissure.

terminalis, fornix, and basal forebrain, including septal nuclei, nucleus accumbens, diagonal band nuclei, and medial part of the substantia innominata. They also supply the corpus callosum and anterior cingulum (Perlmutter & Rhoton, 1976; Crowell & Morawetz, 1977; Gomes et al., 1984).

A2 segment The outer diameter of the A2 segment at its origin is approximately 2.5 mm. The A2 segment has perforating branches that penetrate the brain at the gyrus rectus, olfactory sulcus, optic chiasm, and lamina terminalis (Perlmutter & Rhoton, 1978; Gomes et al., 1984). The number of these branches can range from none to 10. The A2 branches terminate in the gyrus rectus, the inferior frontal area, the suprachiasmatic area, the anterior diencephalon, and the rostrum of the corpus callosum (Perlmutter & Rhoton, 1978).

Recurrent artery of Heubner Fig. 32.1. Schematic representation of the territories supplied by basal perforating branches. Hatched areas represent the perfusion bed of the A1 segment, stippled area that of Heubner’s artery. The left-hemisphere distribution represents maximal perfusion volume, and the right represents minimal perfusion volume. Areas of crosshatching and asterisks depict the territory of ACoA perforating branches (Adapted from Dunker & Harris, 1976).

The recurrent artery of Heubner is reported to have a mean diameter of 0.8–1.0 mm, with a length of 20–23 mm. It originates from the portion near the ACoA, the proximal 5 mm of the A2 segment in 10–78% of cases, the junction of the ACA and ACoA in 8–55%, and the distal A1 segment in 8–35%. Heubner’s artery usually arises as a single vessel and, as suggested by its name, courses backward along the A1 segment. It penetrates the brain at the level of the lateral anterior perforating substance, medial sylvian fissure, or orbital frontal lobe and has up to 12 branches (Perlmutter

Anterior cerebral artery

Table 32.2. Frequency, site of origin, and area of supply for cortical branches Site of origin (%) Cortical arteries

Presence (%)

A2

Orbitofrontal Frontopolar Anterior internal frontal Middle internal frontal Posterior internal frontal Paracentral Superior parietal Inferior parietal

100 100 86 90 76 90 78 64

100 90 14 2

A3

48 42 24 18

A4

4 24 32 10 10

A5

CM

Areas of supply

14 50 52

10 24 42 28 26 18 2

GR, OB, OT, FL (medial orbital surface) FP (medial, lateral surface) Anterior third of SFG Middle third of SFG Posterior third of SFG, part of CG Paracentral lobule Superior precuneus Inferior precuneus, adjacent cuneus

Note: CM, callosomarginal artery; CG, cingulate gyrus; FL, frontal lobe; FP, frontal pole; GR, gyrus rectus; OB, olfactory bulb; OT, olfactory tract; SFG, superior frontal gyrus. Source: From Perlmutter and Rhoton (1978).

& Rhoton, 1976; Dunker & Harris, 1976; Gomes et al., 1984). Heubner’s artery supplies the head of the caudate nucleus, the anterior inferior part of the internal capsule’s anterior limb, the anterior globus pallidus and putamen, and the anterior hypothalamus.

Cortical branches (distal ACAs) The distal ACAs are composed of two main vessels, the pericallosal (A2–A5) and callosomarginal arteries, and usually eight cortical branches originating from them: the orbitofrontal, frontopolar, anterior internal frontal, middle internal frontal, posterior internal frontal, paracentral, superior parietal, and inferior parietal arteries (Table 32.2, Fig. 32.2). The pericallosal arteries typically are not found side by side; one (usually the left) is often posterior to the other. The entire course of the pericallosal artery, except for the posterior portion, is below the free margin of the falx cerebri and is free to shift across the midline. The callosomarginal artery, on the other hand, has only the most anterior portion below the free margin of the falx; the remainder lies above the free edge, and its displacement across the midline is limited by the rigidity of the falx. The callosomarginal artery, originating most often from the A3 segment of the ACA and coursing parallel to the pericallosal artery in the cingulate sulcus around the cingulate gyrus, is absent in 18% to 60% of hemispheres (Perlmutter & Rhoton, 1978). In hemispheres without the callosomarginal artery, all cortical branches originate from the pericallosal artery.

The orbitofrontal artery arises from the A2 segment and supplies the gyrus rectus, the olfactory bulb and tract, and the medial part of the orbital surface of the frontal lobe. The frontopolar artery arises mainly from the A2 segment and supplies the medial and lateral surfaces of the frontal pole. The anterior internal frontal artery originates from the callosomarginal artery, at the A2 or A3 segment, and supplies the anterior portion of the superior frontal gyrus. The middle internal frontal artery originates from the callosomarginal artery or A3 segment and supplies the middle portions of the medial and lateral surfaces of the superior frontal gyrus. The posterior internal frontal artery originates from the callosomarginal artery, at the A3 or A4 segment, and supplies the posterior third of the superior frontal gyrus and part of the cingulate gyrus. The paracentral artery most frequently arises from the A4 segment or the callosomarginal artery and supplies the paracentral lobule. The superior parietal artery originates from the A5, A4, or callosomarginal artery and supplies the superior portion of the precuneus. The inferior parietal artery most commonly arises from the A5 segment of the pericallosal artery and supplies the posterior inferior part of the precuneus and adjacent portions of the cuneus. The ACA is the principal artery supplying the corpus callosum. The pericallosal artery sends branches into the rostrum, genu, and body, extending often to the splenium and sometimes passing inferiorly around the splenium. The splenium is usually supplied mainly by the splenial branches of the posterior cerebral artery.

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CENTRAL SULCUS

PARACENTRAL LOBULE M A

N

E LAT

R

GU CIN

CM

PRECUNEUS

GYRUS

CALLO S SUM RPU body CO (trunk)

PC

AIF

RIO PE

S IF

SP

O FR

M

PIF

L TA

ParC

US GYR

SU

442

IP

splenium

genu

FP

rostrum

GY

RU

OF S S RECTU

Fig. 32.2. Distal ACAs and their areas of supply: PC, pericallosal artery; CM, callosomarginal artery; OF, orbitofrontal artery, FP, frontopolar artery; AIF, anterior internal frontal artery; MIF, middle internal frontal artery; PIF, posterior internal frontal artery; ParC, paracentral artery; SP, superior parietal artery; IP, inferior parietal artery; SMA, supplementary motor area. Superimposed asterisks show the areas that can be supplied by the ACoA. (Adapted from Crowell & Morawetz, 1977, and from Perlmutter & Rhoton, 1978).

Variations

Etiology

The anterior circle of Willis is highly variable among normal individuals, although the rates of such variations reported in the literature have differed considerably (Table 32.3). A large callosal branch with a luminal diameter as great as that of either pericallosal artery arises from the ACoA in 1.5–20% of brains. This artery is also called the median artery of the corpus callosum, the arteria termatica of Wilder, or the median ACA. A high rate of association of ACoA aneurysm with a hypoplastic ACA has been reported. Considerable variability also exists in the boundaries (or border zones) between the anterior, middle, and posterior cerebral arteries. Postmortem injection studies reveal that in subjects with the most extensive ACA distribution, the primary sensorimotor cortex is supplied by the ACA not only medially but also over the convexity as far as the inferior frontal sulcus. In subjects with the least extensive ACA distribution, the ACA supplies little or none of the primary sensorimotor cortex, even medially (Van der Zwan et al., 1992).

Patients with ACA-territory infarctions often also have lesions in the MCA (Table 32.4). Thus, isolated infarction in the ACA territory is uncommon; its incidence, as reported in the literature, varies from 0.6% (Kazui et al., 1993b) to 3% (Gacs et al., 1983) of ischemic stroke cases. The incidence of infarction caused by arterial vasospasm following rupture of a saccular aneurysm of the ACoA is estimated to be similar to the incidence of ischemic stroke, on the basis of the available epidemiological data concerning the incidence of intracranial aneurysms, the distribution of ACoA aneurysms, and the rate of symptomatic vasospasm. Occlusion of the A1 segment usually is well tolerated, because adequate collateral flow will come from the ACA of the opposite side. Ischemic stroke in the ACA territory is most often the result of emboli from the heart or the ICA. In some cases the ACA is occluded by distal propagation of thrombus from the ICA (Lhermitte & Gautier, 1975; Gacs et al., 1983; Bogousslavsky & Regli, 1990). Local thrombosis of the ACA is a rarity in Western countries. In contrast, in situ throm-

Anterior cerebral artery

Table 32.3. Normal variation in the anterior circle of Willis

Table 32.4. Etiology of ACA-territory infarction

Variation

Cerebral aneurysm Vasospasm following rupture of aneurysm Artery-to-artery embolism from unruptured aneurysm Surgery-related Cardioembolic stroke Atherothrombotic infarction Local thrombosis Artery-to-artery embolism from proximal occlusive lesion Propagation from ICA occlusion Lacunar infarction Others Dissection Fibromuscular dysplasia Wegener’s granulomatosis Isolated angiitis Reversible segmental vasoconstriction and vasodilatation Sickle-cell anemia Transfalcial herniation

A1 segment Absent Hypoplasia (diameter ⬍ 1.0 mm) Fenestration Anterior communicating artery Absent Hypoplasia (diameter ⬍ 1.0 mm) Duplication Triplication Plexiform Arteria termatica of Wilder Heubner’s artery Absent Duplication Distal ACAs Azygous (unpaired) Absence of callosomarginal artery Triplication Branch(es) to opposite hemisphere

Incidence (%)

0.2–2 2.0–11 0.1–7.2 0.2–2 1–37 4.5–33.3 6–10 6–9 1.5–20 0–35 3–20 0.5–5 18–60 7.8–8.4 30–64

bosis of the ACA without significant carotid lesions is more common in Asian populations (Bogousslavsky & Regli, 1990; Kazui et al., 1993b) (Fig. 32.3). Embolization to the ACA is frequently associated with unusual hemodynamic circumstances, such as unilateral ICA occlusion (Gacs et al., 1983), azygous ACA, or hypoplastic A1 segment (Kazui et al., 1993b) (Fig. 32.4). In such cases, emboli derived from the heart, aorta, or carotid arteries are prone to reach the distal ACAs through the proximal ACA when there is increased blood flow, as compared with that seen in normal vascular structures. Rodda (1986) found that ACA-territory infarction was often associated with bilateral ICA disease and ACA stenosis or a small-calibre ACoA, which could limit perfusion. The extent of the infarction depends on the arterial patterns of the anterior circle of Willis, the location of arterial boundary zones, and the site of obstruction. The sparse anastomoses of deep penetrating vessels arising from the proximal ACA, ACoA, or Heubner’s artery predispose to small deep infarcts (‘lacunes’) in individual arterial territories, including the basal ganglia and the internal capsule. Other reported mechanisms of ACA territory infarction include dissection of the ACA itself or of the ICA, fibromuscular dysplasia, Wegener’s granulomatosis, isolated angiitis, sickle-cell anemia, transfalcial herniation, alcohol

intoxication, disseminated intravascular coagulation, arteritis secondary to subarachnoid neurocysticercosis, radiation vasculitis, and unknown factors causing reversible segmental vasoconstriction and vasodilatation (Call et al., 1988; Kazui & Sawada, 1993).

Symptoms and signs Several characteristic features differentiate patients with ACA-territory infarctions from others.

Motor deficit Motor deficits are among the most common manifestations in patients with ACA-territory infarctions. In classic descriptions, cortical branch occlusion usually results in motor deficits of the foot and leg and, to a lesser degree, paresis of the arm, with the face and tongue largely spared (Critchley, 1930). Leg weakness is most severe distally. Muscle tone is initially flaccid and then becomes spastic. Tendon reflexes may be initially decreased or increased, and an extensor plantar response is often present. Most patients have a relatively good recovery. The responsible lesions involve the paracentral lobule and the upper portion of the motor cortex, as well as subcortical fibers extending from those regions to the corona radiata. Some

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(a )

(b)

(c )

(d )

Fig. 32.3. A 64-year-old right-handed man with atherothrombotic occlusion of the left ACA developed transient muteness, right hemiparesis with crural predominance, unilateral ideomotor apraxia, agraphia and tactile anomia of the left hand, and compulsive manipulation of tools with the right hand. (a)–(c) CT scans showing hypodense areas in the left mesial hemisphere and anterior twothirds of the corpus callosum. (d) Left carotid angiogram showing occlusion of the left ACA in the A2 segment (arrow), with leptominingeal collaterals arising from branches of the left middle cerebral artery.

patients develop crural monoplegia (Wilson, 1923) (Fig. 32.5). However, weakness of the same degree in both the arm and leg (Weisberg, 1979), or even hemiparesis with brachial predominance (Bogousslavsky & Regli, 1990), has been reported in patients with infarction extending deeply.

Of 14 consecutive patients with isolated ACA territory infarctions seen by two of the authors (TS and SK), all developed limb weakness contralateral to the infarction side: hemiparesis with crural predominance in 86%, crural monoparesis in 7%, and hemiparesis with brachial pre-

Anterior cerebral artery

(a )

(b)

(c )

Fig. 32.4. A 57-year-old man with mitral stenosis and atrial fibrillation suddenly developed left hemiparesis with crural predominance (cardioembolic stroke). (a) CT shows a hypodense area in right ACA territory (arrow). (b) Right carotid angiogram demonstrating occlusion of the right pericallosal artery. (c) Left carotid angiogram showing hypoplasia of the left A1 segment.

dominance in 7%. Pure motor hemiparesis (Weisberg, 1979) or homolateral ataxia and crural paresis (Bogousslavsky et al., 1992), which have been ascribed to lacunar infarction, may result from occlusion of distal ACAs. Hemiparesis with faciobrachial predominance has been attributed to infarction in the head of the caudate nucleus, the putamen, and the anterior portion of the internal capsule, as a result of occlusion of the recurrent artery of

Heubner (Critchley, 1930). Dunker and Harris (1976), however, claimed that hemiparesis of that type was due to occlusion not of Heubner’s artery but of the perforating branches arising from the most proximal portion of the A1 segment, because those perforators supply the genu and contiguous posterior limb of the internal capsule. Damage to the medial frontal lobe (usually on the right side), including the supplementary motor area (SMA), can produce motor neglect, an underutilization of the arm

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Fig. 32.5. A 62-year-old man suddenly developed monoparesis of the right lower extremity. Sagittal T1-weighted MR image after injection of gadolinium-DTPA showing an area of increased intensity (recent infarction) in the right paracentral lobule.

(and leg) on the side contralateral to the lesion, despite normal strength and sensation. Infarction in the territories of both ACAs causes paraparesis, with or without sensory loss. Causes include bilateral ACA vasospasm following rupture of an ACA/ACoA aneurysm or occlusion of an ACA in the presence of a hypoplastic A1 segment or an azygous distal ACA. In such patients spinal cord disease may be erroneously suspected.

Sensory deficits Sensory impairments may be found in the affected half of the body, particularly in the lower limb, although usually they are mild or indefinite, or sometimes totally absent. The modalities most often involved are discriminative and proprioceptive.

Akinetic mutism, abulia, and other psychomotor disorders Transient loss of consciousness has been described in patients with ACA-territory infarctions, but it is uncommon; sustained unresponsiveness most often indicates abulia or akinetic mutism. Abulia refers to decreased spontaneous activity and speech, prolonged latency in responding to queries or directions, and reduced ability to

persist with a task (Caplan et al., 1990). Severely abulic patients are akinetic and mute, and the condition must then be differentiated from true stupor or coma, the locked-in-state, extrapyramidal akinesia, catatonia, hysteria, and the vegetative state. Persistent abulia can follow bilateral ACA territory infarction. Unilateral lesions tend to produce abulia lasting days, with replacement of abulia by contralateral motor neglect (which might be viewed as unilateral abulia). The specific structural damage causing abulia is uncertain. The cingulate gyrus, supplementary motor area (SMA), and the caudate have been variably implicated in clinical and experimental reports (Brust, 1998). Infarction in the mesial frontal lobe can cause psychiatric symptoms, such as emotional lability, euphoria, paralogia, or witzelsucht. Restlessness, hyperactivity, anxiety, agitation, and talkativeness are also common among patients with unilateral caudate infarction (Caplan et al., 1990). Patients with left-sided caudate lesions have shown a high frequency of severe depression (Starkstein et al., 1988). These behavioural and psychiatric disorders have suggested disturbances of frontocaudate circuits.

Sphincter dysfunction Urinary incontinence has been described as one of the classic symptoms in unilateral or bilateral ACA occlusion,

Anterior cerebral artery

but its incidence is relatively low. Damage to the midportion of the superolateral and medial superior frontal gyrus, as well as the anterior part of the cingulate gyrus, is a likely cause. There is the same disorder of defecation, although it occurs less frequently and less severely (Andrew & Nathan, 1964).

Language disorders As noted, muteness is often acutely present following occlusion of the right or left ACA. Most of these patients have a relatively rapid recovery from muteness. Some patients have a tendency to speak in whispers. In such patients the language disturbance is a manifestation of abulia. Whether unilateral ACA occlusion can produce a true aphasia is uncertain. Some reports have described impaired speech comprehension, anomia, alexia, and spoken or written paraphasias. Others have emphasized the absence of paraphasias. ‘Transcortical aphasia’, with reduced spontaneous speech and preserved repetition, has been frequently noted (Brust, 1998; Ross, 1980). Whether or not these speech abnormalities are truly aphasic, they are probably the result of damage to the SMA, and with few exceptions (Brust et al., 1982), the lesion has affected the language-dominant hemisphere. Electrical stimulation to this area in humans has been shown to elicit speech and movement arrest, vocalization, and contraversion and movement of the contralateral arm (Penfield & Welch, 1951). Acquired stuttering can result from infarction in right, left, or bilateral frontal areas, or in the anterior corpus callosum, without aphasic disorders. Mirror writing can develop in patients with infarctions in the left or right SMA.

Amnesia Anterograde amnesia has been known to follow rupture and related surgery for an ACoA aneurysm (Damasio et al., 1987). The responsible lesion has been considered to be an infarction confined to the midline and paramedial basal forebrain supplied by the perforating branch from the ACoA. In cases of additional mesial frontal damage, persistent and spontaneous confabulation can accompany the amnesia.

Pathological grasp phenomenon The grasp reflex is a flexion–adduction response in one or more digits, provoked by a distally moving pressure

contact on a particular area of the palmar aspect of the hand. This reaction can be independent of the patient’s awareness or conscious volition. The instinctive grasp reaction, in contrast to the grasp reflex, is a slower reaction to light stationary touch on the skin of any part of the hand. It encompasses the subvarieties of the reaction, such as the magnet reaction, trap reaction, or instinctive groping, which can be partially inhibited by the patient’s intention (Seyffarth & Denny-Brown, 1948). These pathological grasp phenomena are caused in some patients by unilateral or bilateral ACA-territory infarctions. The grasp reflex results from an infarction in the basal ganglia or frontal lobe of the opposite side. Damage to the medial frontal lobe, including the superior frontal and cingulate gyri, with or without an anterior callosal lesion, can cause an instinctive grasp reflex.

Callosal disconnection syndrome Distinct syndromes of callosal disconnection resulting from ACA-territory infarctions include ideomotor apraxia, agraphia, and tactile anomia restricted to the left hand in right-handed patients. Left unilateral ideomotor apraxia is an inability to execute learned skilled movements, such as waving goodbye, saluting, combing one’s hair, or brushing one’s teeth, with the left hand according to verbal commands, in contrast with correct and flawless performance with the right hand. The patient with a brain tumor who had surgical occlusion of the left ACA, as described by Geschwind and Kaplan (1962), performed correctly when asked to imitate the examiner’s movements; however, most patients with ACA infarctions have shown more or less impaired ability to imitate with the left hand. The most crucial part for manifestation of unilateral apraxia has been considered the callosal body, at which the primary pathway for praxis from the left hemisphere to the right may be disrupted. A low incidence of this sign has been suggested: Only 3 patients (21%) had left-sided apraxia among 14 patients with isolated ACA infarction observed by two of us (TS and SK). Patients with left-hand agraphia tend to produce unrecognizable scrawls, unintelligible letters, added or missed strokes, incorrect words, and substitutions or perseverations to dictation or in spontaneous writing, whereas when using the right hand the same patients will make no linguistic errors even when they have a paresis or a grasp reflex (Geschwind & Kaplan, 1962; Yamadori et al., 1980). In typing or forming block letters, such patients also perform incorrectly. Their ability to write or copy generally has been intact. Kawamura et al. (1989) reported a

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Japanese patient with occlusion of the left pericallosal artery who showed left unilateral agraphia for kanji (the morphograms) but not for kana (the syllabograms), indicating that for these two types of linguistic information, different neural pathways are used from the left hemisphere to the right at the level of the posterior body of the corpus callosum. Ideomotor apraxia and agraphia of the left hand usually have occurred together, and the lesions responsible for these disorders have been ascribed to the callosal body. However, several patients with left-hand agraphia without apraxia (Yamadori et al., 1980; Kawamura et al., 1989), and vice versa (Kazui & Sawada, 1993), caused by ACA infarctions, have been described. The difference in lesion locations suggests that the callosal fibers for praxis cross in the rostral part of the posterior callosal body. Unilateral tactile anomia is an impairment in the ability to name subjects placed in the left hand. When blindfolded, such a patient will name objects placed in the left hand incorrectly, making errors bearing no resemblance to the stimulus object, and will confabulate, whereas such a patient can correctly and promptly name objects in the right hand and can manipulate them appropiately with either hand. After an object is placed in the left hand and then removed and placed in a multiple-choice array, the patient is able to indicate the correct object with eyes closed and is also able to draw it correctly with the left hand, revealing intact stereognostic capacity. The mechanism for this abnormality is failure of tactile information from the right hemisphere to reach the intact speech centre across the corpus callosum. Tactile anomia of the left hand has been closely associated with unilateral agraphia, and thus it results from a lesion situated in the posterior part of the callosal body. In the right hand, unilateral constructional disturbance may occur, suggesting right-hemisphere dominance concerning constructional capacity. A striking phenomenon of bilateral crossed pseudoneglect was reported by Heilman et al., (1984): Both visual and tactile line-bisection tasks demonstrated that the right hand made errors to the right when the task was performed in the left hemispace, and the left hand made errors to the left when the task was performed in the right hemispace, despite no clinical signs of hemispatial neglect or extinction. The infarction was limited to the body of the corpus callosum, perhaps disrupting communication between the cerebral hemisphere important for directing the intent to attend to the contralateral hemispace and the other hemisphere important for controlling sensorimotor processing of the limb. Kashiwagi et al. (1990), on the other hand, described a patient with left hemispatial neglect

observed in tasks executed with the right hand, as well as in tasks involving verbal responses. Such a disconnection neglect supported the hypothesis that the left hemisphere was concerned only with attending to the contralateral hemispace, whereas the right hemisphere was specialized to both sides of space. Extensive damage to the callosal body and mesial hemisphere might be required for manifestation of this type of neglect. Crossed visuomotor ataxia (ataxie optique) can result from damage to the dorsal aspect of the posterior callosum. The patient’s hand will fail to reach and grasp an object placed in the peripheral visual field of the opposite side. A callosal lesion may disrupt the interhemispheric visuomotor pathway. By contrast, a crossed avoiding reaction of the left hand, together with other disconnection syndromes, has recently been reported in a stroke patient with a lesion in the genu and body of the corpus callosum and the left cingulate gyrus (Nagumo et al., 1993). The patient was unable to mobilize the left hand, with any effort, when she intended to reach and grasp the stimulus placed in the right hemispace.

Alien-hand sign Brion and Jedynak (1972) have described le signe de la main étrangère (the ‘strange hand’ sign, according to their translation): Such a patient, with a callosal tumour, will express the impression, despite no defect in deep sensation, that the left hand does not belong to the patient when it is held by the right hand behind the back. Bogen (1979) used the term intermanual conflict, referring to the dissociative phenomenon in which one hand is acting at crosspurpose to the other. The term alien-hand sign denotes a wide variety of dissociative movements between the right and left hands, some of which follow infarction of the medial frontal lobe, corpus callosum, or both. These include motor perseveration, compulsive manipulation of tools, utilization behaviour, and diagonistic dyspraxia. Motor perseveration has been used to refer to spontaneously occurring simple, repetitive, stereotyped movements of the hand, such as rubbing the thumb and index finger together, or smoothing or patting bedclothes (Shahani, Burrows, & Whitty, 1970). Patients consider these movements troublesome and, unable to stop them voluntarily, restrain them with the other hand. Motor perseveration invariably is associated with the grasp response and instinctive grasp reaction, without a concomitant disconnection syndrome. The causative lesion probably involves the medial frontal lobe contralateral to the affected hand. Mori and Yamadori (1982) described a patient with

Anterior cerebral artery

infarction in the left ACA territory who could not help grasping a familiar object (such as a comb, pencil, or toothbrush) placed before her and using it appropriately with her right hand against her will. These movements could not be inhibited by an examiner’s verbal command, and they were restrained by the patient’s left hand. The authors called this abnormal behaviour compulsive manipulation of tools. It accompanied a grasp reflex and instinctive grasp reaction, without a disconnection syndrome. Such unrestrained movement is likely a kind of release phenomenon of learned praxis due to damage to the left mesial frontal lobe, including the SMA and cingulate gyrus, in addition to the genu of the corpus callosum. The utilization behaviour described by Lhermitte (1983) is apparently a phenomenon similar to the compulsive manipulation of tools, in that objects in front of the patient are used, but this syndrome is distinctively different because of its lack of compulsiveness, its bilateral hand involvement, and its causative lesions found in various locations. Diagonistic dyspraxia, originally described by Akelaitis (1945), has been reported as a peculiar dissociative movement in which one of the patient’s hands (usually the left) acts at cross-purpose to the other (e.g. putting on one’s clothes with the right hand, immediately followed by pulling them off with the left hand). The abnormal behaviour of one hand is triggered by voluntary activities of the other hand (usually the right). Diagonistic dyspraxia has invariably been associated with disconnection syndrome. Damage to the body of the corpus callosum is apparently required to produce this behaviour (Tanaka et al., 1990). Unclassified alien-hand signs include simple or purposeless movements of either the right or left hand, such as drifting upward, keeping it tucked within the axilla, or grasping one’s throat (McNabb et al. 1988; Banks et al., 1989). These abnormal movements result from damage to the contralateral medial frontal lobe and the genu and body of the corpus callosum.

iReferencesi Akelaitis, A.J. (1945). Studies on the corpus callosum. IV. Diagonistic dyspraxia in epileptics following partial and complete section of the corpus callosum. American Journal of Psychiatry, 101, 594–9. Andrew, J., & Nathan, P.W. (1964). Lesions of the anterior frontal lobes and disturbances of micturition and defecation. Brain, 87, 233–62. Banks, G., Short, P., Martínez, J., Latchaw, R., Ratcliff, G. & Boller, F. (1989). The alien hand syndrome: clinical and postmortem findings. Archives of Neurology, 45, 456–9.

Bogen, J.E. (1979). The callosal syndrome. In Clinical Neuropsychology, ed. K.M. Heilman & E.V. Valenstein, pp. 308–59. Oxford University Press. Bogousslavsky, J. & Regli, F. (1990). Anterior cerebral artery territory infarction in the Lausanne Stroke Registry: clinical and etiologic patterns. Archives of Neurology, 47, 144–50. Bogousslavsky, J., Assal, G. & Regli, F. (1987). Infarctus du territoire de l’artère cérébrale antérieure gauche. II. Troubles du langage. Revue Neurologique, 143, 121–7. Bogousslavsky, J., Martin, R. & Moulin, T. (1992). Homolateral ataxia and crural paresis: a syndrome of anterior cerebral artery territory infarction. Journal of Neurology, Neurosurgery and Psychiatry, 55, 1146–9. Brion, S. & Jedynak, C.P. (1972). Troubles du transfert interhémisphérique (disconnection calleuse). A propos de trois observation de tumeurs du corps calleux. Le signe de la main étrangère. Revue Neurologique, 126, 257–66. Brust, J.C.M. (1998). Anterior cerebral artery disease. In Stroke: Pathophysiology, Diagnosis, and Treatment, 3rd edn, ed. H.J.M. Barnett, J.P. Mohr, F. Yatsu & B. Stein, pp. 401–25, ChurchillLivingstone. Brust, J.C.M., Plank, C., Burke, A. et al. (1982). Language disorder in a right-hander after occlusion of the right anterior cerebral artery. Neurology, 32, 491. Call, G.K., Fleming, M.C., Sealfon, S., Levine, H., Kistler, J.P. & Fisher, C.M. (1988). Reversible cerebral segmental vasoconstriction. Stroke, 19, 1159–70. Caplan, L.R., Schmahmann, J.D., Kase, C.S. et al. (1990). Caudate infarcts. Archives of Neurology, 47, 133–43. Critchley, M. (1930). The anterior cerebral artery, and its syndromes. Brain, 53, 120–65. Crowell, R.M. & Morawetz, R.B. (1977). The anterior communicating artery has significant branches. Stroke, 8, 272–3. Damasio, A.R., Graff-Radford, N.R., Eslinger, P.J., Damasio, H. & Kassell, N. (1987). Amnesia following basal forebrain lesions. Archives of Neurology, 42, 263–71. Dunker, P.O. & Harris, A.B. (1976). Surgical anatomy of the proximal anterior cerebral artery. Journal of Neurosurgery, 44, 359–67. Fischer, E. (1938). Die Lageabweichungen der vorderen Hirnarterie im Gefässbild. Zentralblatt für Neurochirurgie, 3, 300–12. Gacs, G., Fox, A.J., Barnett, H.J.M. & Vinuela, F. (1983). Occurrence and mechanisms of occlusion of the anterior cerebral artery. Stroke, 14, 952–9. Geschwind, N. & Kaplan, E. (1962). A human cerebral deconnection syndrome: a preliminary report. Neurology, 12, 675–85. Gomes, F., Dujovny, M., Umansky, F. et al. (1984). Microsurgical anatomy of the recurrent artery of Heubner. Journal of Neurosurgery, 60, 130–9. Heilman, K.M., Bowers, D. & Watson, R.T. (1984). Pseudoneglect in a patient with partial callosal disconnection. Brain, 107, 519–32. Huber, P. (1982). Cerebral Angiography, 2nd edn, pp. 79–105. Stuttgart: Thieme. Kashiwagi, A., Kashiwagi, T., Nishikawa, T., Tanabe, H. & Okuda, J. (1990). Hemispatial neglect in a patient with callosal infarction. Brain, 113, 1005–23.

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Kawamura, M., Hirayama, K. & Yamamoto, H. (1989). Different interhemispheric transfer of kanji and kana writing evidenced by a case with left unilateral agraphia without apraxia. Brain, 112, 1011–18. Kazui, S. & Sawada, T. (1993). Callosal apraxia without agraphia. Annals of Neurology, 33, 401–3. Kazui, S., Naritomi, H., Kuriyama, Y. & Sawada, T. (1993a). Reversible segmental dilatation of the anterior cerebral artery. Cerebrovascular Diseases, 3, 316–21. Kazui, S., Sawada, T., Naritomi, H., Kuriyama, Y. & Yamaguchi, T. (1993). Angiographic evaluation of brain infarction limited to the anterior cerebral artery territory. Stroke, 24, 549–53. Lhermitte, F. (1983). Utilization behaviour and its relation to lesions of the frontal lobes. Brain, 106, 237–55. Lhermitte, F. & Gautier, J.C. (1975). Sites of cerebral arterial occlusions. In Modern Trends in Neurology, Vol 6, ed. D. Williams, pp. 123–40. London: Butterworth. McNabb, A.W., Carrol, W.M. & Mastaglia, F.L. (1988). ‘Alien hand’ and loss of bimanual coordination after dominant anterior cerebral artery territory infarction. Journal of Neurology, Neurosurgery and Psychiatry, 51, 218–22. Mori, E. & Yamadori, A. (1982). Compulsive manipulation of tools and pathological grasp phenomenon. Clinical Neurology, 22, 329–35 (in Japanese, with English abstract). Nagumo, T., Yamadori, A., Soma, Y., Kayamori, R. & Ito, M. (1993). Crossed avoiding reaction: a disturbance of the manual spatial function. Journal of Neurology, Neurosurgery and Psychiatry, 56, 552–5. Penfield, W. & Welch, K. (1951). The supplementary motor area of the cerebral cortex. A clinical and experimental study. Archives of Neurology and Psychiatry, 66, 289–317. Perlmutter, D. & Rhoton, A.L., Jr. (1976). Microsurgical anatomy of the anterior cerebral–anterior communicating–recurrent artery complex. Journal of Neurosurgery, 45, 259–72.

Perlmutter, D. & Rhoton, A.L., Jr. (1978). Microsurgical anatomy of the distal anterior cerebral artery. Journal of Neurosurgery, 49, 204–28. Rodda, R.A. (1986). The arterial patterns with internal carotid disease and cerebral infarctions. Stroke, 17, 69–75. Ross, E.D. (1980). Left medial parietal lobe and receptive language functions: mixed transcortical aphasia after left anterior cerebral artery infarction. Neurology, 30, 144–51. Seyffarth, H. & Denny-Brown, D. (1948). The grasp reflex and the instinctive grasp reaction. Brain, 71, 109–83. Shahani, B.T., Burrows, P. & Whitty, C.W.M. (1970). The grasp reflex and perseveration. Brain, 93, 181–92. Starkstein, S.E., Robinson, R.G., Berthier, M.L., Parikh, R.M. & Price, T.R. (1988). Differential mood changes following basal ganglia vs. thalamic lesion. Archives of Neurology, 45, 725–30. Tanaka, Y., Iwasa, H. & Yoshida, M. (1990). Diagnostic dysplaxia: case report and movement-related potentials. Neurology, 40, 657–61. Van der Zwan, Hillen, B., Tulleken, C.A.F. et al. (1992). Variability of the territories of the major cerebral arteries. Journal of Neurosurgery, 77, 927. Weisberg, L.A. (1979). Computed tomography and motor hemiparesis. Neurology, 29, 490–5. Wilson, G. (1923). Crural monoplegia and paraplegia of cortical origin with a discussion of the cortical centers for the rectum, bladder and sexual functions. Acta Neurologica et Psychiatrica, 10, 669–79. Yamadori, A., Osumi, Y., Ikeda, H. & Kanazawa, Y. (1980). Left unilateral agraphia and tactile anomia: disturbances seen after occlusion of the anterior cerebral artery. Archives of Neurology, 37, 88–91.

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Anterior choroidal artery territory infarcts Philippe Vuadens and Julien Bogousslavsky Department of Neurology, University of Lausanne, Switzerland

Introduction Since the first reports of an anterior choroidal artery (AChA) infarct by Kolisko in 1891, and Foix et al. in 1925, the clinical pattern of this type of infarction has varied according to isolated cases and small series. The classical triad of Foix et al., consisting of hemiplegia, hemianesthesia, and homonymous hemianopia is rare and it is not specific of the AChA territory (Foix et al., 1925). This clinical pattern can also result from infarction of the deep or superficial branches of the middle cerebral artery (MCA) and the penetrating brainstem arteries. Until the utilization of brain CT scanning in the French studies by Cambier et al. (1983), and Masson et al. (1983), there were less than 25 cases of AChA-territory infarction reported in the literature (Kolisko, 1891; Foix et al., 1925; Cambier et al., 1983; Masson et al., 1983; Poppi, 1928a,b; Ley, 1932; Abbie, 1933a,b; Austregesilo & Borges Fortes, 1983; Steegman & Roberts, 1935; Trelles & Lazorthes, 1939; Hansen & Peters, 1940; Mettler et al., 1954; Morello & Cooper, 1955; Pertuiset et al., 1962; Denecheau, 1963; Fisher, 1965a; Buge et al., 1979; Takahasi et al., 1980; Cooper, 1954). With the development of new radiological technology, infarcts in the AChA-territory have received a new interest (Bruno et al., 1989; Decroix et al., 1986; Ghika et al., 1989; Helgason & Wilbur, 1990; Levy et al., 1995; Leys et al., 1994; Mohr et al., 1991; Paroni Sterbini et al., 1987; Helgason, 1988; Helgason et al., 1986; Hupperts et al., 1994). These studies have confirmed that AChA-territory infarctions are the second most common infarct in the territory of the deep perforators of the carotid system and that the classical triad is rare (Takahasi et al., 1980; Ghika et al., 1989; Paroni Sterbini et al., 1987). Partial clinical patterns, such as lacunar syndromes are more frequent. Moreover, presumed causes of strokes and risk factor profile often differ between studies, probably because of differences in patient selection.

Despite numerous anatomical studies of the AChA vascular territory, the precise area supplied by this artery is always in dispute (Bruno et al., 1989; Mohr et al., 1991; Helgason, 1988; Hupperts et al., 1994). The particular anatomy of the AChA with its richly developed anastomoses can explain the different opinions on the causes of AChA infarctions and also the different clinical patterns.

Vascular territory of the anterior choroidal artery The course of the AChA has been documented in several detailed anatomical or microsurgical studies (Abbie, 1933a, b; Beevor, 1907, 1909; Carpenter et al., 1954; Fujii et al., 1980; Herman et al., 1966, Hussein et al., 1988; Percheron, 1977; Rhoton et al., 1979; Saeki & Rhoton, 1977; Takahashi et al., 1994a,b; van der Zwan et al., 1992; De Reuck, 1971; Gibo et al., 1981; Goldberg, 1974; Hara et al., 1989; Moyer & Flamm, 1992; Erdem et al., 1993; WolframGabel et al., 1987; Rosner et al., 1984; Morandi et al., 1996; Mounier-Kuhn et al., 1955; Otomo, 1965; Theron & Newton, 1976; Furlani, 1973; Pacholec et al., 1996). They have demonstrated numerous variations in size, course, branching segments and brain regions supplied by this artery. Absence of AChA has been reported but it is rare (Carpenter et al., 1954). Usually, it originates from the internal carotid (more than 75% of cases) and it is often the first branch of the internal carotid artery distal to the posterior communicating artery. However, the middle cerebral artery, the posterior communicating artery or the bifurcation of the internal carotid artery may be the site of origin (Fujii et al., 1980; Rhoton et al., 1979; Goldberg, 1974). Sometimes a double anterior choroidal artery from the internal carotid artery can be found. The initial course of AChA is lateral to the optic tract, which it crosses to

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reach the lateral margin of the cerebral peduncle (Carpenter et al., 1954; Rhoton et al., 1979). Next to the lateral geniculate body, the AChA passes to the crural cisternae to reach the uncus, before penetrating through the choroidal fissure to join the choroidal plexus and terminate in the choroidal plexus of the lateral ventricle. The mean length is 25 mm (Carpenter et al., 1954). During its course the AChA gives off many branches which can be divided on the basis of whether they arise from the cisternal or plexual segment (Rhoton et al., 1979; Goldberg, 1974). According to Rhoton et al. each AChA has from 4 to 18 branches (average 9) (Rhoton et al., 1979). The branches arising from the cisternal segment are distributed to the optic tract, uncus, cerebral peduncle, lateral geniculate body, anterior perforated substance, tip of the temporal lobe, choroid plexus of the temporal horn, and dentate gyrus (Fujii et al., 1980). The superior branches penetrating within the brain supply the medial two segments of the globus pallidus and the genu of the internal capsule in approximately 50% of cases (Percheron, 1977; Rhoton et al., 1979). The distal branches supply the inferior half of the posterior limb of the internal capsule, the retrolenticular fibres of the internal capsule and the origin of the optic radiations (Goldberg, 1974). According to Abbie, the AChA always supplies the optic tract, lateral part of the geniculate body, posterior twothirds of the posterior limb of the internal capsule, most of the globus pallidus, the origin of the optic radiations and the middle one-third of the cerebral peduncle (Abbie, 1933a,b). Usually, most authors agree that the AChA supplies the posterior two-thirds and the retrolenticular part of the posterior leg of the internal capsule (Abbie, 1933a,b; Decroix et al., 1986; Mohr et al., 1991; Paroni Sterbini et al., 1987; Helgason, 1988; Beevor, 1907; Saeki & Rhoton, 1977; Pullicino, 1993). Other branches may supply the substantia nigra, part of the red nucleus, a portion of the subthalamus and the superficial part of the ventro-lateral thalamus (Helgason, 1988; Fujii et al., 1980; Rhoton et al., 1979; Takahashi et al., 1994a,b; Pullicino, 1993). Contrary to some authors, the lateral thalamic border is also supplied by the AChA (Helgason & Wilbur, 1990; Mohr et al., 1991; Fujii et al., 1980; Percheron, 1977; Rhoton et al., 1979; Takahashi et al., 1994a,b). In a pathological study of 50 hemispheres, Fujii et al. (1980) demonstrated involvement of the thalamus in 10%. This was confirmed by other studies (Helgason & Wilbur, 1990; Percheron, 1977; Rhoton et al., 1979). Hupperts et al. demonstrated involvement of the medial part of the lentiform nucleus in 42% of cases. This concurs with other studies (Helgason & Wilbur, 1990; Mohr et al., 1991; Hupperts et al., 1994). The posterior paraventricular corona radiata has been a

matter for debate for a long time (Mohr et al., 1991; Hupperts et al., 1994; Pullicino et al., 1995). Many studies has demonstrated extension of AChA infarcts into the posterior corona radiata region (Decroix et al., 1986; Helgason & Wilbur, 1990; Helgason, 1988; Ghika et al., 1990; GraffRadford et al., 1985). According to several autopsy studies, the posterior paraventricular region belongs to AChA-territory (Abbie, 1933a,b; Beevor, 1907, 1909; Carpenter et al., 1954). A recent study has confirmed the extension of AChAterritory to the posterior paraventricular corona radiata (Hupperts et al., 1994). In a series of 51 AChA infarcts, Hupperts et al. showed that 71% of these extended into this area. However, Pullicino et al. (1995) refuted that this area has ever been demonstrated to be supplied by the AChA according to different anatomical and angiographical studies. Moreover, they pointed out the possibility of watershed infarcts to explain this vascular extension. According to Hupperts et al., it seems that none of these studies aimed to evaluate the vascular supply of the posterior paraventricular corona radiata. Furthermore angiographic studies do not allow visualization of the full extent of the cerebral penetrators’ vascular area (Pullicino et al., 1995). When the posterior paraventricular corona radiata is involved by AChA infarcts, the size of the lesion is usually compatible with occlusion of a single penetrator and pleads against the possibility of coincidentally adjacent watershed infarcts in different territories. As such, it is unlikely that the lower parts of these infarcts are due to AChA obstruction; meanwhile the ischemic lesion in the upper part results from simultaneous occlusion of a separate vessel in another vascular territory. The alternative possibility that the lenticulostriate arteries supply the posterior paraventricular corona radiata is also unlikely. Only one of the infarcts located in the lenticulostriate territory and involving the internal capsule and basal ganglia that extended upwards was continuous with the posterior part of the corona radiata, whereas seven extended into the anterior part in the study by Hupperts et al. (1994). The distribution of the AChA branches is quite variable (Abbie, 1933a,b; Carpenter et al., 1954; Rhoton et al., 1979). Sometimes the AChA supplies a great part of the posterior cerebral artery (Morandi et al., 1996). Numerous anastomoses with branches of the posterior cerebral, posterior communicating, internal carotid middle cerebral and lateral posterior choroidal arteries are reported (Abbie, 1933a,b; Carpenter et al., 1954; Rhoton et al., 1979; Takahashi et al., 1994a,b). Anastomoses with the lateral choroidal artery are constant and they are the most developed at the level of choroid plexus and tela choroidea of the lateral ventricle (Morandi et al., 1996). This variability of AChA branches and anastomoses may explain the

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misinterpretation and the difficulties encountered in defining the precise vascular territory of the AChA according to the different studies.

Syndrome of AChA-territory infarcts The classical pattern of AChA infarcts consists in hemiplegia, hemianesthesia, and lateral homonymous hemianopia, often associated with neuropsychological signs (Foix et al., 1925; Abbie, 1933a,b; Decroix et al., 1986). However, this triad is rare and not specific of this arterial territory. Absence of aphasia, modification of consciousness and head deviation may help for distinction between infarct in AChA-territory or superficial middle cerebral artery territory (Decroix et al., 1986; Levy et al., 1995; Hupperts et al., 1994). These infarcts represent between 1% and 10% of all infarcts and 2,9% of all hospitalized infarct patients (Paroni Sterbini et al., 1987; Helgason et al., 1986; Hupperts et al., 1994; Ghika et al., 1990; Bogousslavsky et al., 1986). Hupperts et al., (1994) even estimated that 48% of all small deep infarcts verified by CT were in the AChA-territory. Presenting symptoms include headaches, drowsiness, nausea, vomiting, falls, diplopia, paresthesias, hemiparesis and clumsiness. On examination, clinical patterns of lacunar syndrome are the most frequent type of presentation in AChA-territory infarction. In a series of 77 patients who had AChA infarcts, 87% had one of the lacunar syndromes (Hupperts et al., 1994). There were, however, no clear clinical differences with the 83 other cases that had small deep infarcts. Motor hemiparesis has been reported in almost 90% of cases, with or without sensory deficit (Kolisko, 1891; Foix et al., 1925; Masson et al., 1983; Pertuiset et al., 1962; Buge et al., 1979; Rascol et al., 1982; Derouesné et al., 1985; Viader et al., 1984). Motor deficit is caused by the involvement of the pyramidal tract in the posterior limb of the internal capsule, the cerebral peduncle, and the posterior paraventricular corona radiata (Foix et al., 1925; Ross, 1980; Hiramaya et al., 1962). At the level of this latter area there is a somatotopic anterior-to-posterior arrangement of motor fibres for the face, arm, and leg (Donnan et al., 1982; Ishii, 1989). On the contrary, a somatotopic arrangement in the internal capsule seems less evident because motor fibres are tightly packed in the posterior portion of the posterior limb of the internal capsule (Ross, 1980; Hiramaya et al., 1962; Bogousslavsky & Regli, 1990; Brion & Guiot, 1964). The sensory deficit is of variable intensity and may involve the entire half of the body. Usually, it is incomplete

and temporary and in rare cases it may be an isolated findings (Derouesné et al., 1985). All modalities are often affected, but sparing of proprioception has been reported (Pertuiset et al., 1962; Graff-Radford et al., 1985). Severe residual sensory loss is seldom. Abbie reported the frequent presence of painful paresthesias in the AChAterritory infarction (Abbie, 1933a,b). In fact a ‘thalamic-like’ syndrome has been rarely reported in other studies (Bogousslavsky et al., 1986). At the onset of stroke, pain in the arm or leg, burning or tingling sensation can temporarily be present (Pertuiset et al., 1962; Bogousslavsky et al., 1986; Derouesné et al., 1985). Sensory dysfunction happens in two-thirds of the cases, which is more frequent than in other small deep infarct in the internal carotid territory (Ghika et al., 1989). The involvement of the sensory radiations within the posterior limb of the internal capsule and at the level of the ventral lateral nucleus of the thalamus explains such a sensory deficit in AChA-territory infarction. An homonymous hemianopia is the most variable feature of the classical triad of AChA infarction. It can result from lesions at any of three localizations: the optic tract, the lateral geniculate body, or the optic radiation. This latter one is the most frequently affected (Decroix et al., 1986). Besides homonymous hemianopia, which is most common, different visual field deficits are reported. Upper quadrantanopia, upper and lower sectoranopia with sparing of the horizontal meridian are described in unilateral AChA infarcts (Cambier et al., 1983; Decroix et al., 1986; Helgason et al., 1986, 1988; Luco et al., 1992). The classical triad on one side with a homonymous superior quadrantanopia on the other was reported in a patient with bilateral occlusion of the AChA (Abbie, 1933a,b). A quadruple sectoranopia or a superior congruent homonymous quadrantic defect is usually related to ischemic lesion of the lateral geniculate body in the AChA-territory (Luco et al., 1992; Frisen, 1979; Frisen et al., 1978). Visual field deficits are more frequent in large AChA infarcts than in infarcts of small size (Takahashi et al., 1994a,b). Hemianopia may be present in about one-third of patients with AChA infarcts (Levy et al., 1995; Mohr et al., 1991; De Bleecker et al., 1988). This percentage is quite variable according to different studies. Decroix described visual field deficit in only 3 out of 16 patients (Decroix et al., 1986). A large series of 77 AChA infarcts reported only 4% of cases with hemianopia (Hupperts et al., 1994). Ghika et al., (1989) estimated the presence of heminanopia in 13% of patients with AChA infarcts. The visual field disturbances are often transient because the optic tract and lateral geniculate body may receive anastomoses from the posterior choroidal artery, the posterior communicating artery

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or leptomeningeal arteries. Therefore, the absence of hemianopia should not preclude an AChA-territory infarct.

Lacunar syndromes 60–70% of lacunar infarcts occur in the internal capsule, basal ganglia or corona radiata (De Bleecker et al., 1988; Chamorro et al., 1991). Out of 72 patients with capsular infarcts, 20.8% were located in the AChA vascular territory (Tei et al., 1993). Pure motor stroke in AChA-territory infarction was first described by Fisher (Fisher & Curry, 1965). Although this clinical pattern is considered the most common lacunar syndrome, it is rare in AChA infarcts (Bamford et al., 1987; Melo et al., 1992; Arboix et al., 1990). In a recent study, lacunar syndrome was present in 67 of 77 patients (87%) with AChA-territory infarcts, out of which 45% were pure motor stroke (Hupperts et al., 1994). From the Lausanne Stroke Registry among 39 patients with CT or MRI proven AChA infarcts, 19 cases presented a pure motor stroke (data in preparation). Pure sensory stroke is infrequent and Desrouesné et al. (1985) were the first to describe such a clinical picture related to AChA-territory infarct. Three patients with undissociated hemisensory loss are reported with ischemic lesion in the posterior limb of the internal capsule (Decroix et al., 1986; Rosenberg & Koller, 1981). Sensorimotor syndrome, unaccompanied by any signs of visual defects or higher cortical dysfunction, has been reported in many cases and represents 27% of AChA infarcts according to Hupperts et al. (Kolisko, 1891; Foix et al., 1925; Masson et al., 1983; Pertuiset et al., 1962; Buge et al., 1979; Helgason, 1988; Hupperts et al., 1994; Rascol et al., 1982; Hiramaya et al., 1962; Staff et al., 1998). Recent MRI studies have demonstrated that infarct size in patients with sensorimotor syndrome is usually larger than in those with other lacunar syndromes (Chamorro et al., 1991; Hommel et al., 1990; Samuelsson et al., 1994; Rothrock et al., 1987). Although sensorimotor syndrome may be due to ischemic lesions in the internal capsule, thalamo-capsular region, corona radiata, putamen, brainstem, or cortex, the capsular/thalamocapsular localization predominates and accounts for 77% of lesions proven by MRI (Staff et al., 1998).

(Hypaesthetic) ataxic hemiparesis Fisher et al. also described this lacunar syndrome. It combines pyramidal and cerebellar signs on the same side (Hommel & Besson, 1993; Weiller et al., 1990; Fisher & Cole, 1965; Moulin et al., 1995). French neurologists previously reported this syndrome but Fisher et al. introduced the

term ataxic hemiparesis to designate this clinical pattern (Babinski & Jumentie, 1911; Marie & Foix, 1913; Foix & Hillemand, 1925; Garcin, 1955; Nicolesco et al., 1930; Fisher, 1978). Ischemic lesion in the pons, corona radiata, or internal capsule may produce this syndrome involving both the corticospinal and the cerebello-thalamo-corticoponto-cerebellar tracts (Fisher & Cole, 1965; Fisher, 1978, 1965a,b, 1969). However, lesions in the thalamus or cortical areas may also produce ataxic hemiparesis (Fisher, 1982; Bamford & Warlow, 1988; Bogousslavsky, 1992). In 100 firstever stroke cases with ataxic hemiparesis, Moulin et al. (1995) demonstrated that the main localization of the lesion was the posterior part of the internal capsule (39% of cases). This percentage increases when the lower part of the internal capsule and the superior part of the corona radiata (near the ventricular body) are included in the vascular territory of the AChA. Moreover, the role of the corona radiata in the development of ataxic hemiparesis had already been pointed out (Gutmann & Scherer, 1989; Huang & Lui, 1984). Hupperts et al. (1994) found no difference in the frequency of ataxic features between the AChA infarcts that were restricted to the posterior limb of the internal capsule and those located in the posterior paraventricular corona radiata. This series showed that 14% of patients with AChA infarcts had ataxic features, a similar result to 13% in the series of Ghika et al. (1989).

Neuropsychological and cortical signs The absence of ‘cortical signs’ despite the classical triad of Foix et al. is generally suggestive of AChA-territory infarction. However, several case reports prove that neuropsychological dysfunctions are not uncommon in this type of stroke (Cambier et al., 1983; Masson et al., 1983; Decroix et al., 1986; Hommel et al., 1985; Bogousslavsky et al., 1988; De la Sayette et al., 1995; Ferro & Kertesz, 1984). In four patients with CT-proven AChA-territory infarction Cambier et al. (1983) found visual neglect, constructional apraxia, anosognosia and motor impersistence in three patients with a right lesion; the fourth case had decreased speech fluency, semantic paraphasias, and speech perseverations. The neuropsychological features usually resemble those of thalamic aphasia (Decroix et al., 1986; Hommel et al., 1985). The speech disturbances are probably more related to the extent of the ischemic lesion in the lateral thalamus than in the internal capsule (Cambier et al., 1983; Graff-Radford et al., 1985; Damasio et al., 1982; Weiller et al., 1993). Graff-Radford et al. (1985) documented eight patients with infarcts in the lateral thalamus and posterior limb of the internal capsule corresponding to the territory of the AChA. The patients with an involvement of the lateral thalamus had dysarthria, slight

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language processing difficulties, and short-term verbal memory deficit. On the contrary, in 12 patients with a posterior lesion involving the posterior limb of the internal capsule, mostly extending into the putamen and in three patients into the deep white-matter as well, none of them presented aphasia (Weiller et al., 1993). Hemispatial neglect is usually observed with right-sided lesions. According to Decroix et al. (1986), it is essentially seen in visuospatial activities in which the attentional component predominates. On the other hand, in intentional activities, hemispatial neglect seems absent or less marked. Neglect syndrome is a consequence of the interruption of connections between the thalamus and the frontal cortex at the level of the posterior limb of the internal capsule. Modifications of emotional expression are also reported in patients with AChA-territory infarction. Nine patients with acute pseudobulbar mutism are documented with bilateral capsular infarcts (Helgason, 1988; Helgason et al., 1988). A severe pathological crying after left AChA infarct has also been described (Derex et al., 1997). The authors claim that this syndrome may be due to damage of the capsular ascending projections of serotonergic raphe nuclei.

Rare syndromes In 1928, Poppi reported a patient with abnormalities of eye movement, and ptosis contralateral to the hemiplegia due to AChA infarction and an ischaemic paramedian lesion in the midbrain. Buge et al. (1979) described paralysis of upward eye movement in a patient with bilateral AChA infarcts. Defective upward eye movement on the side of the lesion had already been reported by Viader et al. (1984). A patient with transient contralateral gaze preference, ptosis, and Horner’s syndrome ipsilateral to the AChA infarct and transient hemiballism was reported by Mohr et al. (1991). Another patient developed a right-side hemiplegia after a few days with spasms. This symptomatology was related to the combination of a mid AChA aneurysm and ischemic stroke in the AChA-territory (Morgensten et al., 1996). Recently, Archer et al. (1998) reported a case with bilateral pallor of the optic disc. The findings were due to an occlusion of the internal carotid artery proximal to the origin of the ophthalmic artery, causing also an insufficiency in the AChA-territory.

Risk factors and presumed causes of AChA infarcts AChA syndromes are not limited to ischemic lesions in the AChA-territory, but they may be also due to tumours, aneurysms, and arterio-venous malformations. The ligation of

AChA has been employed for the treatment of Parkinson’s disease (Cooper, 1954; Rand et al., 1956). This procedure revealed that AChA occlusion could be entirely asymptomatic. This confirms the rich anastomotic connections of AChA and may also explain the discrepancy concerning the causes of AChA infarcts between the studies (Bruno et al., 1989; Leys et al., 1994; Hupperts et al., 1994). Hemorrhages may induce AChA syndromes, but they are rarely limited to this territory. Even if the AChA-territory infarcts are the second most common infarct in the territory of the deep perforators of the carotid system after lenticulostriate, their etiologies are often uncertain (Takahashi et al., 1980; Paroni Sterbini et al., 1987; Hupperts et al., 1994). Moreover, the simple classification between small artery disease and large artery disease according to the size of ischemic lesions does not necessarily preclude the underlying cause of stroke (Bruno et al., 1989; Mohr et al., 1991; Fisher et al., 1980; Mayer et al., 1992).

Large ischaemic infarcts Large ischaemic infarcts may result from large artery thrombo-embolism or cardiac embolism (Mayer et al., 1992; Ward et al., 1984; Ueda et al., 1990). Leys et al. (1994) studied 16 patients with CT/MRI proven AChA infarcts. In 11 cases the lesion was larger than 15 mm in diameter and in 7 of these the mesiotemporal territory was also involved. No cardioembolic source was demonstrated in the group of small AChA infarcts. On the other hand, four out of seven large infarcts had a presumed cardioembolic stroke cause. Carotid emboli were suggested in one case and two were due to carotid dissection. Moreover, concomitant ischemic lesion in another vascular territory was documented in six cases. In another series of 29 large striatocapsular infarcts, 11 of them were partially located in AChA-territory (Weiller et al., 1993). Occlusive disease of the internal carotid was documented in seven cases, a cardioembolic source in three cases, and in one case the cause was undetermined. Other studies have confirmed that large striatocapsular infarcts often involve AChA-territory and mainly result from occlusion of a large artery due to local occlusive disease or from cardiac or carotid embolism (Boiten & Lodder, 1992; Blecic et al., 1993; Landi et al., 1991). In a neuropathological study of 35 patients with large infarcts involving the AChA territory at least, embolic occlusions were found in 74% of cases (54% of cardiac source) (Levy et al., 1995).

Small ischemic infarcts Most AChA-territory infarcts are small (Decroix et al., 1986; Ghika et al., 1989; Mohr et al., 1991; Paroni Sterbini et al.,

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1987; Helgason et al., 1986; Hupperts et al., 1994). They represent 48% of all small deep infarcts proven by CT. Including posterior corona radiata infarcts would result in a higher percentage of small deep infarcts (Hupperts et al., 1994). Moreover, the low rates of carotid stenosis or potential cardioembolic sources in most studies suggest that small-vessel disease is the principal cause of AChA-territory infarcts. In 1989, Bruno et al. concluded that smallvessel disease was the most frequent vasculopathy with hypertension as a single most important risk factor. In 31 cases of AChA infarcts, they found 65% with hypertension, 33% with diabetes mellitus and only 6% with a cardioembolic source. In the study by Ghika et al. (1989) the presumed cause of stroke was small-artery disease in at least 43% of cases that had hypertension or diabetes mellitus. This clear predominance of hypertension was also confirmed by another series of 28 AChA cases with varying infarct size: 41% with hypertension, 26% with diabetes mellitus, and 30% with a possible embolic source (Paroni Sterbini et al., 1987). Hupperts et al. compared AChA-territory infarcts with other remaining small or superficial infarcts and demonstrated that small-vessel disease is most likely the cause of small-sized AChA infarction as it is usually in ‘lacunar’ infarcts (Hupperts et al., 1994; Bogousslavsky, 1992; Lodder et al., 1990). However, a carotid or cardiac source of embolism may also be a cause of AChA infarcts. In the same study, homolateral carotid stenosis, ischemic heart disease or cardioembolic source were less frequent in AChA infarcts compared with superficial infarcts. A homolateral significant carotid stenosis was more strongly, and a cardioembolic source less strongly associated with AChA infarcts than with remaining small deep infarcts (Hupperts et al., 1994). In the series by Ghika et al. (1989), 27% of patients had possible embolism from a carotid source, and 17% from a cardiac source. Even if the cause of small-size AChA infarcts is mainly due to small-vessel obstruction, a potential embolic source must be considered and searched for.

year was also higher in the AChA infarcts group than in superficial infarcts and even more favourable in small deep AChA infarcts than in the remaining small deep infarcts.

Conclusions AChA infarcts represent the second most common infarct in the territory of the deep perforators of the carotid system. The classical triad of Foix et al., which generally defines the AChA-territory syndrome (hemipareis, hemianesthesia, and homonymous hemianopia) is rare and more often incomplete or associated with cortical signs. Most AChA infarcts present like one of the lacunar syndromes. The high prevalence of arterial hypertension or diabetes mellitus as an isolated risk factor of stroke in small size AChA infarcts suggests that small-artery disease is probably the leading etiology of AChA infarcts. However, potential sources of embolism may be found in a significant proportion of cases, mainly in large AChA infarcts. The results of recent studies confirm that large-artery disease and cardioembolism seem to be a more frequent cause of stroke in AChA than in other small deep infarcts. Therefore, carotid and cardiac investigations must not be neglected in this type of stroke and particularly in larger AChA infarcts resembling superficial infarcts. Finally, neither clinical syndromes, vascular risk factor profile, presumed cause of stroke, nor prognosis allow us to consider small or large AChA-territory infarcts like an entity different from other small deep infarcts or superficial infarcts respectively. Even if there is no neuroradiological or neurological predictor of embolic infarction a potential embolic source must always be considered. Therefore, AChA infarcts must be investigated and treated as small deep or superficial infarct subtypes, especially according to the size of infarct.

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Thalamic infarcts and hemorrhages Alain Barth1, Julien Bogousslavsky2 and Louis R. Caplan3 Inselspital Neurological Clinic and Poliklinik, Bern, Switzerland 2 Department of Neurology, University of Lausanne, Switzerland 3 Beth Israel Deaconess Medical Center, Boston, MA,USA

1

Introduction The thalamus is a large ovoid structure composed of several groups of grey-matter nuclei. The right and left thalami are strategically located at the top of the brainstem and act to provide a key relay to and from the cerebral cortex. Because of its complex anatomy and vascularization, the thalamus can give rise to a great variety of hemorrhagic and ischemic stroke syndromes. These various syndromes are characterized by prototypic clinical findings and abnormalities revealed by imaging that allow clinicians to locate an infarct in one of the thalamic nuclear groups and to infer the identity of the occluded artery and the pathogenesis of the stroke.

Blood supply to the thalamus Knowledge of the vascular anatomy and supply zones of the thalamus is mandatory if one is to understand the clinical findings in patients with thalamic infarcts and hemorrhages. The thalamus receives most of its blood supply from four arterial pedicles that arise from the basilar artery bifurcation, the posterior communicating artery (PCoA), and the proximal portions of the posterior cerebral arteries (PCA) (Fig. 34.1).

Polar artery The polar artery (also called the tuberothalamic, anterior internal optic: Duret (1874), or premamillary pedicle: Foix & Hillemand (1925a) usually arises from the PCoA. In about one-third of hemispheres, the polar artery is missing, and its territory is supplied by the thalamic–subthalamic arteries from the same side (Percheron, 1976a). The polar artery supplies the anteromedial and anterolateral regions of the

thalamus, including the reticular nucleus, the mamillothalamic tract, part of the ventral lateral nucleus, the dorsomedial nucleus, and the lateral aspect of the anterior thalamic pole (Percheron, 1976a). The anterior nucleus is not supplied by the polar artery.

Thalamic–subthalamic arteries The thalamic–subthalamic arteries, also called the paramedian thalamic: Percheron (1976b), deep interpeduncular profunda, posterior internal optic: Foix & Hillemand, (1925a), or thalamoperforating pedicle: Foix & Hillemand (1925b) arise from the proximal P1 peduncular segment of the PCA. In about one-third of brains, the thalamic– subthalamic arteries arise from one side or from a common pedicle. They supply the posteromedial thalamus, including the rostral interstitial nucleus of the medial longitudinal fasciculus (MLF), the posterior inferior portion of the dorsomedial nucleus, the nucleus parafascicularis, the intralaminar nuclei, and sometimes the mamillothalamic tract.

Thalamogeniculate arteries The thalamogeniculate arteries arise as a pedicle of six to ten arteries from the P2 ambient cistern segment of the PCA. They supply the ventrolateral thalamus, including the ventral posterior medial and lateral nuclei, the lateral part of the centromedian nucleus, and the rostrolateral portion of the pulvinar.

Posterior choroidal arteries The medial and lateral posterior choroidal arteries originate from the P2 cistern segment of the PCA just after the thalamogeniculate arteries. They supply the pulvinar and

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Fig. 34.1. Schematic representation of the blood supply to the thalamus, including the polar artery, the thalamic–subthalamic arteries, the thalamogeniculate arteries, and the posterior choroidal arteries.

posterior thalamus, the geniculate bodies, and also the anterior nucleus (Percheron, 1977). In summary, the vascular territories of the thalamus can be divided into four major regions: (i) the ventrolateral region supplied by the thalamogeniculate arteries, (ii) the anterolateral region supplied by the polar artery, (iii) the medial region supplied by the thalamic-subthalamic arteries, and (iv) the dorsal region supplied by the posterior choroidal arteries (Figs. 34.2, 34.3). Thalamic supply by the anterior choroidal artery is variable and is of little, if any, clinical consequence. Thalamic infarcts and small hemorrhages can be divided into four groups, corresponding to the four main arterial territories and into territories combining lesions in two of the four previous territories.

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microangiopathy (Bogousslavsky et al., 1988). These infarcts can cause three common syndromes. (i) In patients with pure sensory stroke, the onset is usually marked by paresthesias or numbness on one side of the body, soon followed by the development of an isolated hemisensory deficit (Garcin & Lapresle, 1954, 1960; Fisher, 1965, 1978). The sensory impairment is often slight and involves only a part of the hemibody, (. . .) especially the acral parts (Garcin & Lapresle, 1954). All modalities of sensation can be affected, but a dissociated loss, with sparing of pain and temperature senses, is rather common (Sacco et al., 1987; Combarros et al., 1991). Sensory dysfunction can be transitory or permanent. Pure sensory syndrome in thalamic stroke is due to involvement of nucleus ventrocaudalis or ventro-oralis intermedius. After weeks or months, a delayed painful syndrome sometimes develops in the affected area – the anesthésie douloureuse of Déjerine and Roussy (1906) (Bogousslavsky et al., 1988). (ii) In patients with sensorimotor stroke, the same sensory disturbances are accompagnied by motor abnormalities on the same side, with hemiparesis, increased tendon reflexes, and the Babinski sign (Déjerine & Roussy, 1906; Mohr et al., 1977). This syndrome results from extension of the infarcted area to the posterior limb of the internal capsule adjacent to the ventrolateral nuclei. (iii) The more extensive form of lateral thalamic infarction was described by Déjerine et Roussy in 1906 as the ‘thalamic syndrome’. The clinical features of pure sensory strokes and sensorimotor strokes are associated with abnormal movement patterns resulting from interruption of extrapyramidal and cerebellar tracts that synapse in the lateral thalamus (Caplan et al., 1988). Even when there is impairment of position sense, patients can show features of cerebellar-type hemiataxia, with oscillations, hypermetria, and dysdiadochokinesia. In some patients, an inhability to stand and walk is predominant and is called ‘thalamic astasia’ (Masdeu & Gorelick, 1988). Abnormal movements, such as hemidystonia and jerks in the hand, can develop after several weeks, particulary in patients with marked sensory loss and ataxia. The hand is held in a fixed dystonic posture: la main thalamic (Foix & Hillemand, 1925a; Caplan et al., 1988). Cognition ability and behaviour are characteristically preserved in patients with lateral thalamic infarcts.

Infarcts in the territory of the polar artery Lateral thalamic infarcts The lateral thalamic territory supplied by the thalamogeniculates arteries is the territory the most frequently involved by thalamic infarcts. Their major etiology is

The characteristic clinical findings in patients with infarcts in the territory of the polar artery are neuropsychological disturbances. Patients are abulic, apathetic, and slovenly, as in cases of acute lesions of the frontal lobe (Sanson et al.,

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Fig. 34.2. Arterial territories of the thalamus, corresponding to slice levels used in computed tomography: thalamic–subthalamic (or paramedian or thalamoperforate), areas with black dots; polar (or tuberothalamic), areas with white dots on black background; thalamogeniculate (or inferolateral), areas with vertical hatch lines; posterior choroidal, areas with hatch lines at 45° to the horizontal. (From Bogousslavsky, 1993, with permission.)

1991). Loss of self-activation is frequently observed (Lisovsky et al., 1993; Clarke et al., 1994). Left-side infarcts are associated with minor aphasic disturbances, mainly dysnomia (Gorelick et al., 1984; Bogousslavsky et al., 1986b). In patients with unilateral left-side or right-side infarcts, the main neuropsychological dysfunction may be acute amnesia, with inability to make new memories (Bogousslavsky et al., 1986a; Graff-Radford et al., 1990). Verbal- recall impairment is more common in those with left-side infarcts, whereas visual-memory deficits predominate in those with right-side infarcts. In patients with bilateral infarcts in the territory of the polar artery, abulia and amnestic disturbances are severe and do not tend to dimish with time. Occasionally, a mild transient hemiparesis or hemisensory abnormality will be noted on the contralateral side.

Infarcts in the territory of the paramedian thalamic–subthalamic arteries Infarcts in this territory are the second most frequent after lateral infarcts. The main etiology is embolism. Patients with unilateral infarcts of the paramedian

thalamic–subthalamic arteries are characterized by a classic triad of symptoms: an acute decrease of conscioussness, neuropsychological disturbances, and abnormalities of vertical gaze (Castaigne et al., 1981; Graff-Radford et al., 1984; Bogousslavsky et al., 1988). These patients usually are lethargic and difficult to arouse. They can be hypersomnolent – they are arousable, but will lapse into deep sleep as soon as the stimulation ceases – or they can be comatose, as if in anoxic or metabolic coma. Impairment of consciousness is probably due to involvment of the intralaminar nuclei and the rostral midbrain formation. The role of these structures is double: maintenance of wakefulness and promotion of NREM sleep (Bassetti et al., 1996). Absence of such impairment of consciousness at the onset of paramedian thalamic–subthalamic infarcts has occasionally been reported (Karabelas et al., 1985). In these patients, vertical-gaze function is characteristically disturbed, with up-gaze palsy or combined up- and down-gaze palsy (Büttner-Ennever et al., 1982) Skewdeviation is also common. Pure down-gaze palsy is found only in cases of bilateral paramedian infarcts. Horizontalgaze dysfunction is much less common and consists of hypometric contralateral saccades and low-gain ipsilateral

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Fig. 34.3. Arterial territories of the thalamus with reference to the thalamic nuclei (n.) and tracts: Apr, n. anterior principalis: Cemc, n. centralis magnocellularis; Cepc, n. centralis parvocellularis; Co, commisural nuclei; Dc, n. dorsocaudalis; Fa, n. fascicularis; Hl, n. habenularis lateralis; Hm, n. habenularis medialis; IML, internal medullary lamina; Lpo, n. lateropolaris; M, n. dorsomedialis; MTM, tract of Meynert; MTT, mamillothalamic tract; Pma, n. paramedianus anterior; Pmp, n. paramedianus posterior; Pt, n. parataenialis; Pu, pulvinar; R, reticular nuclei; Vc, n. ventrocaudalis; Vim, n. ventro-oralis intermedius; Voe, n. ventro-oralis externus; Voi, n. ventro-oralis internus. (From von Cramon et al., 1985, with permission.) Arterial territories: posterior choroidal, areas with hatch lines at 45° to the horizontal; polar (or tuberothalamic), areas with small dots; thalamogeniculate (or inferolateral), areas with large dots; thalamic–subthalamic (or paramedian or thalamoperforate), areas of conglomerate with various-size inclusions.

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pursuit, with interposed saccades (Brigell et al., 1984). Disconjugate abnormalities, such as acute esotropia, have occasionally been reported (Gomez et al., 1988). As the impairment in consciousness diminishes and patients become more alert, neuropsychological abnormalities will be more evident: patients will be disoriented, unconcerned and apathetic. Amnesia is prominent, with difficulty in making new memories. And confabulations are common (Stuss et al., 1988). Temporary neglect may be observed in patients with right-side lesions. Some patients will have slight hemiparesis or hemisensory abnormalities on the contralateral side (Bogousslavsky et al., 1986a). Abnormal movements, such as asterixis, tremor, or dystonia, may occur in the controlateral limbs, usually after a delay of several weeks (Sigwald & Monnier, 1936; Garcin & Lapresle 1969). Blepharospasm has also been reported (Powers, 1985). In patients with bilateral paramedian thalamo-subthalamic infarcts, the neuropsychological disturbances are more marked than in those with unilateral infarcts and can be long-lasting (Castaigne et al., 1981; Guberman & Stuss, 1983; Swanson & Schmidley, 1985; Eslinger et al., 1991). The most prominent features are amnesia and abulia, with reduced spontaneity and increased inertia. Some patients may have a compulsive need to assume a sleeping position. Some may engage in utilization behaviour (Hashimoto et al., 1985), with compulsive use of objects out of behavioural context, as observed in patients with frontal-lobe lesions.

Infarcts in the territory of the posterior choroidal artery The characteristic clinical findings in patients with infarcts in the territory of the posterior choroidal artery are visualfield defects due to involvment of the lateral geniculate body (Frisen et al., 1978; Besson et al., 1991; Serra Catafan et al., 1992; Luco et al., 1992). Involvement of medial posterior choroidal artery causes visual-field cuts including upper- or lower-quadrantanopia, whereas involvement of lateral posterior choroidal artery causes horizontal wedgeshaped or tubular sectoranopias (Neau & Bogousslavsky, 1996). Visual-field cuts can include upper- or lower-quadrantanopia or, more typically, horizontal wedge-shaped or tubular sectoranopias. Involvment of the pulvinar, posterior nuclei, and probably also the anterior nucleus can produce numerous spontaneous symptoms that are less specific, including impairment of ipsilateral pursuit, contralateral saccades, mild hemiparesis or hemisensory abnormalities, abnormal dystonic movement and neuropsychological disturbances such as aphasia, amnesia, abulia and visual hallucinosis.

Rostral basilar artery disease with diencephalic–mesencephalic ischemia The superior mesencephalic arteries occasionally can form a common pedicle with the thalamic–subthalamic arteries. Blockade of these arteries by occlusion of the basilar apex can lead to an infarcted area, including the bilateral mesencephalic periaqueducal grey matter, thirdnerve nuclei and their fascicles, intralaminar and parafascicular nuclei, portions of the median and central nuclei and the superior cerebellar peduncle (Tatemishi et al., 1987). In addition to the clinical features seen with thalamic–subthalamic paramedian infarction, patients can present a third-nerve palsy with contralateral hemiparesis or hemiataxia, a vertical one-and-a-half syndrome, bilateral complete ptosis, down-gaze palsy or both up-gaze and down-gaze palsies, retraction nystagmus, and a pseudosixth nerve palsy with hyperadduction of the eyes (Caplan, 1980; Bogousslavsky & Regli, 1984; Mehler, 1988)

Proximal posterior cerebral artery disease with thalamic infarction Proximal occlusion of the posterior cerebral artery (PCA) can cause infarction in the territory of the paramedian and peduncular perforating arteries as well as in the thalamus and occipital and temporal lobes. Ipsilateral third-nerve palsy and contralateral hemiplegia are associated with hemisensory loss, hemianopia, and behaviour abnormalities, mimicking infarction in the territory of the middle cerebral artery (Hommel et al., 1990; Chambers et al. 1991). More often, the occlusion of the proximal PCA spares the very origin of the artery, and the resulting infarct involves the lateral thalamus and a portion of the hemispheral territory of the PCA (Foix & Masson, 1923). Patients present the clinical findings of lateral thalamic infarction due to occlusion of the thalamogeniculate or posterior choroidal arteries, combined with temporal and occipital deficits, including hemianopia, amnesia, dyslexia, anomic or transcortical sensory aphasia, or visual neglect (Yamamoto et al., 1999).

Thalamic hemorrhages The two most important factors affecting the symptoms seen with thalamic hemorrhages are size and location of the hematoma (Kwak et al., 1983; Chung et al., 1986). Small hemorrhages are defined as having a diameter of less than 2 cm. They produce clinical findings similar to those of thalamic infarcts limited to an arterial territory (Kawahara et

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al., 1986). Large thalamic hemorrhages, defined as more than 2 cm in diameter, involve more nuclei and tracts, with or without ventricular extension, resulting in overlapping clinical syndromes. Common features seen in patients with thalamic hemorrhages include rapid onset of symptoms, inconstant impairment of consciousness even in large size hematomas, and a relatively good prognosis as compared with that for hemorrhages in the pons and basal ganglia.

Large thalamic hemorrhages The most typical clinical features seen in patients with large thalamic hemorrhages include a rapidly progressive hemiparesis, with sensory loss, vertical-gaze abnormalities, with up-gaze palsy and tonic down-gaze eye deviation and convergence, and small, fixed or sluggish pupils (Lhermitte, 1936; Fisher, 1959; Fazio et al., 1973; Walshe et al., 1977; Barraquer-Bordas et al., 1981; Chung et al., 1986) In contrast with the findings that accompany thalamic infarction, motor deficits are more prominent than sensory abnormalities in patients with thalamic hemorrhages (Lhermitte, 1936). Hemiparesis results from compression of the internal capsule by the hematoma and can range from transient simple paresis to flaccid hemiplegia. More complex motor abnormalities, such as motor neglect after right-side hemorrhages (Watson & Heilman, 1979) or asterixis (Donat, 1980), may occasionally be observed. Sensory ataxic hemiparesis with incoordination of the contralateral limb and severe impairment of proprioceptive sensation has been reported in hemorrrhages involving the ventrolateral thalamus (Dobato et al., 1990). Instead of purely vertical-gaze abnormalities, some patients may have skew deviation, dissociated or conjugate eye deviation toward the side of lesion or toward the opposite side (Fisher, 1959; Botinelli et al., 1966; Fazio et al., 1973; Walshe et al., 1977). A decreased level of consciousness is frequent, but inconstant (Fisher, 1959). Patients are mostly obtunded or stuporous, but some have been reported to be fully alert despite extensive hemorrhages (Walshe et al., 1977). Deep coma at onset, without improvement in the first 3 days, is considered to entail a particulary poor prognosis. Neuropsychological disturbances are also commonly observed in patients with thalamic hemorrhages, including speech disorders, amnesia, confusion, anosognosia, hemineglect, and ‘thalamic dementia’. Typically, patients present a mild fluent aphasia, with paraphasic errors and dysnomia, but preserved comprehension and repetition abilities (Mohr et al., 1976; Cappa & Vignolo, 1979; Kirshner & Kirstler, 1982). Mixed aphasia has also

been reported (Ciemins, 1970). Amnesia, with short-term memory impairment, may be prominent in patients with hemorrhages extending to the anterior and medial thalamus (Choi et al., 1983; Hankey & Stewart-Wynne, 1988).

Small thalamic hemorrhages Small-size hemorrhages involving a limited portion of the thalamus have been classified according to their locations as (i) posterolateral, (ii) anterolateral, (iii) medial, and (iv) dorsal (Kawahara et al., 1986; Chung et al., 1996). This classification is grossly identical with that of thalamic infarcts based on the arterial blood supply, as discussed earlier: (i) Posterolateral hemorrhages, corresponding to lateral thalamic infarcts, are usually characterized by severe hemiparesis and sensory loss. Transient impairment of consciousness, vertical-gaze abnormalities, and small, fixed pupils may also be seen in this type. (ii) Patients with anterolateral hemorrhages, corresponding to infarcts in the territory of the polar artery, present frontal-type neuropsychological disturbances associated with mild hemiparesis and hemihypesthesia. (iii) A decreased level of consciousness, vertical- and horizontalgaze palsies, amnesia, and abulia are typical findings in patients with medially located hemorrhages, corresponding to infarcts in the territory of the paramedian thalamic–subthalamic arteries. (iv) Minimal transient hemiparesis and hemihypesthesia, apraxia, aphasia, and amnesia have been noted in patients with dorsal hemorrhages, corresponding to infarcts in the territory of the posterior choroidal artery.

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Fisher, C.M. (1978). Thalamic pure sensory stroke. Neurology, 28, 1141–4. Foix, C. & Hillemand, P. (1925a). Les syndromes de la région thalamique. La Presse Médicale, 1, 113–17. Foix, C. & Hillemand, P. (1925b). Les artères de l’axe encéphalique jusq’au diencéphale inclusivement. Revue Neurologique, 41, 705–39. Foix, C. & Masson, A. (1923). Le syndrome de l’artère cérébrale postérieure. La Presse Médicale, 31, 361–5. Frisen, L., Holmegaard, L. & Rosencranz, M. (1978). Sectorial optic atrophy and homonymous, horizontal sectoranopia: a lateral choroidal artery syndrome? Journal of Neurology, Neurosurgery and Psychiatry, 41, 374–80. Garcin, R. & Lapresle, J. (1954). Syndrome sensitif de type thalamique à topographie cheiro-orale par lésion localisée du thalamus. Revue Neurologique, 90, 124–9. Garcin, R. & Lapresle, J. (1960). Deuxième observation personnelle du syndrome sensitif de type thalamique à topographie cheiroorale par lésion localisée du thalamus. Revue Neurologique, 103, 474–81. Garcin, R. & Lapresle, J. (1969). Incoordination cérébelleuse du membre inférieur par lésion localisée dans la région interne du thalamus controlatéral. Revue Neurologique, 120, 5–13. Gomez, C.R., Gomez, S.M. & Selhorst, J.S. (1988). Acute thalamic esotropia. Neurology, 38, 1759–62. Gorelick, P.B., Hier, D.B., Benevento, L., Levits, S. & Tan, W. (1984). Aphasia after left thalamic infarction. Archives of Neurology, 41, 1296–8. Graff-Radford, N.R. Eslinger, P.J., Damasio, A.R. & Yamada, T. (1984). Non-haemorragic infarction of the thalamus: behavioral, anatomic and physiologic correlate. Neurology, 34, 14–23. Graff-Radford, N.R., Tranel, D., Van Hoesen, O. & Brandt, J.P. (1990). Diencephalic amnesia. Brain, 113, 1–25. Guberman, A. & Stuss, D. (1983). The syndrome of bilateral paramedian thalamic infarction. Neurology, 33, 540–6. Hankey, G.J. & Stewart-Wynne, E.G. (1988). Amnesia following thalamic hemorrhage. Another stroke syndrome. Stroke, 19, 776–8. Hommel, M., Besson, G., Pollak, P., Kahane, P., Le Bas, J.F. & Perret, J. (1990). Hemiplegia in posterior cerebral artery occlusion. Neurology, 40, 1496–9. Karabelas, G., Kalfakis, N., Kasvikis, K. & Vasilopoulos, D. (1985). Unusual features in a case of bilateral paramedian thalamic infarction. Journal of Neurology, Neurosurgery and Psychiatry, 48, 186. Kawahara, N., Sato, K., Muraki, M., Tanaka, K., Kaneko, M. & Uemura, K. (1986). CT classification of small thalamic hemorrhages and their clinical implications. Neurology, 36, 165–72. Kirshner, H.S. & Kirstler, K.H. (1982). Aphasia after right thalamic hemorrhage. Archives of Neurology, 39, 667–9. Kwak, R., Kadoya, S. & Suzuki, T. (1983). Factors affecting the prognosis in thalamic hemorrhages. Stroke, 14, 493–500. Lhermitte, J. (1936). Symptomatologie de l’hémorragie du thalamus. Revue Neurologique, 65, 89–93. Luco, C., Hoppe, A., Schweitzer, M., Vicuna, X. & Fantin, A. (1992).

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Visual field defects in vascular lesions of the lateral geniculate body. Journal of Neurology, Neurosurgery and Psychiatry, 55, 12–15. Masdeu, J.C. & Gorelick, P.B. (1988). Thalamic astasia: inability to stand after unilateral thalamic lesions. Annals of Neurology, 23, 596–603. Mohr, J.P., Watters, W.C. & Duncan, G.W. (1976). Thalamic hemorrhage and aphasia. Brain and Language, 2, 3–17. Mohr, J.P., Kase, C.S., Meckler, R.J. & Fisher, C.M. (1977). Sensorimotor stroke due to thalamocapsular ischemia. Archives of Neurology, 34, 734–41. Percheron, G. (1976a). Les artères du thalamus humain. I. Artères et territoire thalamiques polaires de l’artère communiquante postérieure. Revue Neurologique. 132, 297–307. Percheron, G. (1976b). Les artères du thalamus humain. II. Artères et territoire thalamiques paramédians de l’artère basilaire communiquante. Revue Neurologique, 132, 309–24. Percheron, G. (1977). Les artères du thalamus humain. Territoire des artères, choroïdiennes. Revue Neurologique, 133, 547–59. Powers, J.M. (1985). Blepharospasm due to unilateral diencephalon infarction. Neurology, 35, 283–4. Sacco, R.L., Bello, J.A., Traub, R. & Brust, J.C.M. (1987). Selective proprioceptive loss from a thalamic lacunar stroke. Stroke, 18, 1160–3. Sanson, T.A., Daffner, K.R., Carvalho, P.A. & Mesulam, M.M. (1991).

Frontal lobe dysfunction following infarction of the left-sided medial thalamus. Archives of Neurology, 48, 1300–3. Serra Catafan, J., Rubio, F. & Perres Serra, J. (1992). Peduncular hallucinosis associated with posterior thalamic infarction. Journal of Neurology, 239, 89–90. Sigwald, J. & Monnier, M. (1936). Syndrome thalamo-hypothalamique avec hémitremblement (ramollissement du territoire artériel thalamo-perforé). Revue Neurologique, 66, 616–31. Stuss, D.T., Guberman, A., Nelson, R. & La Rochele, S. (1988). The neuropsychology of paramedian thalamic infarction. Brain and Cognition, 8, 348–78. Swanson, R.A. & Schmidley, J.W. (1985). Amnestic syndrome and vertical gaze palsy: early detection of bilateral thalamic infarction by CT and NMR. Stroke, 16, 823–7. Tatemishi, T.K., Duncan, C.M., Moser, F.G. et al. (1987). Syndromes of the paramedian thalamopeduncular arteries: clinical and MRI correlations in infarctions of the upper midbrain and thalamus. Annals of Neurology, 22, 159. Von Cramon, D.Y., Hebel, N. & Schuri, U. (1985). A contribution to the anatomical basis of thalamic amnesia. Brain, 108, 993–1008. Walshe, T.M., Davis, K.R. & Fisher, C.M. (1977). Thalamic hemorrhage: a computed tomographic–clinical correlation. Neurology, 27, 217–22. Watson, R.T. & Heilman, K.M. (1979). Thalamic neglect. Neurology, 29, 690–4.

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Caudate infarcts and hemorrhages Chin-Sang Chung1, Hye-Seung Lee1 and Louis R. Caplan2 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea 2 Beth Israel Deaconess Medical Center, Boston, MA, USA

1

Introduction Recent advances in brain imaging have made it possible to study clinical, cognitive, and behavioural abnormalities of caudate vascular lesions. Most of the major studies on caudate vascular lesions followed the introduction and widespread use of CT scanning in the 1970s and early 1980s. There are only a few studies of the vascular lesions, either infarcts or hemorrhages, involving the caudate nucleus. Most studies included caudate lesions involving the neighbouring structures like the putamen, internal capsule, and white-matter (Damasio et al., 1982; Richfield et al., 1987; Alexander et al., 1987; Mehler, 1987; Mendez et al., 1989; Caplan et al., 1990; Cambier et al., 1979; Valenstein & Heilman, 1981; Weisberg, 1984; Stein et al., 1984; Waga et al., 1986; Pozzilli et al., 1987; Pedrazzi et al., 1990). Recently Kumral et al. studied a series of patients with caudate infarcts or hemorrhages involving the head of the caudate nucleus(confirmed by CT and MRI), and discussed the stroke etiologies, clinical profiles, and behavioural abnormalities (Kumral et al., 1999).

Anatomy of the caudate nucleus Functional neuroanatomy: ‘parallel frontal–striatal–thalamic–frontal circuits’ According to Alexander et al.(1986) in the striatum including the caudate nucleus there are at least five parallel functionally segregated circuits that link the basal ganglia with the motor, associative, and limbic cortices. Each circuit is defined by the area of cerebral cortex projecting to specified regions of the striatum, and by the corresponding return thalamo-cortical projection to specified areas of frontal cortex. The circuits remain more or less segregated

throughout the basal ganglia and thalamus and there are cross-links between them at various relays therein. Within each circuit, the basal ganglia execute a similar, common function. They transform the cortical input received by the striatal compartment of that circuit into an output signal from the internal nucleus of the globus pallidus(GPi) and the reticular nucleus of the substantia nigra(SNr) to the thalamus directed back to the cerebral cortex and brainstem. The circuits are defined by their source of cortical input and the zones of frontal cortex to which their thalamic output is directed (Alexander et al., 1986). Because the caudate nucleus is a principal crossing area of these circuits, various neurological symptoms and signs can develop with vascular lesions of the caudate nucleus. The five circuits are presented diagrammatically in Fig. 35.1 (Caplan et al., 1990) and include: (i) the classical motor circuit, defined by projections from the sensorimotor cortex, supplementary motor area, and arcuate premotor area to the putamen, and by thalamic projections from the ventralis lateralis pars oralis (VLo) and the ventralis anterior pars parvocellularis/magnocellularis (VApc/mc) to the supplementary motor area and precentral cortex; (ii) the ocular motor circuit, defined by input from the frontal eye fields (Brodmann’s area 8), dorsolateral prefrontal cortex (areas 9 and 10), and posterior parietal cortex (area 7) to the caudate nucleus, with return thalamo-cortical projection from the VAmc and the medialis dorsalis pars paralamellaris(MDpl) to the frontal eye fields and supplementary eye fields; (iii) the dorsolateral prefrontal circuit, defined by input from the dorsal prefrontal convexity (Brodmann’s areas 9 and 10) to the caudate, with overlapping projections from the posterior parietal cortex (area 7) and arcuate premotor area, return thalamic projections from the VApc and the medialis dorsalis pars parvocellularis (MDpc) to the dorsolateral prefrontal cortex in and around the principal sulcus; (iv) the lateral orbitofrontal

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Fig. 35.1. Proposed basal ganglia–thalamocortical circuits. Parallel organization of the five basal ganglia–thalamocortical circuits. Each circuit engages specific regions of the cerebral cortex, striatum, pallidum, substantia nigra, and thalamus. From Alexander et al. (1986). Abbreviations are as follows: ACA: anterior cingulate areas; APA: arcuate premotor area; CAUD: caudate, (b) body (h) head; DLC: dorsolateral prefrontal cortex; EC: entorhinal cortex; FEF: frontal eye fields; GPi: internal segmental of globus pallidus; HC: hippocampal cortex; ITG: inferior temporal gyrus; LOF: lateral orbitofrontal cortex; MC: motor cortex; MDpl medialis dorsalis pars paralamellaris; MDmc: medialis dorsalis pars magnocellularis; MDpc: medialis dorsalis pars parvocellularis; PPC: posterior parietal cortex; PUT: patamen; SC: somatosensory cortex; SMA: supplementary motor area; SNr: substantia nigra pars reticulata; STG: superior temporal gyrus; VAmc: ventralis anterior pars magnocellularis; VApc: ventralis anterior pars parvocellularis; VLm: ventralis lateralis pars medialis; VLo: ventralis lateralis pars oralis; VP: ventral pallidum; VS: ventral striatum; cl-: caudolateral; cdm-: caudal dorsomedial; dl-: dorsolateral; l-: lateral; ldm-: lateral dorsomedial; m-: medial; mdm-: medial dorsomedial; pm: posteromedial; rd-: rostrodorsal; rl-: rostrolateral; rm-: rostromedial; vm-: ventromedial; vl-: ventrolateral. (From Caplan et al., 1990.)

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Fig. 35.2. Blood supply to the caudate nucleus (From Kase & Caplan, 1994, with permission.)

circuit, defined by input from the lateral orbitofrontal cortex (Brodmann’s area 10) to the caudate, overlapping with input from the auditory and visual association areas from the superior and inferior temporal gyri respectively, and return thalamic projections from VAmc and the medialis dorsalis pars magnocellularis (MDmc) to the lateral orbitofrontal cortex; and (v) the limbic circuit, defined by input from the hippocampus, amygdala, and limbic areas of cortex (areas 28 and 35) projecting to the ventral striatum, where it overlaps with inputs from the anterior cingulate region (area 24) and widespread sources in the temporal lobe, and return thalamic projections from MD to the anterior cingulate area and medial orbitofrontal cortex.

Blood supply to the caudate nucleus The blood supply to the caudate nucleus often varies and a given structure can be supplied in different patients by several different deep perforators (Kaplan, 1965; Gillilan, 1968; Dunker & Harris, 1976; Gorczyca & Mohr, 1987; Ghika et al., 1990). The caudate nucleus receives its blood supply mainly through the deep penetrators from the anterior cerebral arteries (ACAs) and middle cerebral arteries (MCAs) (Fig. 35.2). The ACA gives rise to Heubner’s arteries, a series of two

to four vessels that usually arise from the A2 portion of the ACA near the junction of the anterior communicating artery and the ACA(Gorczyca & Mohr, 1987). These vessels supply the inferior part of the head of the caudate nucleus, the adjacent anterior limb of the internal capsule, and the subfrontal white-matter. Direct penetrating arteries from the ACA (called medial striate arteries or anterior lenticulostriate arteries by various authors) supply the anterior portion of the head of the caudate nucleus. The MCA gives rise to medial lenticulostriate arteries that branch from the proximal M1 portion and supply a small portion of the lateral border of the caudate head and the adjacent internal capsule. The lateral lenticulostriate arteries branch from the mainstem MCA or its superiordivision branch to supply the major portion of the head of the caudate nucleus, as well as the adjacent internal capsule and the anterior half of the putamen. There is considerable overlap between the three arteries supplying the head of the caudate nucleus: the lateral lenticulostriate, anterior lenticulostriate, and Heubner’s recurrent artery (Ghika et al., 1990; De Reuck, 1971; Gomez et al., 1984; Caplan & Helgason, 1995). Anterior lenticulostriate arteries primarily supply the lateral caudate nucleus (LCN), medial caudate nucleus (MCN), ventral caudate nucleus (VCN) and partially nourish the anterior limb of the internal capsule. Infarcts in the territory of the anterior

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Fig. 35.3. A CT scan picture showing a densely enhancing infarct limited to the caudate nucleus.

lenticulostriate arteries yield only slight, usually transient, neuropsychological deficits, while infarcts in the territory of the lateral lenticulostriate arteries present prominent motor and neuropsychological deficits.

Fig. 35.4. An MRI picture showing a large caudate infarct involving the left caudate nucleus, anterior limb of the internal capsule, and putamen. A hemorrhagic infarct is seen in the right putamen.

Caudate infarcts Although there has been little mention of arterial territories involved in patients with caudate infarcts (Damasio et al., 1982; Richfield et al., 1987; Alexander et al., 1987; Mehler, 1987; Mendez et al., 1989; Caplan et al., 1990), the most commonly involved arteries in caudate infarcts are the lateral lenticulostriate arteries and the anterior lenticulostriate arteries (Kumral et al., 1999). Infarctions in the territory of the lateral lenticulostriate arteries are limited to the MCN, LCN, VCN, anterior part of the internal capsule, and putamen. The recurrent artery of Heubner affects the inferior part of the caudate nucleus, the anterior part of the capsule, and the nucleus accumbens(Kumral et al. 1999). Caplan et al.(1990) divided caudate infarcts into several groups, according to the anatomic structures involved, in 18 patients. The infarcts were limited to the caudate nucleus in four patients, included the caudate nucleus and the anterior limb of the internal capsule in nine, and affected the caudate nucleus, the anterior limb of the internal capsule, and the anterior putamen in five. Figure 35.3 is an enhanced CT image of a subacute infarct limited to the caudate nucleus. Figure 35.4 illustrates a large infarct

involving the caudate nucleus, the anterior limb of the internal capsule, and the putamen. The caudate nucleus can also be involved as part of a large striatocapsular infarct caused by occlusion of the intracranial internal carotid artery or the mainstem MCA. An analysis of the 49 previously reported cases and the 34 patients studied at the University of Illinois yielded a total of 83 patients with 91 caudate infarcts (Caplan & Helgason, 1995). In 22 patients (24%), CT or MRI showed the infarcts to be confined to the caudate nucleus. The lesions involved the caudate nucleus and the adjacent anterior limb of the internal capsule or corona radiata in 25 patients (28%). The remaining 44 patients (48%), had infarcts that involved the caudate nucleus, the anterior limb of the internal capsule, and the putamen (Table 35.1).

Stroke mechanisms In most of the reported patients, a full evaluation, including angiography and cardiac evaluation, was not performed and the data are insufficient to define the usual precise stroke mechanisms of caudate infarcts.

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Table 35.1. Site of lesions of caudate infarcts (49 prior reports ⫹ Illinois series)

Table 35.2. Risk factors and vascular mechanisms from combined series

Site of lesion

Number(percentage)

Factors

Patients and percentagea

Caudate nucleus(CN) alone CN + anterior limb of IC + corona radiata CN + anterior limb of IC + putamen Total

22 (24%) 25 (28%) 44 (48%) 91

Hypertension Diabetes mellitus Large-artery lesions Cardiac embolic source Total number of patients

92 (67%) 44 (32%) 19 (14%) 18 (13%) 137

Note: IC, internal capsule. Source: Adapted from Caplan & Helgason(1995).

Penetrating-branch disease has been proposed as a common mechanism because the caudate nucleus receives its blood supply from deep penetrating arteries. Risk factors for penetrating-branch disease are prevalent in patients with caudate infarcts. However, evaluation of the heart and large arteries is essential in those without risk factors for penetrating-branch diseases. Echocardiography, duplex ultrasound, transcranial Doppler ultrasound, and magnetic-resonance angiography (MRA) are useful non-invasive screening tests for detection of important occlusive vascular diseases or cardiac sources of emboli. The major risk factors include hypertension, hypercholesterolemia, diabetes mellitus, previous myocardial infarct, cigarette smoking, and family history of ischemic stroke (Caplan et al., 1990; Kumral et al., 1999). Nonvalvular atrial fibrillation(NVAF), cardiac mural dyskinesia, cardiac aneurysm with a mural thrombus, syphilis, and Hodgkin’s lymphoma are also uncommon reported risk factors. Table 35.2 lists the risk factors or stroke mechanisms from the combined series of prior reports and in those patients seen at the University of Illinois (Caplan & Helgason, 1995).

Clinical features Although the symptoms and signs of caudate infarctions vary from report to report, behavioural abnormalities, especially abulia, agitation, and loss of executive abilities, dysarthria or dysphonia, and motor weakness, are common. Movement disorders, such as hemichorea, ballism, and tremor, can occur, but less often (Caplan & Helgason, 1995).

Cognitive and behavioural abnormalities The most prominent clinical features of caudate vascular lesions are behavioural and cognitive abnormalities (Damasio et al., 1982; Richfield et al., 1987; Alexander et al.,

Note: a Some patients had more than one risk factor. Source: Adapted from Chung & Kim (1994), Caplan & Helgason (1995), and Kumral et al.(1999).

1987; Mehler, 1987; Mendez, et al., 1989; Caplan et al., 1990; Cambier et al., 1979; Valenstein & Heilman, 1981; Weisberg, 1984; Stein et al., 1984; Waga et al., 1986; Pozzilli et al., 1987; Pedrazzi et al., 1990). Behavioural changes may occur as a result of loss of function in cortical zones, caused by loss of striatal efferent projections from the caudate nucleus that is a principal crossing area of basal ganglia–thalamocortical loops. The commonest behavioural abnormalities are the reduced activity and slowness of abulia, followed by restlessness, hyperactivity, and agitation, with decreased attention to tasks (Caplan et al., 1990; Mendez et al., 1989). Defective recall is also noted in patients with caudate infarcts(Mendez et al., 1989; Markowitsch et al., 1990). Neuropsychological tests show abnormalities in executive functions, memory, and attention. Deficits do not correlate with the side of the lesion, but patients with affective abnormalities tend to have larger infarcts. Mendez and his colleagues (1989) divided spontaneous behavioural symptoms in patients with caudate infarcts into three groups: (i) apathetic, with decreased spontaneous verbal and motor activities (dorsolateral caudate involvement); (ii) disinhibited, inappropriate, and impulsive (small ventromedial lesions in the caudate nucleus); and (iii) affective symptoms with psychotic features (dorsolateral caudate involvement; larger and extended into adjacent structures than in the first group).

Agitation Agitation, anxiety, and talkativeness are common signs in patients with caudate lesions (Mendez et al., 1989; Caplan et al., 1990). Restlessness, disinhibition, and confusion can develop in patients with lesions limited to the caudate nucleus (Kumral et al., 1999). It is well known that behavioural hyperactivity with restlessness, excitement, agitation, and shouting may also occur because of lesions of the

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middle or posteroinferior temporal lobe and parietooccipital lobes (Caplan et al., 1986).

Abulia Patients with caudate infarcts can present with abulia, which is defined as ‘apathy, disinterest, flattened affect, and lack of initiative for usual daily activities.’ Abulia is more severe and more persistent in patients who have bilateral caudate infarcts (Trillet et al., 1990). Clinically, the patients show decreased spontaneous activity and speech and prolonged latency in responding to questions and other stimuli. The patients show psychic akinesia, characterized by severe mental and affective stagnation and lack of initiative for action and speech. Such akinetic attacks are often prolonged and stereotyped behaviours are common. Patients can become inattentive, disinterested, and lethargic and can show impulsivity, disinhibition, and violent attacks as well (Richfield et al., 1987; Chung & Kim, 1994). These features were also described in patients with bilateral globus pallidus or putaminal lesions (Laplane & Baulac, 1982; Laplane et al., 1984). The abulic patients described by Fisher (1983) had lesions in the frontal lobes and underlying structures or in the thalamus and upper brainstem. The mechanism of abulia is explained by interruption of limbofrontal connection. The quantitative and temporal features of behaviour are more difficult to measure, and a variety of descriptive terms have been used such as bradykinesia, abulia, psychic akinesia, and akinetic mutism. These terms describe a continuum from minor to major absence of observable behaviour, and despite severe behavioural abnormalities, some intellectual and cognitive functions can be retained.

Neglect Contralateral motor and visuospatial hemineglect can develop in one-fourth of the patients with a right caudate lesion, particularly if the anterior limb of the internal capsule is involved also (Caplan et al., 1990; Chung & Kim, 1994; Kumral et al., 1999). All patients with hemineglect have involvement of MCN, LCN, VCN, and neighbouring structures (Kumral et al., 1999). Motor-exploratory hemineglect can develop from disruption of the frontal-striatalthalamo-frontal circuit that includes the associative frontal cortical areas, striatum and substantia nigra.

Mood changes Depression is another common presentation of caudate vascular lesion and is observed in one-third of the caudate lesion patients without cognitive deterioration (Bokura & Robinson, 1997). It suggests that the caudate nucleus may play a role in the regulation of human mood.

Table 35.3. Symptoms and signs in caudate infarctsa Symptoms and signs

Patients and percentage

Dysarthria or dysphonia Motor weakness Behavioural abnormalities Agitation Abulia Neglect Aphasia

18/21(86%) 21/21(100%) 12/21(57%) 6(3L, 3R)b 10(2L, 7R, 1 bilateral) 2(2R) 1(1L)

Notes: a Cases available for clinical–neuroimaging correlation⫽21. b L, left; R, right. Source: Adapted from Caplan & Helgason (1995).

Memory dysfunction One-third of the patients with left caudate lesions have verbal amnesia, while patients with right caudate lesions shows visual amnesia, suggesting a role of the caudate nucleus in the integration of visual and verbal memories. Verbal comprehension and verbal memory deficits are caused by dysfunction of corticocaudate connections (Pozzilli et al., 1987; Chung & Kim, 1994; Kumral et al., 1999). Bilateral caudate lesions may yield global dementia, while unilateral lesions may cause impairment of frontal lobe functions and decreased free recall of episodic and semantic items. One-fourth of the patients, especially those with large caudate lesions, have deficits in tasks requiring planning and sequencing because of disconnection of the caudate nucleus from the frontal lobes (Mendez et al., 1989).

Others Rarely, patients can show motor dysprosody, motor impersistence in eye-closing and inability to maintain grip or hand postures for 20 seconds, and inadequate laughing at stroke onset. Some patients show impairment in frontal lobe tests using the Stroop test and Luria’s conflicting tasks (Table 35.3).

Speech and language disturbances Dysarthria Dysarthria is another common sign of caudate vascular lesions (Saris, 1983; Mendez et al., 1989; Caplan et al., 1990; Pedrazzi et al., 1990; Kim, 1992; Chung & Kim, 1994: Kumral et al., 1999). Dysarthria has no side predominance in caudate stroke. Interruption of the corticolingual tracts to the tongue or corticostriatocerebellar loops seems to be

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responsible for dysarthria because the pathways play crucial roles in uniform speech patterns (Urban et al., 1996).

due to right caudate nucleus infarction. In two further reports (Lodder & Baard, 1981; Tabaton et al., 1985), the infarcts and movement disorders were bilateral, beginning at once in all limbs.

Aphasia Left caudate infarcts can cause minor aphasic abnormalities (Caplan et al., 1990). About one-half of the patients with a left caudate lesion have minor and transient linguistic deficits (Kumral et al., 1999). Different types of aphasia, such as transcortical, non-fluent aphasia, characterized by semantic and verbal paraphasias and perseverations without comprehension impairment, occur in patients with left caudate vascular lesions (Cambier et al., 1979; Valenstein & Heilman, 1981; Damasio et al., 1982; Weisberg, 1984; Stein et al., 1984; Waga et al., 1986; Pozzilli et al., 1987; Richfield et al., 1987; Alexander et al., 1987; Mehler, 1987; Viader et al., 1987; Perani et al., 1987; Mendez et al., 1989; Caplan et al., 1990; Pedrazzi et al., 1990; Chung & Kim, 1994). Transient global-type aphasia can also develop by intrahemispheric diaschisis. Patients with subcortical lesions involving the caudate nucleus, anterior limb of the internal capsule, and putamen can show word-finding difficulty or hesitancy without severe aphasic abnormalities (Alexander et al., 1987). In such cases single-photon emission CT imaging may show decreased perfusion in the left frontal and temporoparietal lobes (Kumral et al., 1999). Acute disconnection of the linguistic pathways between the anterior and posterior speech areas, which are connected with the left caudate nucleus, and anterior limb of the internal capsule may yield a different type of aphasia.

Movement disorders The caudate nucleus has inhibitory projections to the lateral globus pallidus, which in turn projects to the subthalamic nucleus. Loss of inhibitory input to the subthalamic nucleus may allow initiation of abnormal movements. Abnormalities of movement and tone can follow acute lesions of either the striate nuclei or the subthalamic nucleus (Lownie & Gilbert, 1990). Movement disorders after caudate infarcts have been described in several case reports, but most of the reports have not been detailed. The abnormal movements usually have been contralateral to the lesion and usually have occurred at the time of the stroke. These abnormal movements have been described as ballistic, choreic, or both. Midgard et al. (1989) reported an infant with stroke, who presented with a delayed onset of abnormal movements and dystonia more than a decade later. The two patients of Kim (1992) had delayed onset of a rest tremor of the left arm and hand months after recovery from left hemiparesis

Motor abnormalities Motor abnormality or weakness is noted in around 40% of patients with caudate infarcts (Caplan et al., 1990; Mendez et al., 1989; Kim, 1992; Markowitsch et al., 1990; Kumral et al., 1999). In some patients with dystonia and abnormal movements, weakness may be overshadowed by involuntary movements and abnormal tone. The frequency of motor involvement has been underestimated due to selection bias. Most patients reported in the literature had specific abnormalities such as behavioural disorders or abnormal movements. Weakness develops when a lesion extends into the anterior limb of the internal capsule and putamen, interrupting the striatopontine fibers. Lesions confined to the caudate nucleus do not cause weakness. Weakness, when present, is usually slight and relatively transient, rarely leaving any persistent motor disability.

Treatment and prognosis Caudate infarcts usually pursue benign clinical courses. Sixty per cent of the patients become independent. Only a few patients with unilateral caudate infarcts in the territory of lateral lenticulostriate arteries or of anterior lenticulostriate arteries become slightly dependent. Only rarely do patients with unilateral caudate infarcts worsen clinically. Those with bilateral caudate infarcts or large unilateral infarcts in the territory of the lateral lenticulostriate arteries can become dependent. Patients die only rarely of underlying heart disease rather than of the caudate infarct itself (Kumral et al., 1999). Because caudate infarcts can develop from any stroke mechanisms including lipohyalinosis, branch atheromatous diseases, large artery atherothrombosis, or embolism, treatment of patients with caudate infarcts depends on the underlying stroke mechanism and usually requires antiaggregant therapy or anticoagulation with warfarin therapy for prevention of recurrence.

Caudate hemorrhages Caudate hemorrhages account for approximately 7% of all intracerebral hemorrhages (ICH) and only recently have caudate hemorrhages been separated from bleeding into other basal ganglia structures (Stein et al., 1984).

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(a )

(b)

Fig. 35.5. CT scan and MRI pictures showing hematomas located in the head (a) or in the body (b) of the caudate nucleus. The caudate hematomas almost always rupture into the lateral ventricle.

Stroke mechanisms Most caudate hemorrhages are caused by rupture of penetrating arteries. Hypertension is the most common risk factor (Kumral et al., 1999; Chung et al., 2000). Arteriovenous malformations, carotid aneurysms, and cavernous angiomas are other important causes but sometimes no responsible cause is found (Stein et al., 1984; Weisberg, 1984; Waga et al., 1986; Kumral et al., 1999). Rarely, moya–moya disease and moya–moya-like atherosclerotic abnormalities of vessels secondary to hypertension and occlusive intracranial carotid artery disease can cause caudate hemorrhage (Carton & Hickey, 1955; McConnel & Leonard, 1967; Dany et al., 1969; Lapras et al., 1972; Becker et al., 1979; Aoki & Mizutani, 1984; Chen et al., 1988; Steinke et al., 1992). In an international series of striatocapsular hemorrhages (Chung et al., 2000), 23 patients had caudate hemorrhage which mainly involved the caudate head (Fig. 35.5(a)) and occasionally the caudate body (Fig. 35.5(b)). The hematomas are relatively small (less than 1 inch), always rupture into the anterior horn of the lateral ventricle, and occasionally extend posterolaterally into the anterior limb of the internal capsule and anterior putamen.

Clinical features The clinical symptoms and signs of caudate hemorrhages depend on the lesion size and the neighboring structures

involved. The most common clinical presentations are severe headache, nausea, vomiting, and marked meningeal irritation signs, mimicking a subarachnoid hemorrhage (SAH) or primary intraventricular hemorrhage (IVH). These are usually the only clinical signs if the parenchymal hematoma is limited to the head or body of the caudate nucleus and dissects medially into the frontal horn of the ipsilateral ventricle, then causes IVH and ventricular dilatation on the ipsilateral side. The patients show no prominent motor, sensory, or visual abnormalities (Pedrazzi et al., 1990). During the pre-CT era, some conditions diagnosed as ‘primary IVH’ or ‘SAH with negative angiography’ might have been caudate hemorrhages with IVH. When the hematoma is large enough to spread laterally or posterolaterally into the putamen or anterior or posterior limb of the internal capsule, a caudate hemorrhage can cause motor and neuropsychological deficits, including transitory abulia, frontal lobe dysfunction, and transient mild motor weakness which disappear within one week (Chung et al., 2000; Kumral et al., 1999). The patients usually remain alert. Disconnection of the corticocaudate tract secondary to caudate hemorrhage can cause verbal comprehension and verbal memory deficits (Pozzilli et al., 1987). Language dysfunction of transcortical motor dysphasic type can develop in case of large hematomas, which also improve completely with time. However, neglect, sensory deficit, conjugate gaze abnormalities and pupillary abnormalities are only rarely observed (Chung et al.,

Caudate infarcts and hemorrhages

2000) but these are usually less severe and are transitory if the hematoma does not extend across the anterior limb of the internal capsule. When hematomas spread inferiorly, they may cause Horner’s syndrome, because of thalamic involvement or compression of the hypothalamus (Kumral et al., 1999). Rarely a caudate hemorrhage can cause movement disorder like hemiballism (Giroud et al., 1985). Rare, bilateral caudate hemorrhages have been reported (Bertol et al., 1991).

Treatment and prognosis The outcome of patients with caudate hemorrhage is so excellent that more than 80% of patients return to normal activities. Less than 20% of patients remain slightly hemiparetic and deaths are rare (Chung et al., 2000). Kumral et al. (1999) reported a patient who died of generalized cerebral vasospasm following caudate hemorrhage. The patient had no abnormality on cerebral angiography. The parenchymal hematoma itself does not require surgical intervention but emergency extraventricular drainage may be required when acute severe obstructive hydrocephalus develops following bleeding. However, a permanent ventriculoperitoneal shunt is necessary only rarely.

iReferencesi Alexander, G.E., Delong, M.R. & Strick, P.L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357–81. Alexander, M.P., Naeser, M.A. & Palumbo, C.L. (1987). Correlation of subcortical CT lesion sites and aphasia profiles. Brain, 110, 961–91. Aoki, N. & Mizutani, H. (1984). Does moyamoya disease cause subarachnoid hemorrhage? Journal of Neurosurgery, 60, 348–53. Becker, D.H., Towsend, J.J., Kramer, R.A. & Newton, T.H. (1979). Occult cerebrovascular malformations: a series of 18 histologically verified cases with negative angiography. Brain, 102, 249–87. Bertol, V., Gracia-Naya, M., Oliveros, A. & Gros, B. (1991). Bilateral symmetric caudate hemorrhage. Neurology, 41, 1157–8. Bokura, H. & Robinson, R.G. (1997). Long-term cognitive impairment associated with caudate stroke. Stroke, 28, 970–5. Cambier, J., Elghozi, D. & Strube, E. (1979). Hemorrhage de la tête du noyau caudé gauche: désorganisation du discours et de l’expression graphique: perturbation des séries gestuelles. Reviews of Neurology, 135, 763–77. Caplan, L.R. & Helgason, C. (1995). Caudate infarcts. In Lacunar and Other Subcortical Infarctions, ed. G.A. Donnan, B. Norrving, J.M. Bamford & J. Bogousslavsky, pp. 117–30. London, UK: Oxford University Press. Caplan, L.R., Kelly, M., Kase, C.S., Hier, D.B. & White, J.L. (1986).

Infarcts of the inferior division of the right middle cerebral artery. Neurology, 36, 1015–20. Caplan, L.R., Schmahmann, J.D., Kase, C.S. et al. (1990). Caudate infarcts. Archives of Neurology, 47, 133–43. Carton, C. & Hickey, W. (1955). Arteriovenous malformation of the head of the caudate nucleus: report of a case with removal. Journal of Neurosurgery, 12, 414–18. Chen, S.T., Liu, T.H., Hsu, C.Y., Hogan, E.L. & Ryu, S.J. (1988). Moyamoya disease in Taiwan. Stroke, 19, 53–9. Chung, C.S. & Kim, J. (1994). Clinical neurology of striatocapsular infarction. Chungnam Medical Journal, 21, 521–33. Chung, C.S., Caplan, L.R., Yamamoto, Y. et al. (2000). Striatocapsular haemorrhage. Brain, 123, 1850–62. Damasio, A.R., Damasio, H., Rizzo, M., Varney, N. & Gersh, F. (1982). Aphasia with nonhemorrhagic lesions in the basal ganglia and internal capsule. Archives of Neurology, 39, 2–14. Dany, A., Airault, C., Guerin, J. & Pefferkorn, J.P. (1969). A propos d’un anéurisme artério-veineux strié gauche. Bordeaux Médicin, 7, 1579–84. De Reuck J. (1971). Arterial vascularisation and angioarchitecture of the nucleus caudatus in human brain. European Neurology, 5, 130–6. Dunker, R.O. & Harris, A.B. (1976). Surgical anatomy of the proximal anterior cerebral artery. Journal of Neurosurgery, 44, 359–67. Fisher, C.M. (1983). Abulia versus agitated behavior. Clinical Neurosurgery, 31, 9–31. Ghika, J.A., Bogousslavsky, J. & Regli, F. (1990). Deep perforators from the carotid system: template of the vascular territories. Archives of Neurology, 47, 1097–100. Gillilan, L. (1968). The arterial and venous blood supplies to the forebrain (including the internal capsule) of primates. Neurology, 18, 653–70. Giroud, M., Guard, O. & Dumas, R. (1985). Hemiballismus from hematoma in caudate nucleus. Surgical Neurology, 24, 587–8. Gomez, F., Dujovny, M., Umansky, F. et al. (1984). Neurosurgical anatomy of the recurrent artery of Heubner. Journal of Neurosurgery, 60, 130–9. Gorczyca, W. & Mohr, G. (1987). Microvascular anatomy of Heubner’s recurrent artery. Journal of Neurosurgery, 44, 359–67. Kaplan, H.A. (1965). The lateral perforating branches of the anterior and middle cerebral arteries. Journal of Neurosurgery, 23, 305–10. Kase, C.S. & Caplan, L.R. (1994). Intracerebral Hemorrhage. Boston: Butterworth–Heinemann. Kim, J.S. (1992). Delayed onset hand tremor caused by cerebral infarction. Stroke, 23, 292–4. Kumral, E., Evyapan, D. & Balkir, K. (1999). Acute caudate vascular lesions. Stroke, 30, 100–8. Laplane, D. & Baulac, M. (1982). Perte de l’autoactivation psychique: activité compulsive d’allure obsessionnelle: lésion lenticulaire bilatérale. Revue Neurologique, 138, 137–41. Laplane, D., Baulac, M., Widlöcher, D. & Dubois, B. (1984). Pure psychic akinesia with bilateral lesions of basal ganglia. Journal of Neurology, Neurosurgery and Psychiatry, 47, 377–85. Lapras, C., Bochu, M., Russel, F. & Sindou, M. (1972). Les angiomes

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de la tête du noyau caudé: a propos de huit cas opérés. Neurochirurgie, 18, 471–83. Lodder, J. & Baard, W.C. (1981). Parallelism caused by bilateral hemorrhagic infarction in the basal ganglia. Neurology, 31, 484–6. Lownie, S.P. & Gilbert, J.J. (1990). Hemichorea and hemiballismus: recent concepts. Clinical Neuropathology, 9, 46–50. Markowitsch, H.J., Von Cramon, D.Y., Hofmann, E., Sick, C.D. & Kinzler, P. (1990). Verbal memory deterioration after unilateral infarct of the internal capsule in an adolescent. Cortex, 26, 597–609. McConnel, T.H. & Leonard, J.S. (1967). Microangiomatous malformations with intraventricular hemorrhage: report of two unusual cases. Neurology, 17, 618–20. Mehler, M. (1987). A novel disorder of linguistic expression following left caudate nucleus infarction. Neurology, 37 (Suppl. 1), 167(abstract). Mendez, M.F., Adams, N.L. & Lewandowski, K.S. (1989). Neurobehavioral changes associated with caudate lesions. Neurology, 39, 349–54. Midgard, R., Aarli, J.A. & Julsrud, O.J. (1989). Symptomatic hemidystonia of delayed onset. Magnetic resonance demonstration of pathology in the putamen and the caudate nucleus. Acta Neurologica Scandinavica, 79, 27–31. Pedrazzi, P., Bogousslavsky, J. & Regli, F. (1990). Hemorrages limitées à la tête du noyau caudé. Revue Neurologique, 146, 726–38. Perani, D., Vallar, G., Cappa, S., Messa, C. & Fazio, F. (1987). Aphasia and neglect after subcortical stroke: a clinical–cerebral perfusion correlation study. Brain, 110, 1211–29. Pozzilli, C., Passafiume, D., Bastianello, S., D’Antona, R. & Lenzi,

G.L. (1987). Remote effects of caudate hemorrhage: a clinical and functional study. Cortex, 23, 341–9. Richfield, E.K., Twyman, R. & Berent, S. (1987). Neurological syndrome following bilateral damage to the head of the caudate nucleus. Annals of Neurology, 22, 768–71. Saris, S. (1983). Chorea caused by caudate infarction. Archives of Neurology, 40, 590–1. Stein, R.W., Kase, C.S., Hier, D.B. et al. (1984). Caudate hemorrhage. Neurology, 34, 1549–54. Steinke, W., Tatemichi, T.K., Mohr, J.P., Massaro, A., Prohovnik, I. & Solomon, R.A. (1992). Caudate hemorrhage with moyamoya-like vasculopathy from atherosclerotic disease. Stroke, 239, 1360–3. Tabaton, M., Mancardi, G. & Loeb, C. (1985). Generalized chorea due to bilateral small deep cerebral infarcts. Neurology, 35, 588–9. Trillet, M., Croisile, B., Tourniaire, D. & Schott, B. (1990). Perturbations de l’activité motrice et lésions des noyaux caudés. Revue Neurologique, 146, 338–44. Urban, P.P., Hopf, H.C., Zorowka, P.G., Fleischer, S. & Andreas, J. (1996). Dysarthria and lacunar stroke: pathophysiologic aspects. Neurology, 41, 1135–41. Valenstein, E. & Heilman, K.M. (1981). Unilateral hypokinesia and motor extension. Neurology, 31, 445–8. Viader, F., Lechevallier, B. & Eustache, F. (1987). Un cas d’aphasie avec troubles du discours par infarctus des noyaux caudé et lenticulaire gauches. Revue Neurologique, 12, 814–22. Waga, S., Fujimoto, K., Okada, M., Miyazaki, M. & Tanaka, Y. (1986). Caudate hemorrhage. Neurosurgery, 18, 445–50. Weisberg, L. (1984). Caudate hemorrhage. Archives of Neurology, 41, 971–4.

36

Posterior cerebral artery Claudia J. Chaves and Louis R. Caplan Beth Israel Deaconess Medical Center, Boston, MA, USA

Anatomy The posterior cerebral arteries (PCAS) are the major sources of blood supply to the midbrain, thalamus, occipital lobes, inferior and medial temporal lobes, and portions of the posterior inferior parietal lobes. The PCAs originate from the terminal bifurcation of the basilar artery, encircle the midbrain, and then divide into cortical branches as they reach the dorsal surface of the midbrain (Margolis et al., 1974). The peduncular, ambient, and quadrigeminal segments of the PCAs are named after the cisterns through which the arteries pass. The initial portion of a PCA, before the posterior communicating artery anastomosis from the internal carotid artery, is referred to as the PI segment, the mesencephalic artery, or the precommunal portion of the PCA. In about 10% of individuals, a fetal pattern of origin of one PCA from the internal carotid artery will persist into adult life, in which case the PI segment from the basilar artery will be hypoplastic (Hoyt et al., 1974). One PCA may be unusually large (29% of individuals) or unusually small (24%) (Hoyt et al., 1974). Arterial branches that supply the medial portions of the midbrain and the posteromedial thalamus, including the paramedian mesencephalic arteries, the thalamic subthalamic arteries (also called the thalamoperforating arteries), and the medial posterior choroidal arteries, arise from the peduncular, precommunal segments of the PCAs. The anterior and anterolateral portions of the thalamus are usually fed by the tuberothalamic (polar) arteries, which branch from the posterior communicating arteries, not the PCAs. However, in some patients the tuberothalamic arteries are absent, and their usual territory is supplied by the thalamic-subthalamic arteries. The peduncular perforating arteries supplying the lateral midbrain, and the thalamogeniculate arteries supplying the ventrolateral thalamus, arise from the ambient

portions of the PCAs. After the PCAs have circled the midbrain, the lateral posterior choroidal arteries arise, followed by the four cortical branches: the anterior temporal, posterior temporal, parieto-occipital, and calcarine arteries. Figure 36.1 shows a PCA and its branches diagramatically. The anterior temporal arteries arise first from the ambient segment; next, the posterior temporal arteries arise and course laterally, travelling along the hippocampal gyrus. The posterior temporal arteries course between the tentorium and the medial temporal lobe, where the vessels can be compressed by the tentorium when there is increased intracranial pressure or transtentorial herniation. Compression of the posterior temporal arteries at the tentorial notch causes infarction of the hippocampus and the medial temporal lobe (Lindenberg, 1955). The parietooccipital arteries usually originate from the ambient segment and supply the occipital and medial inferior parietal lobes, usually also giving off the posterior pericallosal arteries, which circle the splenium of the corpus callosum. In about 16% of individuals the calcarine arteries also arise from the parieto-occipital arteries (Margolis et al., 1974). Usually the calcarine arteries arise as single branches of the PCAs, travelling at first lateral to the parieto-occipital arteries and then following a winding course medially along the calcarine fissure.

Unilateral PCA-territory ischemia and infarction Symptoms and signs (Table 36.1) PCA stenosis Patients with PCA stenosis (Fisher, 1986; Pessin et al., 1987a) may have transient ischemic attacks (TIAs) alone, or TIAs may precede infarction. The TIAs are predominantly

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Fig. 36.1. Drawings of the PCAs and their supply to the midbrain, thalamus, and temporal and occipital lobes: BA, basilar artery; SCA, superior cerebellar artery; PCoA, posterior communicating artery; PCA, posterior cerebral arteries; PMA, paramedian mesencephalic arteries; PPA, peduncular perforating arteries; TPA, thalamoperforating arteries; TGA, thalamogeniculate arteries. (Drawn by Laurel Cook-Lhowe.)

visual and sensory. Visual symptoms are the most common and can be negative in nature, (i.e., loss of vision) or positive (taking the form of photopsias and visual illusions). Patients may describe a temporary hemianopic field defect in which they suddenly realize that they cannot see to one side; they may describe a homonymous hole or scotoma in the visual field. A patient reported by Fisher (1986) saw a light-chocolate-coloured spot in the central vision that came and went for 2 weeks. Other patients have reported flashes of light, striped vision, coloured objects, or geometric objects in one visual field. These positive phenomena are identical with those described in classic migraine attacks, except that in patients with PCA

stenosis the attacks are briefer and the visual phenomena do not develop or progress over minutes as do migraine auras. Paresthesias are also relatively common, most often involving the face and hand, but they can affect the arm and leg, or face, arm, and leg. Transient spells of numbness and loss of feeling are also common. Occasional patients with PCA stenosis have reported limb clumsiness, lightheaded dizzy feelings, and brief periods of bewilderment and confusion. Usually patients have multiple brief attacks lasting seconds to minutes, less often hours. Most patients have more than one type of symptom. Visual and sensory symptoms can occur during different attacks in a given

Posterior cerebral artery

Table 36.1. Clinical signs in series of patients with posterior cerebral artery territory infarcts Clinical signs

Pessin et al., N ⫽ 35a

Brandt & Thie, N ⫽ 127

Yamamoto et al., N ⫽ 79

Visual field defect Sensory Motor Cognitive and behaviouralb Ataxia

100% 20% 9% 20% 3%

93% 29% 28% 32% NM

84% 15% 29% 25% 27%

Notes: a Only patients with occipital infarcts and hemianopic visual field defects were included. b Most often alexia, anomia and other language abnormalities, memory defects, confusion, visual neglect and agnosias. NM: not mentioned in the report.

patient or can occur together. Repeated pure sensory TIAs, with no visual or other components, occurring over a period of weeks to months are rarely due to PCA disease, but are common in patients with pure sensory stroke caused by disease of the thalamogeniculate arteries or their branches (Fisher, 1986).

PCA-territory unilateral infarcts The clinical findings depend heavily on the portion of the PCA occluded and on the location and extent of infarction (Bogousslavsky et al., 1981; Brandt et al., 2000; Fisher, 1986; Pessin et al., 1987b; Caplan, 1988; Mohr & Pessin, 1992, Caplan, 1996; Yamamoto at al. 1999). The most common location for occlusions is in the ambient segment, affecting one or more of the hemispheric branches. Unilateral PCAterritory infarcts can be conveniently divided into four groups, each having characteristic findings: (i) occlusion of the extreme proximal portion of the PCA, causing midbrain, thalamic, and hemispheric infarctions; (ii) occlusion of the PCA in the proximal ambient segment, before the branching of the thalamogeniculate arteries, causing lateral thalamic and hemispheric infarctions; (iii) occlusion of a single PCA branch, predominantly involving the calcarine artery; (iv) large hemispheric infarctions of PCA territories, often involving calcarine, parieto-occipital, and posterior temporal artery territories. Patients in the first two groups usually have both deep and superficial infarcts, whereas those in the latter two groups have only superficial, hemispheric infarcts. Posterior cerebral infarcts are also frequently associated with other infarcts in the posterior and anterior circulation. Yamamoto et al (1999) found that, among 79 patients with PCA strokes from the New England Medical Center Posterior Circulation Registry, 39% also had other territory infarcts that they called PCA⫹. The most common region involved outside of the PCA territory was the cerebellum,

especially the territories of the postero-inferior and superior cerebellar arteries. Fisher (1986) estimated that precommunal PCA occlusions account for about one of seven unilateral PCA infarcts. In a CT angiographic study of PCA-territory infarcts, lesions involving the thalamus and posterior cerebral hemispheres accounted for 14 of 38 cases (37%), whereas 63% of patients had infarcts that were entirely hemispheric (Goto et al., 1979). Infarction is most common in the territory of the calcarine artery (Goto et al., 1979; Kinkel et al., 1984; Pessin et al., 1987b; Yamamoto et al., 1999). The territories of the occipito-parietal and posterior temporal arteries are often affected together.

Proximal PCA occlusions (precommunal) Occlusion of the PCA near its origin from the basilar artery causes infarction in the medial midbrain and posteromedial thalamus, as well as lateral thalamic and posterior hemispheric infarction. The anatomy of the perforating penetrating arteries and the mechanism of occlusion explain why rostral brainstem infarction is often bilateral and paramedian, even when only one PCA is occluded. Penetrating arteries to the bilateral paramedian rostral brainstem structures can arise from one PCA. Occlusions of the PCA origins usually are embolic; thrombi and fragments that arise from the heart, aorta, or proximal vertebrobasilar arteries often rest at the basilar artery bifurcation (‘top of the basilar’) before going into one of the PCAs (Caplan, 1980). In patients with unilateral PCA occlusions, necropsy, MRI, and CT may show bilateral rostral paramedian tegmental mesencephalic and posteromedial diencephalic infarcts. Patients with these bilateral infarcts often have prolonged stupor or coma, or, later, hypersomnolence, amnestic deficits, and vertical-gaze palsies (Fisher, 1986). The main clinical feature distinguishing proximal PCA

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occlusion from the other types of PCA strokes is hemiplegia (Benson & Tomlinson, 1971; Caplan et al., 1988; Hommel et al., 1990, 1991; Chambers et al., 1991; North et al., 1993). Paralysis is due to ischemia of the cerebral peduncle, which is supplied by the paramedian mesencephalic and the peduncular perforating arteries. Patients with lateral thalamic and occipitoparietotemporal infarcts may have severe sensory loss, hypotonia, clumsiness, and abnormal movements, but they are not hemiplegic. Partial or complete ipsilateral third-nerve palsy, bilateral ptosis, loss of vertical gaze, lethargy, and abulia are variable features associated with proximal PCA occlusion. Sometimes occlusion of the precommunal portion of the PCA can simulate the clinical picture of a MCA stroke. Chambers et al. (1991) described a series of 12 of such patients. The majority of their patients had contralateral hemiparesis, homonymous hemianopia, hemispatial neglect and sensory loss with sensory inattention. The patients with left PCA infarcts were also aphasic. Intact repetition, fading or decreased voice volume and presence of oculomotor signs secondary to the midbrain involvement often suggests that the lesion involves the PCA rather than the MCA territory. Other signs of posterior hemispheric cortical involvement, such as visual agnosia, colour anomia, visual hallucinations or illusions can also be helpful in distinguishing these two entities, but at times, they are difficult to elicit or can be overlooked in patients with acute severe strokes.

Occlusion of the postcommunal, ambient segment of one PCA Occlusion of one PCA proximal to the thalamogeniculate arteries usually causes infarction in the ventrolateral thalamus and the hemispheric territories of the PCA (Caplan et al., 1988). The territory of the lateral posterior choroidal artery is also usually affected, but the clinical symptoms and signs are usually overshadowed by involvement of the other branches of the postcommunal PCA. Isolated infarcts in the lateral posterior choroidal artery territory are rare and usually associated with a homonymous quadrantanopia or horizontal sectoranopia, with or without hemisensory loss and neuropsychological dysfunction, such as transcortical aphasia and memory disturbances. Small vessel disease is the most common etiology (Neau & Bogousslavsky, 1996). The combination of infarctions of the lateral thalamus and of the posterior temporal lobe was called the syndrome of the PCA by Foix and Hillemand (Caplan, 1990). Figure 36.2 is a reproduction of the original drawing showing this lesion (Foix & Hillemand, 1925). Lateral thalamic infarction in patients with PCA occlusion is analo-

Fig. 36.2. Diagram of typical PCA-territory infarct involving the lateral thalamus and temporal lobe. (From Foix & Hillemand, 1925, with permission.)

gous to lenticulostriate-territory infarction in patients with occlusive disease of the middle cerebral artery (MCA). Lateral thalamic or striatocapsular infarctions can occur because of atheromatous branch occlusions (Caplan, 1989) or can occur secondary to occlusive lesions of the main trunk arteries before the penetrating artery branches (Caplan et al., 1988) (Fig. 36.3). Infarction in the ventrolateral thalamus most often causes sensory symptoms and signs involving the contralateral face, limbs and trunk. Paresthesias are most common and usually consist of tingling, prickling, burning, or crawling feelings. Usually there is some loss of pinprick, touch, or thermal sensation, but the objective loss of sensation may be slight. Many of the fibres in the spinothalamic tract do not reach the thalamic somatosensory nuclei, the ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei. Fibres from the spinal cord and from the nucleus and descending tract of nerve V leave the spinothalamic tract in the brainstem to reach the ascending reticular formation in the paramedian brainstem tegmentum. When infarctions include the medial and ventrolateral thalamus, or involve the thalamoparietal white-matter fibres travelling to somatosensory areas I and II of the cortex, then a severe sensory loss ensues, with marked impairments for position sense, touch, pain, and temperature. Infarction in the lateral thalamus, in the territory of thal-

Posterior cerebral artery

ing large infarcts in the temporal and occipital lobes in the hemispheral territory of the PCA. The signs of hemispheral infarction are added to those of deep infarction already described.

PCA-territory hemispheral infarction

Fig. 36.3. Cartoons illustrating the vascular lesions underlying deep infarctions. Panels 1A and 1B show MCA-territory infarcts; 1A, occlusion of the mainstem MCA, with striatocapsular infarction; 1B, occlusion of a single lenticulostriate artery, with resulting lacunar capsular infarct. Panels 2A and 2B show PCAterritory infarcts; 2A, occlusion of the mainstem PCA, causing a large lateral thalamic infarct extending into the adjacent whitematter; 2B, occlusion of a thalamogeniculate artery causing a lateral thalamic infarct. (From Caplan et al., 1988, with permission.)

amogeniculate artery branches of the postcommunal PCA, also cause motor abnormalities. Clumsiness and ataxia are due to interruption of extrapyramidal fibres from the basal ganglia, via the ansa lenticularis, and cerebellofugal fibres from the superior cerebellar peduncle and red nucleus that synapse in the ventrolateral nucleus of the thalamus, as well as to infarction of the posterior limb of the internal capsule adjacent to the ventrolateral thalamus (Dejerine & Roussy, 1906; Caplan et al., 1988) The results are slight hemiparesis, abnormal spontaneous contralateral limb movements that are often choreic or athetoid, ataxia of the contralateral limbs, and abnormal posture of the contralateral hand, with flexion and entrapment of the thumb in the fist. Usually the hemiparesis is not severe, and improvement is rather rapid. In patients with ventrolateral thalamic infarction or ischemia including the thalamoparietal pedicle, pain may develop weeks or months after the stroke. Pain, burning, or dysesthetic feelings can be severe and can involve any parts of the contralateral limbs or trunk. Pain is usually increased by touch or movement of the affected limbs. The sensory loss and pain may be limited to any part of the contralateral hemicorpus. In patients with deep infarctions that involve the midbrain and/or the thalamus, usually there are accompany-

Signs of hemispheral dysfunction will vary with the branch territories involved. The most common abnormality is a contralateral visual-field defect. PCA-territory infarction without hemianopia or any visual abnormalities is quite rare. John et al. (1984) reported a single patient with an angiographically documented left PCA occlusion and right hemisensory and hemimotor signs who had no visual abnormalities and normal findings on CT scan. Among 42 patients with PCA-territory infarcts and persistent deficits in one study, 41 had visual-field abnormalities (Brandt et al., 1995). Visual-field abnormalities are due to infarction of striate cortex or the optic radiations or to deep infarction involving the lateral geniculate body. In our experience, about half of the patients with visual abnormalities are aware that the visual loss is limited to a half-field. They may report being unable to see to that side or may report greyness, a void, a spot, or difficulty in focusing on objects in that visual field. The remainder of the patients will recognize a visual problem but cannot define or localize it well. They may report difficulty in seeing, a problem of bumping into things, poor focus, blurred vision, spots before the eyes, and so forth. (Fisher, 1986). Most of these patients become aware of the lateralization of the visual abnormality during the acute stroke, especially after the hemifield defect is shown and explained. During the acute stroke period, or after a visual-field defect has begun to clear, patients may report hallucinations of spots, colours, objects, or people in the defective field (Lance, 1976; Brust & Behrens, 1977). The most common visual-field abnormality is hemianopia. Often the macular region is spared, at least partially, when the infarct does not reach the occipital pole. The hemianopia is usually congruent, but may spare or selectively involve the ipsilateral temporal crescent of vision, depending on inclusion of the most anterior portion of the calcarine striate cortex. The field defect may be limited to a quadrantanopia. Superior-quadrantanopias are caused by infarction of the lower bank of the striate cortex or the inferior optic radiations in the temporal occipital lobes. An inferior-quadrantanopia is due to infarction of the upper calcarine bank or involvement of the upper optic radiations in the inferior parietal lobe or occipital lobe. At times, the visual defect is a homonymous scotoma involving the fixation macular region (occipital-pole infarcts) or the lateral, more peripheral portions of the contralateral visual

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field (more anterior infarction of VI along the calcarine fissure). More complex visual abnormalities are often present and are virtually diagnostic of PCA-territory infarction. Visual perseverations consist in (i) seeing an object within the field of vision repeated, sometimes multiple times, in the defective hemifield, despite continued gaze fixation, (ii) after turning one’s gaze to the hemianopic field, seeing an object that was formerly in view, and (iii) continuing to see an object (palinopsia) as an afterimage, despite the fact that the object or the viewer has moved (Critchley, 1951). Patients may be able to detect motion and the presence of an object in a defective half-field, but may be unable to tell either the colour or the nature of the object. Perceptions of distance and depth and localization of objects in the halffield may also be defective. The visual abnormalities and visual phenomena are discussed more extensively in Chapter 6. Sensory symptoms and signs compose the second most frequent category of abnormalities in patients with PCA territory hemispheric infarcts. The abnormalities can be slight, including mostly paresthesias and subjective numbness, or there can be severe, virtually complete loss of position sense and loss of pain and thermal sensations. In some patients, despite severe sensory loss, the ability to execute movements is relatively preserved. There have been no extensive clinicopathological correlations of the sensory deficits in patients with PCA-territory infarctions.

Left-hemisphere infarction Some abnormalities are found exclusively in patients with infarctions of the PCA territory in the left (dominant) hemisphere. These phenomena usually involve memory or language-related defects. The abnormalities of higher cortical function are invariably related to extrastriate infarction involving the parieto-occipital and/or temporal branches of the left PCA. Reading abnormalities can compose either of two different syndromes. In the syndrome of alexia without agraphia, patients write, speak, and spell normally, but fail to read words and sentences and cannot name colours (Dejerine, 1892; Geschwind & Fusillo, 1966; Caplan & Hedley-White, 1974). They may be able to read letters and numbers. The responsible lesions usually involve the splenium of the corpus callosum or white-matter fibers in the parieto-occipital region that intercept the radiations from the corpus callosum (Damasio & Damasio, 1983). The traditional explanation for the syndrome is that visual perceptions engendered in the right visual cortex (the left striate area or the optic radiations are damaged) do not

reach the language zone in the left temporoparietal region (Dejerine, 1892; Geschwind & Fusillo, 1966). Because the left language area is not damaged, writing, speaking, and spelling abilities are preserved. These non-visual aspects likely cross the corpus callosum to provide interhemisphere transfer more anterior in the callosum to the PCA infarct. Colour percepts are the only visual percepts that are purely visual (i.e. regarding which no other sensory modality is able to yield information). Objects, geometric shapes, and scenes can evoke somatosensory, taste, smell, and other memories and associations. Colours are recognized and matched, but cannot be named by the left temporoparietal cortex. In a series of 16 consecutive patients with tomographic evidence of infarcts confined to the territory of the left PCA in whom a battery of neuropsychologic tests were systematically applied, the most common abnormality was alexia without agraphia, a finding present in 75% of the patients (De Renzi et al., 1987). In patients with alexia with agraphia, reading, writing, and spelling abilities are all abnormal. The responsible infarct usually involves or undercuts the angular gyrus region. Left-side PCA-territory infarcts can cause this syndrome if they are large and involve white matter of the inferior parietal lobe adjacent to the angular gyrus. Dejerine (1892) posited that the region of the left angular gyrus was the anatomic residence of literacy. The inferior parietal lobe is situated in a strategic position to receive both visual afferent information from the striate and peristriate areas and auditory input from the temporal lobe. Poor ability to read letters and paragraphs (with occasional word recognition) and impaired spelling and writing abilities are found on examination. Elements of Gerstmann’s syndrome (dyscalculia, right-left confusion, finger agnosia, constructional apraxia, dysgraphia) are also often present (Caplan & Hedley-White, 1974). Patients with inferior-parietal-lobe lesions may also have elements of conduction aphasia, characterized by the use of paraphasias and abnormal speech repetition. Paralexia, in patients with left-hemisphere infarctions, is a term that describes reading errors toward the ends (right sides) of words. Having seen the beginning of a word, a patient with right hemianopia may guess or assume the ending of the word. In patients with right-hemisphere infarction and left hemianopia, the first part of the word may be missed. Although aphasia is not common in patients with left side PCA-territory infarction, patients with large infarcts that include the territory of the left posterior temporal artery may have either anomic or transcortical sensory aphasia (Kertesz et al., 1982, Servan et al., 1995). In patients

Posterior cerebral artery

with transcortical sensory aphasia, speech is fluent, but contains paraphasic errors and occasionally jargon. Naming ability is poor, and speech is often circumlocutory. Although patients may be unable to understand what is said, they retain the ability to repeat language, the hallmark of transcortical aphasia. Patients with anomic aphasia, sometimes called amnestic aphasia, have word-finding and naming difficulties, but retain normal abilities for speech repetition and comprehension and normal reading, writing, and spelling skills. Visual agnosia can also occur in patients with left-side PCA-territory infarction, usually in patients who also have alexia without agraphia and colour-naming deficits (Caplan & Hedley-White, 1974). In this syndrome, patients have difficulty in recognizing and naming objects presented visually, but can identify the same objects when the presentation is tactile or auditory. For example, one patient could not name a cat when looking at a picture, but quickly used the word when she felt the animal, heard the characteristic meow, or was asked to list household pets (Caplan & Hedley-White, 1974). Infarctions of the left medial temporal lobe, including the hippocampus and adjacent white-matter in the territory of the temporal arteries, can cause persistent amnesia that can last at least 6 months (Caplan & Hedley-White, 1974; Caplan, 1988). These patients cannot make new memories or readily learn new techniques. One patient was reported with extensive infarction of the left medial temporal lobe in whom the ability to make new memories returned after 6 months, but the patient never regained any memories of her acute stroke and convalescence, nor of the activities that transpired during the 6 months that she was amnestic (Caplan & Hedley-White, 1974).

Right-hemisphere PCA-territory infarction Lesions of the right hemisphere have been less extensively analysed. Neglect of the contralateral visual field occurs more often with right-side PCA infarcts than with left. Some patients with infarcts that include the parietal and temporal lobes also have constructional apraxia. Their drawings often omit the left-side constituents, and sizes, angles, and proportions often are wrongly displayed. Copying ability is also poor and may not show improvement over original figure drawings (Piercy et al., 1960; Hier et al., 1983). Some patients with infarctions of the right posterior parietal lobe are quite disoriented to place (Fisher, 1982). They may duplicate their locale, saying that they are in an institution that in reality is located far distant, or that they are in a branch of such an institution. This belief that there are two versions of a geographic loca-

tion is referred to as reduplicative paramnesia, after the original description by Pick (Benson et al., 1976).

Mechanisms of unilateral PCA infarcts All published studies that have investigated patients with unilateral PCA-territory infarcts have shown that embolism is the most common etiologic mechanism. (Caplan & Tettenborn, 1992). Castaigne et al. (1973) (Caplan, 1996), in their necropsy study of posterior circulation infarcts, found that among 30 patients with PCA-territory infarcts, only three had thrombosis of the PCA superimposed on atheromatous stenosis. Pessin et al. (1987b) studied the stroke mechanisms among 35 patients with hemianopia and CT-documented PCA infarctions and found that ten patients (28.5%) had cardiac-origin embolism, six (17%) had embolism from lesions of the proximal vertebrobasilar arteries, and another 11 patients (31.4%) had embolism for which the site of origin was not certain. Brandt et al. (1995) found that 83 of 127 PCA infarcts in their series (65%) were embolic, almost half of them secondary to intra-arterial embolism. Steinke et al (1997) studied 74 consecutive patients with PCA strokes documented by CT or MRI and found that cardiac embolism was the most probable etiology in 31%, vertebrobasilar artery disease in 22% and intrinsic disease of the PCA in 8% of the patients. Hypercoagulopathy or paradoxical embolism were present in 15% of the patients. In 24% of the patients, the mechanism was undetermined despite complete investigation. Recently, Yamamoto et al. (1999) described the stroke mechanisms in 79 patients with PCA strokes; 61% of these patients had infarcts limited to the PCA territory (pure PCA) while 39% also had other territory infarcts (PCA⫹). The most frequent stroke mechanism was embolism, secondary to cardiac sources in 40.5%, intra-arterial embolism in 31.6% and cryptogenic embolism in 10% of patients. Intrinsic PCA disease, vasoconstriction and coagulopathy occurred in 9%, 5% and 4% of the patients, respectively. Patients with cardioembolism and intrinsic PCA disease frequently had pure PCA strokes, while patients with intra-arterial embolism more often had PCA⫹ infarcts (Table 36.2). As in the anterior circulation, emboli often arise from atheromatous plaques or very recent occlusions of the proximal vertebral artery (Pelouze, 1989; Caplan et al., 1992a). We recently reported ten patients with intracranial embolism that arose from proximal vertebral artery occlusions in seven patients and from severe stenosis in three patients (Caplan et al., 1992). Koroshetz and Ropper (1987) reported 11 patients with artery-to-artery embolism to the

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Table 36.2. Mechanisms of PCA territory infarction in various series Mechanisms

Castaigne et al., N ⫽ 30

Pessin et al., N ⫽ 35

Brandt & Thie, N ⫽ 127

Steinke et al., N ⫽ 74

Yamamoto et al., N ⫽ 79

CSOE CPE PAD IPD VCN COAG Others Unknown

3% NM 50% 10% NM NM 26.5% 10%

28.5% 31.4% 17% 0 14% 9% 0 0

28% 20% 16.5% 16% 3% NM NM 16%

31% NM 22% 8% NM NM 11% 24%

40.5% 10% 31.5% 9% 5% 4% 0 0

Notes: CSOE: Cardiac source of embolism; CPE: cryptogenic embolism; PAD: proximal arterial disease; IPD: intrinsic PCA disease; VCN: vasoconstriction; COAG: coagulopathy; NM: not mentioned in the report.

PCA arising from extracranial (five patients), intracranial (three), or combined extracranial and intracranial (three) potential sources. Embolism to the PCA can arise from the internal carotid artery (ICA) in cases of fetal origin of that PCA. Even a shotgun pellet embolus to the PCA has been described (Hungerford et al., 1981). In some patients, especially African–Americans and those of Japanese, Thai, and Chinese origin, PCA infarction can result from PCA stenosis, often with in situ thrombosis. Transcranial Doppler ultrasound has documented distal PCA embolism in a patient with a proximal PCA occlusive lesion (Diehl et al., 1993). Migraine is another important cause of thrombosis of the PCA. In one series, five of 35 (14%) PCA infarcts were likely due to migrainous strokes; in all five patients, occlusions of the PCA or its branches were documented angiographically, in two patients thrombi were seen (Pessin et al., 1987b). Monitoring by transcranial Doppler ultrasound has documented coagulopathies, with in situ thrombus formation, as another mechanism of PCA occlusion, and it was present in three of 35 patients (8%) in one series (Pessin et al., 1987b). Unilateral and even bilateral PCA-territory infarctions can also result from mass lesions that cause transtentorial herniation and increased intracranial pressure. The temporal and calcarine artery branches are most often involved (Lindenberg, 1955). Hemianopia or cortical blindness can result from calcarine artery compression (Lindenberg, 1955; Keane, 1980). Unilateral, large ICA-territory infarctions or large hematomas can lead to edema and mass effect, with compression of PCA branches and secondary PCA-territory infarction. Subdural hematoma likely is the most common clinical condition in which secondary PCA-territory infarction develops. The signs of

PCA-territory infarction can be recognized after drainage of the hematoma (Keane, 1980).

Bilateral PCA-territory infarcts Symptoms and signs The clinical findings will depend greatly on the size, distribution, and localization of the infarction. Often, infarcts are restricted to the bilateral inferior bank or bilateral superior bank of the calcarine fissures. Cortical blindness results from bilateral infarction of the striate cortex (Symonds & MacKenzie, 1957; Caplan, 1980). Some cortically blind patients will not recognize or will not admit that they cannot see (Anton’s syndrome). Patients who are cortically blind may be able to avoid bumping into objects and may blink to visual threat. The most frequently posited explanation for this ‘blind-sight’ is preservation of the extrageniculate optic pathway involving connections between the superior colliculus and the peristriate cortex. Some patients have bilateral hemianopias, with sparing of parts of the visual field, or bilateral scotomas. Amnesia can be a permanent sequela of bilateral infarction of the medial temporal lobes (Victor et al., 1961; Benson et al., 1974). These patients lose the ability to make new memories. Memory loss is never an isolated finding. Amnesia is invariably accompanied by visual and sensory abnormalities and often by an acute decrease in level of consciousness. Emboli to the rostral basilar artery often pass into the bilateral PCAs, and they have a predilection for PCA branches that perfuse structures below the calcarine fis-

Posterior cerebral artery

sures, including the striate and peristriate cortices in the occipital and temporal lobes. Bilateral inferior-bank infarcts result. Patients usually have upper-quadrant attitudinal hemianopias, accompanied by abnormal colour perception, difficulty in recognizing faces, loss of the ability to revisualize the form of an object, and sometimes an agitated delirium. Colours may seem drab or washed out, and the environment may seem devoid of colour. Patients with colour perception abnormalities, central achromatopia, cannot name or match colours or identify or distinguish hues, but may be able to perform acceptably on the Ishihara isochromic-plate test (Damasio et al., 1980). Prosopagnosic patients usually cannot match or identify faces and often cannot recognize individual animals or cars or other single items within a category (Damasio et al., 1982). The structures below the calcarine fissure are parts of an occipitofugal system that contains specialized networks that relate to the nature, form, shape, and general morphology of objects. This has been called the ‘what’ pathway, as opposed to the occipitofugal pathway occupying the superior bank of the calcarine fissure, which is specialized for the visual-spatial ‘where’ aspects of objects (Mishkin et al., 1983; Livingstone & Hubel, 1988; Mesulam, 1994). Patients with bilateral inferior-bank infarcts often cannot revisualize objects or people, but they can revisualize and picture directions and place relationships (Levine et al., 1985). Patients with bilateral (and sometimes unilateral) infarctions involving the lingual and fusiform gyri in the inferior portions of the temporal lobes often manifest a restless, hyperactive state (Horenstein et al., 1962; Medina et al., 1974; Caplan, 1980). These patients usually have rambling loquacious speech, easy distractibility, difficulty in concentrating, and sometimes aggressive and combative behaviour. This agitated delirium probably results from infarction of limbic cortex. Agitated delirium can also be seen after unilateral infarction of the posterior inferior temporal lobe, especially involving the left side (Devinsky et al., 1988). Bilateral superior-bank infarcts are much less common than lower-bank lesions. The most common cause of bilateral upper-bank posterior infarcts is severe hypotension, with infarction in the posterior PCA-MCA border-zone regions. Patients usually have features of Balint’s syndrome, disorientation to place, and difficulty in revisualizing locations. Balint’s syndrome includes asimultagnosia, optic ataxia, and gaze apraxia, but any of the elements can be found alone or can be limited to one visual field (Hecaen & de Ajuriaguerra, 1974; Caplan, 1980). Asimultagnosia is an inability to direct a panoramic view. Patients see things

piecemeal. When several objects are presented, the patient will identify them one by one, often after executing head and eye search movements and being reminded that more than one object is present. Sometimes, only parts of objects, letters, words, or faces will be seen and identified. Optic ataxia is an inability to direct hand movements under visual guidance – a lack of coordination of eye and hand motions. Apraxia of gaze is an inability to look directly at a position or object on which the patient has been instructed to focus. Patients with upper-bank lesions often have difficulty in revisualizing directions and relationships (i.e. where objects, people, or places are topographically) (Levine et al., 1985). They may also be quite disoriented to location, often believing themselves to be in different remote locations that are somehow connected to their actual locations (Fisher, 1982).

Mechanisms of bilateral PCA-territory infarcts Bilateral PCA infarcts can develop consecutively or simultaneously. Those that develop consecutively have the same causes as unilateral PCA infarcts in general, except, perhaps, for an over-representation of patients with bilateral PCA stenosis and intrinsic atherosclerosis. Simultaneously developing bilateral infarcts are mostly due to embolism or spread of a thrombus in the basilar artery to the PCAS. Some borderzone PCA infarcts are due to hypotension and hypoperfusion. An important consideration in the differential diagnosis is that PCA infarction be distinguished from an acute metabolic–edematous posterior leukoencephalopathy or a capillary-leak syndrome following acute elevation of blood pressure, seen in hypertensive encephalopathy, eclampsia, and administration of antineoplastic drugs, such as cyclosporine (Hinchey et al., 1996). Infarcts tend to be mostly cortical or cortical–subcortical, whereas acute edema predominantly or exclusively involves white-matter. Fisher (1986) reviewed 47 of his personally studied necropsy cases of bilateral PCA infarcts, often accompanied by butterfly-distribution rostral brainstem infarctions. He found that, in 44 of the 47 cases (94%), the available evidence favoured embolism. Emboli often came from the heart or proximal vertebrobasilar arteries. In some patients, more-proximal infarcts were taken as evidence of an ‘embolus in transit’ that had stopped temporarily before reaching the final recipient artery (Fisher, 1986). Mehler recently reported a series of 61 patients with rostral brainstem and PCA-territory infarcts, among whom only 64% were given full investigations, including angiography

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(Mehler, 1989). In 28 of 61 patients (47.5%), Mehler thought the data favoured or substantiated embolism as the cause; among those, 14 were cardioembolic, and 14 were arteryto-artery emboli (Mehler, 1989). In some patients, in situ occlusion of the distal basilar artery, with propagation to the PCAs, and dissection of the distal basilar artery can cause bilateral PCA territory infarcts. Bilateral posterior cerebral artery strokes have also been described in association with migraines (Moen et al., 1988).

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Medina, J., Rubino, F. & Ross, E. (1974). Agitated delirium caused by infarction of the hippocampal formation and fusiform and lingual gyri: a case report. Neurology, 24, 1181–3. Mehler, M.F. (1989). The rostral basilar artery syndrome: diagnosis, etiology, prognosis. Neurology, 39, 9–16. Mesulam, M.M. (1994). Higher visual functions of the cerebral cortex and their disruption in clinical practice. In Principles and Practice of Ophthalmology, vol. 4, ed. D.M. Albert & F.A. Jakobiec, pp. 2640–53. Philadelphia: W.B. Saunders Company. Mishkin, M., Ungerleider, L.G. & Macks, K.A. (1983). Object vision and spatial vision: two cortical pathways. Trends in Neuroscience, 6, 414–17. Moen, M., Levine, S.R., Newman, D.S., Dull-Baird, A., Brown, G.G., Welch, K.M. (1988). Bilateral posterior cerebral artery strokes in a young migraine sufferer. Stroke, 19, 525–8. Mohr, J.P. & Pessin, M.S. (1992). Posterior cerebral artery disease. In Stroke: Pathophysiology, Diagnosis, and Management, 2nd edn, ed. H. J. M. Barnett, J. P. Mohr, B. M. Stein & F. Yatsu, pp. 419–41. London: Churchill Livingstone. Neau, J.P. & Bogousslavsky, J. (1996). The syndrome of posterior choroidal artery territory infarction. Annals of Neurology, 39(6), 779–88. North, K., Kan, A., Desilva, M. & Ouvrier, R. (1993). Hemiplegia due to posterior cerebral artery occlusion. Stroke, 24, 1757–60. Pelouze, G.A. (1989). Plaque ulceree de l’ostium de l’artere vertebrale. Revue Neurologique, 145, 478–81. Pessin, M.S., Kwan, E.S., Dewm, L.D., Hedges, T.R., III, Gale, D. & Caplan, L.R. (1987a). Posterior cerebral artery stenosis. Annals of Neurology, 21, 85–9. Pessin, M.S., Lathi, E.S., Cohen, M.B., Kwan, E.S., Hedges, T.R., III & Caplan, L.R. (1987b). Clinical features and mechanism of occipital infarction. Annals of Neurology, 21, 290–9. Piercy, M.F., Hecaen, H. & De Ajuriaguerra, J. (1960). Constructional apraxia associated with unilateral cerebral lesions. Brain, 83, 225–42. Servan, J., Verstichel, P., Catala, M., Yakovleff, A. & Rancurel, G. (1995). Aphasia and infarction of the posterior cerebral artery territory. Journal of Neurology, 242, 87–92. Steinke, W., Mangold, J., Schwartz, A. & Hennerici, M. (1997). Mechanisms of infarction in the superficial posterior cerebral artery territory. Journal of Neurology, 244, 571–8. Symonds, C. & MacKenzie, I. (1957). Bilateral loss of vision from cerebral infarction. Brain, 80, 415–54. Victor, M., Angevine, J., Mancall, E. & Fisher, C.M. (1961). Memory loss with lesions of hippocampal formation: report of a case with some remarks on the anatomical basis of memory. Archives of Neurology, 5, 244–63. Yamamoto, Y., Georgiadis, A., Chang, H-M. & Caplan, L.R. (1999). Posterior cerebral artery territory infarcts in the New England Medical Center (NEMC) posterior circulation registry. Archives of Neurology, 56, 824–32.

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Large and panhemispheric infarcts Stefan Schwarz, Stefan Schwab and Werner Hacke Department of Neurology, University of Heidelberg, Germany

Introduction Within the first few days after hemispheric stroke, mortality is mainly determined by the extent and location of space-occupying postischemic brain edema which leads to intracranial hypertension, brain tissue shifts, and tentorial herniation (Hacke et al., 1996). Medical complications and co-morbidity are the predominant causes of death in those patients who survive this critical time period of approximately 1 week. Until a few years ago, large hemispheric strokes were commonly accepted as an untreatable disease with a uniformly poor prognosis. However, recent developments in diagnosis and pathophysiology have led to new monitoring and treatment strategies which may improve mortality and lead to a better functional outcome of the surviving patients. In this chapter we will review the basic diagnostic and therapeutic approach to patients with large life-threatening hemispheric infarcts. We define hemispheric infarcts as ‘large’ when more than 50% of the MCA territory is affected and as ‘panhemispheric’ when the ACA or PCA territory is infarcted in addition to a large MCA territory stroke. Brainstem and cerebellar infarcts will not be discussed here.

Epidemiology and etiology Because the infarct size was not considered in most epidemiological stroke studies, the incidence of large hemispheric infarcts according to our definition is not known exactly. As a rough estimate, 5–10% of all ischemic strokes are taken to meet the above-mentioned criteria of large or panhemispheric strokes (Hacke et al., 1996; Krieger et al., 1999; Wijdiks & Diringer, 1998). The vast majority of large infarcts are embolic in origin.

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The main source of embolism is the heart, with atrial fibrillation as the most common cause, followed by artery-toartery embolism after dissection of the internal carotid artery. Less frequent causes are embolism in patients with cardiomyopathy, recent myocardial infarction, metallic heart valves, coagulation abnormalities, and venous embolism through a patent foramen ovale. In contrast to other stroke types, local arteriosclerosis of the intracranial arteries rarely causes large supratentorial infarcts (Hacke et al., 1996; Krieger et al., 1999; Wijdiks & Diringer, 1998). As a consequence of these specific etiological factors, patients who suffer large strokes are younger, common vascular risk factors are absent, and the male predominance is lower than in average stroke patients.

Pathophysiology The most frequent underlying vascular cause of large hemispheric infarcts is embolic occlusion of the proximal MCA trunk (M1 or M2 segments) or distal occlusion of the ICA (at the so-called ‘carotid-T’, see Fig. 37.1) (Hacke et al., 1996; Krieger et al., 1999; Wijdiks & Diringer, 1998). With distal occlusion of the ICA, the blood flow to both the MCA and ACA is interrupted, resulting in a combined ACA plus MCA territory infarct if the ACA is not sufficiently perfused via collateral blood flow through the communicating anterior artery. Simultaneous infarctions in the anterior circulation and in the PCA territory result from multiple emboli or, in patients with an atypical origin of the PCA, from the anterior circulation. The size of the resulting infarcted area is determined not only by the site of occlusion, but is also substantially influenced by the highly variable collateral blood supply from leptomeningeal vessels, which can preserve a residual perfusion of proximally occluded vessels (Ringelstein et al., 1992).

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Fig. 37.1. Complete MCA and ACA infarction 20 hours after distal ICA occlusion (at the carotid-T) of embolic origin.

The cerebral vascular bed is capable of maintaining a constant cerebral blood flow (CBF). The phenomenon of ‘autoregulation’ is achieved either through a reduction (vasodilatation) or an increase (vasoconstriction) of arterial resistance when the cerebral perfusion pressure (CPP) decreases or increases correspondingly. Normal CBF is approximately 60 ml/100 g brain tissue/min and remains constant between a mean arterial blood pressure of 60–150 mmHg (Fig. 37.2). When ischemia occurs and the CPP falls below the threshold of autoregulation, the brain tissue first extracts more oxygen from the vascular compartment and, when the CPP is further reduced, produces energy via anaerobic glycolysis. When the CBF reaches a critical threshold of 10–20 ml/100 g brain tissue/min, the capacity to maintain the membrane potential is rapidly and irreversibly lost. After depolarization of the cell membrane, sodium ions freely enter the cell, accompanied by water. This overloading of the cell with water is the basic mechanism of ‘cytotoxic’ brain edema. Simultaneously, a massive influx of calcium ions and release of excitatory transmitters precipitate a cascade of various biochemical mechanisms, further aggravating ischemic cell damage. Neuronal cells are primarily affected by ischemia due to their high energy demand. ‘Vasogenic’ brain edema ulti-

Fig. 37.2. Autoregulation of cerebral blood flow (CBF). The cerebral vascular bed is capable of maintaining a constant CBF between a mean arterial blood pressure of approximately 60 to 150 mmHg. This phenomenon of ‘autoregulation’ is achieved either through a reduction (vasodilation) or an increase (vasoconstriction) of arterial resistances when the cerebral perfusion pressure (CPP) decreases or increases. If the autoregulation is impaired (dotted line), the CBF passively changes with the CPP.

mately occurs when ischemic damage of the endothelial cells causes disruption of the blood–brain barrier, allowing plasma, containing osmotic active macromolecules, to pass into the intercellular space. While the postischemic edema in the initial phase of ischemia is predominantly cytotoxic within the first few minutes and up to a few hours, after the secondary disruption of the blood–brain barrier it becomes vasogenic. Reperfusion injury may contribute to the development of brain edema in some patients. This has been extensively studied in animals; however, the clinical relevance of this phenomenon is less certain. It is thought that, if sudden reperfusion by spontaneous fibrinolysis or clot fragmentation of a previously occluded vessel occurs, the ischemic damaged endothelium allows a massive leakage of protein-rich fluid, leading to a sudden increase in vasogenic brain edema. It should be stressed that the concept of reperfusion injury is not contradictory to the therapeutic approaches of early recanalization, before irreversible neuronal and endothelial damage has been caused. Because of its osseous boundaries, an expansion of the contents within the cranium is not possible. According to the Monro–Kellie doctrine, an increase in edematous brain tissue therefore requires a compensatory decrease in the other two physiological compartments contained in the skull – intravascular blood and cerebrospinal fluid

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Fig. 37.3. Cerebral compliance. An increase of edematous brain tissue requires a compensatory decrease of the other two physiological compartments contained in the skull, intravascular blood and cerebrospinal fluid (CSF). After the failure of these very limited compensatory mechanisms; the ICP rapidly rises; and even a small increase in the intracranial volume (䉭 volume) may substantially raise the ICP (䉭 ICP). However, in this situation, even a small reduction of brain edema can dramatically lower the ICP.

(CSF) – which together account for approximately 20% of the intracranial volume (Fig. 37.3). If these very limited compensatory mechanisms fail, the intracranial pressure (ICP) rapidly rises and even a small increase in the intracranial volume may substantially raise the ICP. In most patients, postischemic brain edema follows a predictable time course. After 24 hours, the first radiological signs of space-occupying brain edema are already visible, but the ICP is not yet markedly increased. Between the second and the fifth day after onset of symptoms the brain edema and intracranial hypertension have reached their maximum (Fig. 37.4) (Frank, 1995; Hacke et al., 1996). Postischemic hemispheric brain edema is the leading cause of neurological deterioration and death in patients with large hemispheric infarcts. The two main mechanisms for neurological deterioration from postischemic brain edema are tissue shifts and increased ICP (Frank, 1995). Increased ICP globally reduces the cerebral perfusion, leading to further ischemic damage. If increased ICP is compartmentalized, displacement of tissue away from the mass occurs, compressing parts of the brain at a distance from the lesion. With increasing space-occupying effects, the ischemic brain edema leads to compression of the lateral ventricle, midline shift (best monitored at the pineal gland) and, finally, compression of the basal cisterns and subsequent brainstem dysfunction and tentorial herniation. These brain tissue shifts are not always accompanied by a mas-

sively elevated ICP, and herniation syndrome in the absence of elevated ICP has been repeatedly described (Ropper, 1998, 1990; Ropper & Shafran, 1984). The traditional concept of ‘uncal’ tentorial herniation was described as the consequence of displacement of the medial temporal lobe over the edge of the tentorium into the space between the tentorium and the midbrain, compressing the midbrain at this level (Plum & Posner, 1983). In ‘central’ herniation, there is predominant axial downward displacement of midline structures through the tentorial notch. Recently, the role of herniation syndromes has been questioned, and at least in the initial phase of the herniation syndrome, the neurological symptoms of brainstem dysfunction are probably more the consequence of horizontal displacement and distortion of the brainstem than axial downward displacement (Ropper, 1998; Ropper & Shafran, 1984).

Radiological findings While cranial computed tomography (CT) was previously believed to be of limited use in the detection of an ischemic lesion in the early phase of the disease, it is now known that early parenchymatous signs of infarctions, i.e. parenchymal hypoattenuation, loss of differentiation between grey and white matter, and hemispheric sulcus effacement, are present within the first 6 hours in almost all patients with large infarctions (von Kummer et al., 1994, 1996; Moulin et al., 1996). An early hypodensity of over 50% of the MCA territory is a predictor of a poor clinical outcome, and the mortality in these patients reaches 85% if only medical treatment is employed. After 24 hours, compression of the ipsilateral ventricle and the extent of midline shift are markers of the extent and progression of the postischemic brain edema. The very early development of perifocal brain swelling within the first 24 hours is probably an indicator of an aggressive course and poor clinical outcome. Doppler ultrasound, CT angiography and magnetic resonance angiography are used as complementary techniques to study the underlying vascular pathology. A unilateral hyperdense MCA sign on the native CT scan indicates the occlusion of the MCA trunk, although the sensitivity of this radiological sign is not very high (Manelfe et al., 1999). The bilateral presence of the hyperdense MCA sign is a frequent finding in asymptomatic subjects and of no diagnostic value. Occlusion of the distal ICA or proximal (M1 segment) MCA is associated with the development of complete MCA infarctions and is an ominous prognostic finding (Moulin et al., 1985; Hacke et al., 1996). This is particularly true for patients with distal ICA occlusion, in

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Fig. 37.4. Development of ischemic brain edema in a patient with subtotal left-hemispheric MCA infarction. 20 h after onset of symptoms (a), day 1, the infarct is clearly demarked. During the next days ((b): day 3; and (c): day 5), the ischemic brain edema leads to compression of the lateral ventricle, shift of the midline structures, contralateral hydrocephalus, caused by blockade of the foramen Monroi, distortion, and terminally downward hernation of the brainstem.

whom mortality has consistently been shown to be very high. Leptomenigeal collateral blood supply can preserve a residual perfusion of the ischemic penumbra and may reduce infarct size. In patients with proximal MCA occlusion, survivors typically have a good collateral blood supply while most patients with no or little collateral blood flow die. Recently, the rapid new MRI techniques of diffusionweighted imaging (DWI) and perfusion-weighted imaging (PWI) have been developed (Lutsep et al., 1997; Fisher & Albers, 1999; Jansen et al., 1999). Using these techniques, new insights can be gained into the pathophysiology and ultra-early diagnostic criteria of cerebral ischemia (Fig. 37.5). In animal models it has been shown that DWI detects an increased diffusion of fluid into brain tissue as a marker of potentially irreversible cytotoxic cell damage within minutes after occlusion of the supplying blood vessel, and the first clinical studies confirming these results have been published. It is presently assumed that DWI shows the area of irreversible ischemic damage, i.e. the infarct core, while the size and extent of the tissue with reduced perfusion but which is still viable can be measured with perfusionweighted imaging (PWI). The mismatch between these areas, with the PWI abnormality being larger than the DWI abnormality, may represent the ischemic penumbra which

can be potentially saved if early reperfusion can be achieved (Jansen et al., 1999). In the near future, a complete set of DWI and PWI scans and MR angiograms, implemented into routine evaluation of the most acute phase of ischemia may replace CT examinations, providing more information about the underlying vascular pathology, extent of the already infarcted tissue, and the tissue at risk which could be saved by a tailored therapeutic approach.

Clinical course The clinical course follows a predictable pattern in many patients (Hacke et al., 1996; Wijdiks & Diringer, 1998; Krieger et al., 1999). At the time of initial clinical assessment within the first few hours after onset of symptoms, patients with large supratentorial infarcts are typically fully awake. Mild drowsiness may occasionally be present. Unresponsiveness due to aphasia or hemineglect should not be misinterpreted as loss of consciousness. Usually, a severe contralateral hemiparesis/hemiplegia and hemihypesthesia is present and pyramidal tract signs such as Babinski’s sign are present on this side. Hemianopia is another frequent finding if the PCA territory or the dorsal portion of the MCA territory is affected. Patients with infarcts of the speech-dominant hemisphere present with

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Fig. 37.5. One hour after onset of a severe hemiparesis the cranial CT is normal. MR angiography (a) demonstrates occlusion of the MCA (arrow). Diffusion-weighted imaging (b) shows the already infarcted brain tissue which is surrounded by a much larger area with reduced perfusion (c).

global aphasia, although some residual speech comprehension may be preserved. Fixed conjugate eye and head deviation towards the affected side are typical findings in patients with large supratentorial strokes, although this clinical sign is neither highly sensitive nor specific (Tijssen et al., 1991; Hacke et al., 1996). Bilateral motor signs, coma, posturing, or pupillary abnormalities are usually not present in the very early phase of large supratentorial infarcts. Neurological deterioration ensues during the first 24 hours in most patients with large supratentorial infarcts, corresponding to the development of brain edema. The patient shows loss of consciousness to varying degrees from drowsiness to coma, and the neurological deficit which already exists may worsen. Pupillary enlargement and areactivity to light, at first uni- and later bilaterally present, nausea, vomiting, posturing, and abnormal breathing patterns are further signs of brainstem dysfunction in patients with space-occupying infarcts. In the uncal herniation syndrome, as extensively described by Plum and Posner (1983), the pupil ipsilateral to the lesion first becomes sluggishly reactive and then gradually enlarges, accompanied by progressive loss of consciousness. If the opposite cerebral peduncle is compressed, hemiparesis ipsilateral to the lesion occurs. The progression of the clinical signs reflects the brainstem damage in a cranio-caudal direction from the midbrain to the medulla, manifesting as loss of oculomotor responses, contralateral pupillary enlargement, loss of corneal

reflexes, posturing, and terminally leading to respiratory arrest and cardiac arrhythmias. Central herniation syndrome is characterized by loss of consciousness and bilaterally small, reactive pupils in the initial phase. If ICP is monitored, at the time of first deterioration, it is typically only moderately elevated (ca. 20 mmHg). ICP values will subsequently rise over the next 24–48 hours. Elevated ICP is a reliable prognostic sign; and an ICP exceeding 30 mmHg is usually associated with a fatal course (Schwab et al. 1996).

Prognosis With medical therapy only, the outcome of patients with large supratentorial infarcts is generally poor, and mortality rates from 55 to 80% have been reported (Hacke et al., 1996; Krieger et al., 1999; Wijdiks & Diringer, 1998). Most patients who deteriorate neurologically after the first few hours will eventually die. Various predictors for deterioration and poor clinical outcome have been identified. Regarding vascular pathology, distal ICA occlusion almost uniformly indicates fatal outcome. Proximal occlusion of the MCA stem is also an unfavourable radiological finding. This typically leads to a complete MCA infarction, including the basal ganglia, which are often spared in patients with a more distal MCA occlusion. It seems plausible that the extent of the infarcted area closely correlates with mortality. Complete MCA plus ACA infarcts and panhemispheric

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Table 37.1. Predictors of early mortality Distal ICA or proximal MCA occlusion Panhemispheric infarcts Poor collateral blood flow Early loss of consciousness Increased intracranial pressure Need for mechanical ventilation

infarcts are usually lethal. The prognostic importance of collateral blood supply, which shows a considerable interindividual variation, has been already mentioned. With regard to clinical signs, progressive loss of consciousness during the first few hours after onset of symptoms is probably the most reliable predictor of a poor outcome (Hacke et al., 1996). Rapid onset of neurological deterioration with loss of consciousness already during the first 6 hours indicates an aggressive course of the disease and is associated with a high mortality. Once coma, pupillary abnormalities, or abnormal breathing patterns are observed, the further course will be fatal in most patients (Table 37.1). The extent of brain edema depends largely on the infarct size and location, but also shows a substantial individual variability. As a general rule, young and middle-aged patients have less compensation capacity for space-occupying intracranial lesions than older patients with cerebral atrophy. As a consequence, younger patients tend to develop raised ICP more often and an infarct of the same size may result in higher mortality in these patients.

Therapy The following survey summarizes some aspects of critical care in patients who have suffered a large stroke, with special emphasis on the management of raised ICP.

General management Large hemispheric infarcts must be recognized in the emergency department as a life-threatening condition which requires prompt and massive intervention (Hacke et al., 1994). After stabilization of the airway, breathing, and circulation, the initial diagnostic work-up and transfer to a neurointensive care unit should not be delayed. If indicated, early reperfusion therapies can already be initiated in the emergency room. Venous access, continuous monitoring of blood pressure, ECG, and pulse oxygenation are part of routine inten-

sive care measures. Continuous ECG monitoring is especially important because neurogenic cardiac arrhythmias are frequently observed, especially in patients with large right-hemispheric infarcts. While respiratory problems are uncommon upon presentation, their frequency sharply increases within the first 24 hours, reflecting increasing brain edema and brainstem dysfunction. Most patients with large infarcts require ventilatory support. To achieve sufficient cerebral oxygenation, oxygen should be insufflated via a face mask to reach arterial Po2 values above 90 mmHg. Indications for intubation and mechanical ventilation are hypoventilation with either hypercapnia or hypoxia, or maintenance of stable airways in patients with reduced consciousness and a high risk of aspiration. Both hypercapnia and hypoxia lead to vasodilatation, resulting in an increase of the intracranial blood volume and thereby raising the ICP. Although the majority of patients with large infarcts who have to be intubated eventually will die despite maximum therapy, a small percentage have a chance of a satisfactory outcome. If the decision for an aggressive medical management has been made, elective intubation should not be delayed to a point when additional complications from hypoxia or aspiration have already occurred (Grotta et al., 1995). During the intubation, arterial hypotension must be meticulously avoided. Patients with large strokes have an increased risk of secondary hemorrhage into the infarcted area. This is one of the reasons why i.v. heparin, which has been advocated for many years, despite the lack of evidence supporting its use, should be restricted to patients with a clear indication for anticoagulant therapy (e.g. patients with prosthetic heart valves). However, stroke patients, in general, are at high risk for venous thrombosis and pulmonary embolism and should be prophylactically treated with low-dose heparin. Intravenous or intra-arterial thrombolysis with tissue plasminogen activator as a revascularizing therapy are treatment options which can only be employed in the very early course of cerebral ischemia before a large infarction has resulted. If baseline radiological findings already demonstrate changes that are suggestive of a large infarction, then thrombolytic therapy is contraindicated because of an excessively high risk of intracranial hemorrhage (Hacke et al., 1995). The use of thrombolytic therapy is also questionable in the presence of distal ICA occlusion because revascularization rarely occurs in these patients.

Conventional therapy of postischemic brain edema As already mentioned, subsequent neurological deterioration due to increasing brain edema is a common

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phenomenon in patients with large infarcts. Several treatments for postischemic brain edema are currently employed. Traditionally, the mainstay of conventional therapy has consisted of ventilation, sedation, blood pressure control, hyperventilation, osmotic agents and barbiturates. The recommendations for these therapies are based upon small case series, evidence from animal experiments, or theoretical observations (Hacke et al., 1994). None of them has been evaluated in a randomized study. Whether ICP monitoring should be included into the routine management of patients with large strokes is still a matter of controversy (Schwab et al., 1996). However, without knowledge of the ICP, cerebral perfusion pressure (CPP)- or ICP-targeted therapies appear to be futile, since the effects of these therapies cannot be estimated. The head should be positioned upright at approximately 20°. Fever has detrimental effects in cerebral ischemia and should be rigorously treated. Electrolyte imbalance should be avoided, especially hyponatremia, which potentially aggravates the developing cerebral edema. One of the primary goals of medical management is maintaining a sufficient CPP. This is of particular importance because the cerebral autoregulation may be impaired in and around the ischemic lesion and the blood flow changes passively in these regions as the perfusion pressure changes. In addition, in patients with long-standing arterial hypertension the lower limit of autoregulation may be shifted towards a higher level. The effective CPP results from the difference between the systemic mean arterial blood pressure (MAP) and the ICP: CPP⫽MAP–ICP. In patients with elevated ICP, high blood pressure values spontaneously present in most patients immediately after the stroke are definitely desirable. While there is a rather large body of evidence proving that lowering blood pressure in the acute phase can be deleterious, it is less certain as to whether normal blood pressure values should be raised. In analogy to patients with head trauma, it seems prudent to raise the CPP above 70 mmHg in patients with arterial hypotension, although the effects of this strategy have not been proven. The blood pressure should only be lowered if marked hypertension is present (systolic BP ⬎ 220 mmHg or diastolic BP ⬎ 120 mmHg), and this should be done with great care to avoid a sudden drop in the blood pressure or hypotensive values. Hypertonic, low-molecular-weight solutions such as mannitol, sorbitol, glycerol, or hypertonic saline are used to reduce the brain water content by creating an osmotic gradient between brain and plasma, drawing water into the plasma. An intact brain–blood barrier is the prerequisite for establishing an osmotic gradient. It has been

assumed that brain tissue dehydration is more pronounced on the side contralateral to the lesion where the brain tissue is preserved. It appears to be indisputable that hypertonic solutions can at least transiently decrease an elevated ICP and, therefore, may be beneficial in emergency situations in an acutely deteriorating patient before therapies such as hematoma evacuation or decompressive surgery can be initiated. The long-term effects of repeated treatments with hypertonic solutions are still unknown. Repeated infusions of mannitol could aggravate cerebral edema if the osmotic substances migrate through a damaged blood–brain barrier into the brain tissue, reversing the osmotic gradient. Further, osmotic agents predominantly lead to dehydration and shrinkage of normal brain tissue, and may facilitate displacement of brain tissue and even increase the risk of herniation. However, these, largely theoretical considerations could not be substantiated to date in clinical studies. Known complications of the use of osmotic agents are electrolyte imbalances, hypervolemia with cardiac failure, and renal dysfunction. Serum osmolarity should be closely monitored. In principle, the same dilemma as encountered with osmotic agents applies to all other treatment strategies. All these therapies can transiently decrease elevated ICP while the long-term effects are less clear or even potentially noxious. Hyperventilation induces cerebral vasoconstriction via serum and CSF alkalosis, thereby reducing the cerebral blood volume and reducing ICP. The effects of hyperventilation are short-lived because of rapid compensation of CSF alkalosis, and rebound vasodilatation and increase in ICP occurs if normoventilation is resumed too rapidly. Hyperventilation can critically reduce the cerebral blood flow, leading to additional ischemic damage. Therefore, the CO2 levels should not fall below 30 mmHg. Short-acting barbiturates are frequently used in patients with elevated ICP. Barbiturates lead to a prompt and significant reduction in the CBF and ICP. However, their use is limited due to various side effects, such as hypotension, cardiac depression, hepatotoxicity, and predisposition to infection, and two studies failed to demonstrate any longterm beneficial effects of prolonged barbiturate coma in patients with elevated ICP.

New and experimental therapies Recognition of the high mortality in patients with large hemispheric infarcts and the obvious ineffectiveness of medical therapy alone has prompted innovative therapeu-

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tic approaches for these patients. While the effects of these therapies have not yet been proven in randomized trials, the results of pilot studies are promising.

Decompressive surgery To provide additional space for the expanding, infarcted brain tissue, extended craniectomy with dura augmentation (craniectomy without augmentation of the tight dura is ineffective) or lobectomy, i.e. surgical removal of the infarcted tissue, has repeatedly been employed in patients with large supratentorial infarcts (Fig. 37.6). Several authors compared decompressive surgery with conventional medical treatment and drew the conclusion that operative treatment does not only reduce mortality but may also improve the functional outcome of the surviving patients (Rieke et al., 1995; Schwab et al., 1998b, Carter et al., 1997). Most of these studies were small, overall less than 200 patients, and diverse inclusion criteria and different surgical techniques were used. Almost all studies were retrospective case series, and all were uncontrolled. In the largest single study (Schwab et al., 1998b), 63 patients with complete MCA infarction were prospectively treated with extended hemicraniectomy with a trepanation of more than 12 cm in diameter and subsequent dura patch enlargement. No relevant major peri- and postoperative complications occurred. The clinical outcome was favourable, with a survival rate of about 70%. Moreover, the majority of the survivors were only slightly or moderately disabled after 3 months. Age below 50 years, early surgical intervention within the first 24 hours after the infarct, and lack of co-morbidity were identified as favourable prognostic factors. Mortality was high in patients who already showed clinical signs of tentorial herniation at the time of surgery such as loss of consciousness or pupillary abnormalities, although the survival rate for these patients was still markedly higher than for a medically treated patient collective. Although decompressive surgery is increasingly being used, the ideal candidate for surgery, the optimum point of time, and surgical technique are still the subject of debate. Controlled studies are warranted to address these questions and to prove the beneficial effects of this therapeutic concept itself.

Induced hypothermia Animal experiments have consistently shown that induced hypothermia has a neuroprotective effect after focal and

Fig. 37.6. Effect of decompressive surgery in a patient with complete MCA infarction. After extended craniectomy (the arrows show the margins) and dura patch augmentation, the infarcted, edematous tissue expands without compressing the unaffected hemisphere.

global ischemia, reducing secondary neuronal damage and infarct volume and probably improving the neurological outcome (Ginsberg & Busto, 1998). Various mechanisms of action have been proposed, including reduced cerebral metabolism and ICP, decreased release of excitotoxic neurotransmitters, and stabilization of the blood– brain barrier. In patients with severe, acute head trauma, a controlled study indicated that induced hypothermia over a period of 24 hours improved clinical outcome (Marion et al., 1997). Therapeutic hypothermia has not yet been studied in a controlled trial in patients with stroke. Results of a pilot study with mild to moderate hypothermia (ca. 33 °C) over 2 days in patients with complete MCA infarction suggested that hypothermia reduces ischemic brain edema and intracerebral pressure and may even positively influence mortality (Schwab et al., 1998a). Indications as well as optimum temperature, duration of hypothermia, cooling and re-warming techniques, and efficacy of hypothermia itself are issues being addressed by larger controlled trials currently under way.

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iReferencesi Carter, B.S., Ogilvy, C.S., Candia, G.J., Rosas, H.D. & Buonanno, F. (1997). One-year outcome after decompressive surgery for massive nondominant hemispheric infarction. Neurosurgery, 40, 1168–75. Fisher, M. & Albers, G.W. (1999). Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke. Neurology, 52, 1750–6. Frank, J.I. (1995). Large hemispheric infarction, deterioration, and intracranial pressure. Neurology, 45, 1286–90. Ginsberg, M. & Busto, R. (1998). Combating hyperthermia in acute stroke. Stroke, 29, 529–34. Grotta, J., Pasteur, W., Khwaja, G., Hamel, T., Fisher, M. & Ramirez, A. (1995). Elective intubation for neurological deterioration after stroke. Neurology, 45, 640–4. Hacke, W., Schwab, S. & De Georgia, M. (1994). Intensive care of acute ischemic stroke. Cerebrovascular Diseases, 4, 385–92. Hacke, W., Kaste, M., Fieschi, C. et al. (1995). Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. Journal of the American Medical Association, 274, 1017–25. Hacke, W., Schwab, S., Horn, M., Spranger, M., De Georgia, M. & von Kummer, R. (1996). ‘Malignant’ middle cerebral artery infarction. Archives of Neurology, 53, 309–15. Jansen, O., Schellinger, P., Fiebach, J., Hacke, W. & Sartor, K. (1999). Early recanalisation in acute ischaemic stroke saves tissue at risk defined by MRI. Lancet, 353, 2036–7. Krieger, D.W., Demchuk, A.M., Kasner, S.E., Jauss, M. & Hantson, L. (1999). Early clinical and radiological predictors of fatal brain swelling in ischemic stroke. Stroke, 30, 287–92. Lutsep, H.L., Albers, G.W., DeCrespigny, A., Kamat, G.N., Marks, M.P. & Moseley, M.E. (1997). Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke. Neurology, 41, 574–80. Manelfe, C., Larrue, V., von Kummer, R. et al. (1999). Association of hyperdense middle cerebral artery sign with clinical outcome in patients treated with tissue plasminogen activator. Stroke, 30, 769–72. Marion, D., Penrod, L., Kelsey, S. et al. (1997). Treatment of traumatic brain injury with moderate hypothermia. New England Journal of Medicine, 336, 540–6. Moulin, D.E., Lo, R., Chiang, J. & Barnett, H.J.M. (1985). Prognosis in middle cerebral artery occlusion. Stroke, 16, 282–4. Moulin, T., Cattin, F., Crépin-Leblond, T. et al. (1996). Early CT signs in acute middle cerebral artery infarction: predictive value for

subsequent infarct locations and outcome. Neurology, 47, 366–75. Plum, F. & Posner, J.B. (1983). The Diagnosis of Stupor and Coma. 3rd edn. Philadelphia: F.A. Davis. Rieke, K., Schwab, S., Krieger, D. et al. (1995). Decompressive surgery in space occupying hemispheric infarction. Critical Care Medicine, 23, 1576–87. Ringelstein, E.B., Biniek, R., Weiller, C., Ammeling, B., Nolte, P.N. & Thron, A. (1992). Type and extent of hemispheric brain infarction and clinical outcome in early and delayed middle cerebral artery recanalization. Neurology, 42, 289–98. Ropper, A.H. (1986). Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. New England Journal of Medicine, 314, 953–8. Ropper, A.H. (1990). The opposite pupil in herniation. Neurology, 40, 1707–9. Ropper, A.H. (1998). Transtentorial herniation. In Coma and Impaired Consciousness: A Clinical Perspective, ed. G.B. Young, A.H. Ropper & C.F. Bolton, pp. 119–30. New York, St. Louis, San Francisco: McGraw-Hill. Ropper, A.H. & Shafran, B. (1984). Brain edema after stroke. Clinical syndrome and intracranial pressure. Archives of Neurology, 41, 26–9. Schwab, S., Aschoff, A., Spranger, M., Albert, F. & Hacke, W. (1996). The value of intracranial pressure monitoring in acute hemispheric stroke. Neurology, 47, 393–8. Schwab, S., Schwarz, S., Spranger, M., Keller, E., Bertram, M. & Hacke, W. (1998a). Efficacy and safety of moderate hypothermia in the therapy of patients with acute MCA stroke. Stroke, 29, 2461–6. Schwab ,S., Steiner, T., Aschoff, A. et al. (1998b). Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke, 29, 1888–93. Tijssen, C.C., Schulte, B.P.M. & Leyten, A.C.M. (1991). Prognostic significance of conjugate eye deviation in stroke patients. Stroke, 22, 200–2. von Kummer, R., Meyding-Lamadé, U., Forsting, M. et al. (1994). Sensitivity and prognostic value of early computed tomography in middle cerebral artery trunk occlusion. American Journal of Neuroradiology, 15, 9–15. von Kummer, R., Nolte, P.N., Schnittger, H., Thron, A. & Ringelstein, E.B. (1996). Detectability of cerebral hemisphere ischaemic infarcts by CT within 6 h of stroke. Neuroradiology, 38, 31–3 Wijdiks, E.F.M. & Diringer, M.N. (1998). Middle cerebral artery territory infarction and early brain swelling: progression and effect of age on outcome. Mayo Clinic Proceedings, 73, 829–36.

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Multiple, multilevel and bihemispheric infarcts Emre Kumral School of Medicine, Ege University, Bornova, Izmir, Turkey

Recent studies emphasize multiple cerebral infarcts as new clinical patterns. The underlying clinical, topographic, etiologic and functional characteristics are now well known. The term multiple brain infarcts has been used to designate a variety of different infarcts which appear in one or both hemispheres, or in supratentorial and infratentorial arterial territories (multilevel). Multiple brain infarcts are composed either of simultaneous multiple infarcts or of infarcts of different chronological age. We will review in the following sections the current literature on the frequency and causes of multiple brain infarcts, particular clinical and/or topographic patterns that suggest specific underlying mechanisms and causes.

Frequency and incidence of multiple cerebral infarcts Previous studies using different methods (first strokes vs. all strokes, acute and old) give a variety of definitions related to multiple brain infarcts. Disagreement exists about the definition of the disorder. In the Lausanne Stroke Registry, among 2000 consecutive patients whose first strokes were confirmed by cranial computed tomography (CT) or magnetic-resonance imaging (MRI), 3% of the patients had infarcts in ‘multiple territories’ supplied by the carotid arteries, 2% had multiple infarcts in the vertebrobasilar artery territory, and 2% had multiple infarcts in the territories of the carotid and vertebrobasilar arteries (Bogousslavsky, 1991a). In our hospital-based Ege Stroke Registry, we found almost similar frequency of multiple infarcts; 2% of the multiple infarcts were in the carotid territory, 3% were in the vertebrobasilar artery territory, and 3% were in the territories of the carotid and vertebrobasilar arteries (Kumral et al.,1998). Although in another hospital-based series of 116 patients who suffered acute

ischemic strokes and had CT and MRI studies within 10 days of hospital admission, MRI showed ‘multiple infarcts in more than one vascular territory’ in 22 patients (18.9%) (Shuaib et al.,1992). None of the studies provided information on the ages of the infarcts. Previous studies have specifically addressed the issue of the frequency of ‘silent’ cerebral infarctions in patients admitted for acute stroke who had no history of prior stroke. The reported frequencies for silent strokes revealed by CT scan have varied from 10% to 38% (Chodosh et al.,1988; Kase et al., 1989; Ricci et al., 1993; Boon et al., 1994). The silent infarcts were mostly small in size and/or, their locations in the brain were likely to leave the patient asymptomatic or minimally symptomatic in the event of acute infarction. Small lesions involved mostly deep structures of the brain; right-hemisphere non-lacunar infarcts were more frequent than left-hemisphere ones in the NINCDS Stroke Data Bank study (Chodosh et al.,1988) and in the SEPIVAC study (Ricci et al., 1993). In the NINCDS study (Chodosh et al., 1988) among 135 patients with silent strokes, 37 had more than one silent lesion; 14 of them had multiple lesions confined to one hemisphere, and 23 had bilateral lesions. Among those with bilateral silent infarcts, five patients had bilateral large (⬎1 cm) cortical infarcts only, ten had bilateral small deep infarcts, and the remaining eight had various combinations of large superficial and small deep lesions. There were no differences in stroke risk factors between the multiple-lesion and single-lesion subgroups in the NINCDS study (Chodosh et al., 1988), whereas glucose intolerance, in the Framingham study (Kase et al., 1989); male sex, ischemic changes seen on electrocardiograms, and hypertension, in the SEPIVAC study (Ricci et al., 1993); increasing age, hypertension, claudication and male sex in the Copenhagen Stroke Study (Jorgensen et al., 1994); and advanced age and hypertension in the study of Boon et al. (1994) were significantly

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(a )

(b)

Fig. 38.1. A 65-year-old man with hypertension history was admitted because of right hemiparesis and global aphasia. (a) CT scan shows an old right caudate infarct and a new left lenticulostriate infarct. (b) Conventional angiography revealed 80–90% stenosis of the left internal carotid artery.

related to the presence of silent infarction. The underlying mechanism of silent small deep lesions and first symptomatic small deep infarcts is mostly small-vessel disease, whereas cardiogenic embolism and large-vessel thromboembolism are the most likely causes of both silent and first symptomatic territorial infarcts. (Boon et al.,1994). Silent multiple infarcts do not affect 30-day case fatality or 1-year mortality (Chodosh et al., 1988, Ricci et al., 1993; Boon et al., 1994).

Causes of multiple brain infarcts Various diseases associated with multifocal involvement of the cerebral vasculature and/or a high rate of recurrent strokes may be responsible for multiple brain infarcts. Furthermore, some patients may have multiple coexisting causes, which may increase the risk for multiple brain infarctions. A study of 26 patients with ‘infarcts in multiple territories’ revealed the following causes in order of decreasing frequency: atherosclerosis with stenosis, emboligenic heart disease, combined causes (atherosclerosis with stenosis and emboligenic heart disease), hypertensive arteriolopathy, atherosclerosis with stenosis (Bogousslavsky et al., 1988b). The most frequent cause in patients (40 cases) with multiple infarction involving the anterior circulation was ipsilateral internal carotid artery disease (⬎50% stenosis or occlusion) (LAD) in 33% of patients, while 29% had a potential cardiac source of embolism (PCSE). Three patients had coexisting LAD and PCSE. Small-artery

disease was diagnosed in three patients. Two patients had biopsy-proven granulomatous angiitis; two patients had unilateral carotid dissection; and stroke developed in one patient after hypovolemia with hypotension (Bogousslavsky et al. 1996). Etiologic investigation of 27 patients with multiple acute infarcts in the posterior circulation revealed the following causes: large-artery disease of vertebral or basilar artery in 12, cardioembolism in 7, anticardiolipin antibody syndrome in 1, and unknown in 3 (Bernasconi et al.,1996).

Atherosclerosis Atherosclerosis mainly affects the large and medium-sized arteries, particularly at places of arterial branchings. It is associated with high risk for multiple emboli and recurrent strokes, which is related to the severity and nature (i.e. ulceration, hard or soft plaques) of the atherosclerotic lesions (Fig. 38.1 (a) and (b)). Atherosclerotic carotid stenosis is a marker for cerebrovascular disease and indicates an increased risk for stroke, but not necessarily in the territory of the involved vessel. In the European Carotid Surgery Trial (ECSTCG, 1991) to assess the efficacy of carotid endarterectomy in patients with recent carotid transient ischemic attacks or minor ischemic strokes, 58 of 323 patients (18%) in the nonoperated group with severe carotid stenosis (⬎70%) each had a stroke during the next 3 years. Of the 58 strokes, 44 were ipsilateral and nine were contralateral to the carotid stenosis, three involved the vertebrobasilar territory, and two were hemorrhagic strokes. In the non-operated group of patients with mild (⬍30%) stenosis (155 patients), only nine patients had single

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strokes during the next 3 years, and only two of them had strokes ipsilateral to stenosis. Another study, North American Symptomatic Carotid Endarterectomy Trial (NASCET, 1991) found that 26% of patients with severe symptomatic stenosis (70–99%) who were treated medically had ipsilateral ischemic stroke in 2 years, while only 9% of those who underwent endarterectomy had stroke or death within 30 days of surgery, which was similar to the rate found in ECSTCG. Moreover, it is well known that fragmentation of an ulcerated plaque in the aortic arch may cause multiple infarcts in one or both hemispheres (Amarenco et al.,1992).

Small-vessel disease Small-vessel disease (lipohyalinosis) of the deep penetrating arteries of the brain, often associated with arterial hypertension, can cause multiple small deep infarcts, in the putamen, caudate nucleus, pallidum, thalamus, pons, internal capsule, periventricular white-matter (Fig. 38.2). Among other potential causes, hypertension is the most common cause of small-artery disease. Moreover, arteryto-artery and cardiogenic embolism is not a negligible cause of infarction in the territory of deep perforating arteries (Bogousslavsky et al., 1988a; Kumral et al.,1998). In Fisher’s autopsy study (Fisher, 1965), 114 of 1042 consecutive brains contained lacunes (in 77% (88/114) of the patients the lacunes were asymptomatic); 54 brains had one or two lacunes, and 60 had three lacunes or more, making a total of 376 lacunes, or 3.3 per brain. In a prospective study of 100 consecutive patients with lacunar strokes studied by MRI, 153 lacunes were observed of which 18 were bilateral (Hommel et al.,1990). MRI detected at least one lacune appropriate to the symptoms in 89 patients, whereas in 16 patients at least two lesions were correlated with the clinical features. In the Oxfordshire Community Stroke Project (Bamford et al., 1987), the rate of recurrent strokes among patients who had already had their firstever lacunar infarcts was 11.8% in the first year, but the pathological types of the recurrences were not reported. In a recent study on the mechanisms of second and further strokes of 102 patients, the first stroke was a supratentorial lacunar infarct in 13 patients, an infratentorial lacunar infarct in four patients, and multiple lacunar infarcts in two patients. Eight patients with diabetes mellitus as sole risk factor developed three cardioembolic infarcts, four non-lacunar non-cardioembolic infarcts, one brain hemorrhage, and repeated four lacunar infarcts, while another 11 patients developed three cardioembolic infarcts, four non-lacunar non-cardioembolic infarcts, and repeated ten lacunar infarcts (Yamamoto & Bogousslavsky,1998). Other

Fig. 38.2. T2-weighted axial MR images showing multiple small infarcts involving putamen, thalamus, subcortical areas and periventricular leukoaraiosis.

prospective studies have also found that 32–40% of the patients with lacunar infarction may develop non-lacunar non-cardioembolic infarction, which is higher than the rate of subsequent lacunar infarction in patients with a non-lacunar non-cardioembolic infarction as the first stroke (Clavier et al., 1994; Kappelle et al.,1995).

Cardiac sources of embolism Cardiogenic embolism is the second cause of multiple, multilevel infarcts, and recurrent strokes. Non-rheumatic atrial fibrillation is the most common source of cardiogenic embolism, with a stroke recurrence rate of about 10% per year (EAFT, 1993). In the Ege Stroke Registry, 28% of patients with infarcts in the both anterior and posterior circulation (multilevel infarct) had cardiogenic embolism, while 40% had atherosclerosis wihout stenosis (Kumral et al., 1998). Moreover, one-third of the patients having multiple infarcts in the anterior circulation and one-sixth of those having multiple infarcts in the posterior circulation had a cardiac source of embolism. In the Lausanne Stroke Registry patients who had had initial ischemic strokes (Bogousslavsky et al., 1991), multiple pial territory infarcts were seen more frequently in patients with potential cardiac sources of embolism (14 of 305 patients; 4.6%) than in those without such sources (22 of 1006 patients; 2.2%). By contrast, multiple deep infarcts were more common in patients without potential cardiac sources of embolism; 32 patients (3.2%) vs. 1 patient (0.3%) in the group had cardioembolic sources. Among 1267 patients in the NINDS study (Kittner et al., 1992), bilateral anterior circulation cortical infarcts were more common in patients with definite emboligenic heart disease (5.7%) than in

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patients with no evidence of cardioembolic sources (2.9%). There was no significant trend across the risk groups with respect to percentages with anterior-plus-posteriorcirculation cortical infarcts (all lesions considered, both symptomatic and asymptomatic, acute and old). In a recent study (Yamamoto & Bogusslavsky, 1998), patients having cardioembolic stroke as the first attack (20/102), had developed 17 recurrent episodes of cardioembolic infarction, among which ten (76%) were located in the anterior circulation. Eight (80%) of ten patients with initial lesions in the anterior circulation and five (71%) of seven patients with initial lesions in the posterior circulation developed recurrent episodes in the anterior circulation. None of the patients with cardioembolism had border zone infarct. Contrary to this finding, two of three patients who developed recurrent non-lacunar non-cardioembolic infarcts had a border zone infarction associated with carotid artery stenosis.

Among non-inflammatory angiopathies, moya–moya disease, microangiopathy of the retina, inner ear, and brain, Sneddon’s syndrome, antiphospholipid antibody syndrome, Behçet’s disease, MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), CADASIL syndrome (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), Bürger’s disease and intravascular lymphoma are potential causes of multiple and multilevel infarcts. Cerebral amyloid angiopathy can also cause multiple small cortical infarcts, usually associated with intracerebral hematomas. In a large series, among 189 patients with dissections of extracranial carotid arteries or vertebral arteries, 24 patients had bilateral dissections of the internal carotid arteries, and 20 had dissections of both carotid and vertebral arteries. Only one patient had symptoms related to ischemia in different territories (Mas et al., 1993).

Hypoperfusion Other angiopathies Angiopathies were extremely rare in patients having multiple infarcts in the anterior and posterior circulation (Bernasconi et al., 1996; Bogousslavsky et al., 1996) Inflammatory angiopathies can be found either isolated, or associated with a wide variety of disorders such as connective-tissue diseases, drugs, and neoplasm, and can lead to multiple brain infarcts. Depending on the disease, angiitis may be the only mechanism or one of several mechanism leading to brain infarcts. Isolated angiitis of the central nervous system (CNS) is a granulomatous vasculitis involving primarily small and sometimes mediumsized blood vessels. The most frequent macroscopic neuropathological findings are multiple small (but sometimes large) foci of infarction and, less commonly, hemorrhage; multiple localized lesions of the cerebrum, cerebellum, or brainstem are present in more than 75% of patients (Moore, 1989). Vasculitis is not a common cause of CNS involvement in systemic lupus erythematosus (SLE). In a series of 50 patients with SLE, CNS lesions were present in half of the patients. None of them had evidence of active CNS vasculitis (Devinsky et al., 1988). Embolic brain infarctions were the most common causes of stroke (ten patients); the lesions were characterized by multiple hemorrhagic cortical infarcts of different ages. The probable sources of emboli were Libman–Sacks endocarditis (five patients), chronic valvulitis (two patients), and mural thrombus in the left side of the heart (two patients). Clinical features of thrombotic thrombocytopenic purpura develop during the terminal illness in 14 patients, seven of whom also had pathological evidence of syndrome.

Hypoperfusion of the brain during episodes of severe hypotension, cardiocirculatory arrest, cardiopulmonary bypass surgery and prolonged hypoxemia can cause multiple infarcts in the watershed areas often in a symmetrical fashion, or between the deep and the superficial territories of the middle cerebral artery (MCA) (subcortical-junction infarcts) (Bogousslavsky & Regli, 1986). In patients with bilateral anterior watershed infarcts (between the territories of the MCA and the anterior cerebral artery), a picture of bibrachial paralysis (‘man in the barrel syndrome’) can occur (Fig. 38.3). The optico-cerebral syndrome, hemodynamic infarction of the optic nerve and brain, suggests internal carotid artery occlusion with hemodynamic disturbances.

Hematological disorders Essential thrombocythemia can give raise to multiple occlusions of small vessels (Fig. 38.4), but occlusions of multiple large arteries, such as the internal carotid artery, have also been reported (Muller et al., 1990). Similar events can occur in patients with polycythemia vera, where tissue hypoxia is often due to hyperviscosity secondary to a raised hematocrit, but megakaryocytic proliferation may contribute. Strokes occur in 3–17% of patients homozygous for HbSS. Ischemic strokes are the most frequent ones (75%); they usually occur before the age of 15 years, often involve border zone or subcortical areas, and are often recurrent. Disseminated intravascular coagulation (with or without associated nonbacterial thrombotic endocarditis), thrombotic thrombocytopenic purpura, and the hemolytic

Multiple, multilevel and bihemispheric infarcts

Fig. 38.4. A 45-year-old woman with left mild lower limb weakness had essential thrombocythemia. Axial T2-weighted MRI showing multiple cortical and subcortical infarcts.

Fig. 38.3. Anterior, posterior and subcortical watershed territories. (From J. Bogousslavsky, with permission).

uremic syndrome can frequently cause occlusion of small arteries. Although causality has not been demonstrated, positive tests for antiphospholipid antibodies were associated with thrombotic diseases, particularly in patients with SLE. Patients with antiphospholipid antibodies have a predisposition to recurrent and multiple events, which can lead to dementia. Protein C, Protein S and antithrombin III deficiencies and homocystinuria are the potential diseases that can yield multiple occlusion of the large, medium and small vessels. Hyperviscosity states associated with a wide variety of disorders particularly with myeloproliferative diseases and dysglobulinemia, can cause multiple occlusions of small-size vessels.

Venous infarcts Vein thromboses were not reported commonly. Clinical diagnosis is difficult, and in many cases, it was made after

pathologic examination. Focal or generalized seizures followed by hemiparesis, aphasia, hemianopia, or other neurologic dysfunction in the absence of signs of increased intracranial pressure should suggest vein thrombosis. Neuroimaging (CT and MRI) shows single or multiple ischemic lesions that do not follow the boundary of arterial territories and often have a hemorrhagic component without signs of venous sinus thrombosis (Jacobs et al.,1996). In a series of 33 venous infarcts evaluated with CT, lesions were found to be multifocal in 15 cases, and bilateral in seven (Chiras et al., 1985).

Simultaneous multiple infarcts Acute multiple infarcts may involve both hemispheres and may suggest some specific clinical pictures, particular causes, such as cardioembolism, angiitis, hematological disorders, hemodynamic mechanisms, or venous infarcts. Among 751 patients with infarct in the anterior circulation, 5% of the cases (40 patients) represented acute multiple infarcts shown on MRI (Bogousslavsky et al., 1996). There were four topographic patterns of infarction: (i) superficial infarcts in the territories of the pial arteries (28%); (ii) superficial and deep infarcts in the territories of the pial and lenticulostriate arteries (30%); (iii) deep infarcts in the territories of lenticulostriate arteries (8%); (iv) infarcts involving the anterior and posterior circulation (35%). In this series, 20% of the patients had specific clinical pictures which were not encountered in the previous reports: (i) global aphasia with left hemianopia; (ii) Broca’s aphasia

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Fig. 38.5. A 70-year-old man with hemianopia–hemiplegia syndrome due to double infarct of the right hemisphere, CT, without contrast, showed simultaneous infarcts in the anterior choroidal artery territory and posterior cerebral artery territory.

with left hemiplegia and sensory loss; (iii) aphasia with Balint’s syndrome; (iv) transcortical mixed aphasia with hemianopia; (v) acute dementia. Lamy and Mas (1995) identified ten cases of simultaneous multiple supratentorial infarcts among 171 consecutive patients with acute ischemic hemispheric strokes (Lamy & Mas, 1995). All patients were diagnosed with CT, and MRI. Six patients had bihemispheric infarcts: bilateral infarcts of the superficial posterior cerebral artery (PCA) in three patients, associated with infarcts in the territory of the bilateral superior cerebellar artery in one; superficial MCA infarcts plus bilateral infarcts in the posterior watershed territory in one; multiple cortical infarcts in one; and bihemispheric venous infarcts in one. The following causes were found: coagulation disorders (disseminated intravascular coagulation in two patients, and essential thrombocythemia in one patient), acute anterior myocardial infarct (in one patient), intra-arterial embolism (in one patient), and venous thrombosis (in one patient). Four patients had double infarcts in one hemisphere involving MCA plus PCA territories in two, MCA plus ACA territories in one, and venous territories in one. Two of those patients had definite emboligenic heart disease, one patient had disseminated intravascular coagulation, and one patient had cerebral venous thrombosis.

Simultaneous infarcts in one cerebral hemisphere In a previous series, simultaneous double infarction in one hemisphere represented less than 2% of first-ever acute strokes and can be associated with specific clinical and etiological correlates (Bogousslavsky, 1991b). Among

Fig. 38.6. A 45-year-old woman with diagnosis of antiphospholipid antibody syndrome had motor and sensory neglect without hemiparesis. CT, without contrast, showed simultaneous double infarcts in the right anterior and posterior superficial middle cerebral artery (MCA) territory.

1911 consecutive patients with first-time strokes, 32 patients with double infarcts in one cerebral hemisphere were identified. The most common combinations involved the territories of the anterior superficial MCA plus the posterior superficial MCA (15 patients) and the territories of the anterior superficial MCA plus the posterior watershed (ten patients). The double infarction was closely associated with severe internal carotid artery disease, and the incidence of potential cardiac sources of embolism did not differ from that found among patients with ischemic strokes in general. The most common neurological picture mimicked large infarction in the middle cerebral artery territory, but nearly half of the patients had a specific clinical syndrome, including hemianopia and hemiplegia, acute conduction aphasia with hemiparesis, and acute transcortical mixed aphasia. Hemianopia–hemiplegia occurred in relation to simultaneous involvement of motor and visual cortex or pathways by two remote infarcts (Fig. 38.5). Acute conduction aphasia with hemiparesis occurred by involvement of the region of the supramarginal gyrus sparing the sensory cortex, together with involvement of the motor cortex and underlying white matter. Acute mixed transcortical aphasia developed in relation to an infarct in the anterior

Multiple, multilevel and bihemispheric infarcts

Fig. 38.8. A 65-year-old woman with history of atrial fibrillation developed right facio-brachial weakness and quadrantanopia. T2weighted axial MR image showed simultaneous infarcts in the deep middle cerebral artery territory, superficial posterior cerebral artery (PCA) territory and thalamus. Angiography revealed that the left PCA originated from the right internal carotid artery.

Fig. 38.7. A 69-year-old man with akinetic mutism and incontinence. CT, without contrast showed bilateral infarcts in the territory of anterior cerebral arteries (ACA). Angiography revealed an unpaired ACA.

middle cerebral artery pial territory involving precentral/central region and posterior watershed infarct, which spared but isolated the speech areas (Bogousslavsky, 1988). Global aphasia without hemiparesis has been reported in relation to two discrete infarcts involving left frontal and left temporal region (Van Horn & Hawes, 1982; Tranel et al., 1987; Legatt et al., 1987). However, nonischemic lesions and single infarcts may occasionally be responsible, and so this clinical picture cannot be regarded as specific for double infarction (Ferro, 1983; Bogousslavsky, 1988). A unique simultaneous double infarct pattern of the right hemisphere was identified among 688 consecutive patients with right hemisphere stroke which was characterized by exploratory–motor and perceptual–sensory neglect without hemiparesis (Kumral & Evyapan, 1999). All cases had anterior cortical and posterior cortical infarctions in which motor strip and corticospinal pathways were spared (Fig. 38.6). Simultaneous infarct of the optic nerve and brain is

extremely rare. In optico-cerebral syndrome, the mechanism of hemodynamic infarct is unilateral or bilateral carotid artery occlusion and reversed flow in the ophthalmic artery (Bogousslavsky et al.,1987).

Simultaneous multiple infarcts due to a single artery occlusion This type of stroke occurs as a result of occlusion of the proximal segment of ACA, PCA, and thalamic paramedian pedicle or in relation to congenital variation, i.e. PCA may originate from ICA in up to one-fourth of the cerebral hemispheres. Simultaneous bilateral ACA infarction may occur in relation to the anatomy of the junction between the ACA and the anterior communicating artery (Fig. 38.7). Both medial aspects of the hemispheres are supplied by a single artery in 18% of a normal population (Lasjaunias & Berenstein, 1990). Cerebral pseudoparaplegic syndromes, akinetic mutism with incontinence, abulia and the presence of a bilateral grasp reflex are suggestive of this type of infarction, which represents less than 10% of all ACA territory infarctions (Bogousslavsky, 1991a; Minagar & David, 1999). Posterior cerebral artery can originate from the internal carotid artery in up to 25% of cerebral hemispheres, and, because of this anatomical variation, internal carotid artery occlusion can cause simultaneous infarcts in the MCA and PCA territories (Fig. 38.8). The syndrome of

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causes infarctions of midbrain, thalamus, and portions of the temporal and occipital lobes fed by posterior communicating and posterior cerebral arterial tributaries of the basilar artery; this clinical picture is called top-of-thebasilar syndrome (Fig. 38.12(a) and (b)) (Caplan, 1980). The main clinical feature is characterized by oculomotor signs, including convergence spasm, pseudosixth nerve paralysis, elevation and retraction of the upper eyelids, skew deviation and neuropsychologic disturbances including vivid hallucinations, dream-like behaviour, amnestic dysfunctions and agitated behaviour.

Simultaneous multiple infarcts in the posterior circulation Fig. 38.9. A 70-year-old man with cortical blindness. Axial MR proton density image showed bilateral hemorrhagic infarcts in the territory of posterior cerebral arteries.

hemianopia–hemiplegia and global aphasia with left hemianopia without hemiplegia are suggestive of this type of infarct (Bogousslavsky, 1991b; Bogousslavsky et al., 1996). Bilateral infarction in the PCA territory may result from occlusion of the apex of the basilar artery due to either atherothrombosis or embolism (Fig. 38.9). This type of infarct usually causes cortical blindness or double hemianopia, often sparing macular vision. Severe amnesic disturbances can occur in case of bilateral involvement of the posterior part of the parahippocampal gyrus. Bilateral paramedian thalamic infarction may develop due to occlusion of paramedian pedicle which arises from the P1 segment of the PCA as a single pedicle in up to one-third of cases and bilateral paramedian thalamic infarcts are not uncommon (Fig. 38.10(a) and (b)) (Bogousslavsky, 1991a). Bilateral paramedian infarction is characterized by sudden onset of loss of consciousness, somnolence with an ensuing complex of neuropsychological impairments, including apathy, lack of insight, amnesia of varying severity, confabulations, slurred speech, flattened affect, impairment of spontaneous acting, sometimes referred to as thalamic dementia (Graff-Radford et al.,1985; Gentilini et al., 1987). Bilateral infarcts frequently produce selective upgaze, downgaze, or combined dysfunction. Simultaneous bilateral caudate infarction characterized by acute confusion and disorientation at stroke onset is an extremely rare phenomenon, and on the following days the patients may show severe impairment of mental and psychic activity and loss of affective and motor response to external stimuli, referred to as psychic akinesia (Fig. 38.11) (Kumral et al., 1999). Occlusive disease of the rostral basilar artery frequently

In a prospective study of 70 patients with infarcts in the posterior circulation, assessed by MRI, magnetic resonance angiography, and non-invasive cardiac tests (Bogousslavsky et al., 1993), 49 patients (70%) had infarcts limited to the brainstem or cerebellum (bilateral in 14), ten (14%) had partial or complete infarcts in the PCA territory (bilateral in three), 11 (16%) had combined supratentorial and infratentorial infarcts (bilateral in four). In total, 22 patients (31%) had multiple and multilevel infarct in the vertebrobasilar territory. Among the 33 patients with cerebellar infarcts, the following territories were involved: posterior inferior cerebellar artery (PICA) in 16 patients (bilateral in three), superior cerebellar artery (SCA) in 13 patients (bilateral in two) and multiple territories in four patients (bilateral in one). The top-of-the-basilar syndrome was present in two patients. According to this study, it is evident that multiple vertebrobasilar infarcts, mainly both infratentorial and supratentorial may develop either by cardiac or artery-to-artery sources of embolism. Another study of 27 patients with acute multiple infarcts in remote arterial territories of posterior circulation showed that 18 patients had multiple infratentorial and supratentorial infarcts including the cerebellum and posterior cerebral artery territory, with coexisting brainstem involvement in seven patients (Bernasconi et al., 1996). Secondly, seven patients had multiple acute infarcts in the posterior circulation of the cerebellum and lower brainstem. Thirdly, two patients with large-artery disease had multiple acute infarcts in the posterior circulation in the brainstem and posterior cerebral artery territory. This study has also highlighted the fact that embolism from an arterial or a cardiac source is the main etiology of multiple infarcts in the posterior circulation. In one series, 58 of 238 patients (25%) with vertebrobasilar ischemia had multiple ischemic lesions of the brainstem, studied by clinical examination, electrophysiological study and imaging techniques (Tettenborn, 1994). The

Multiple, multilevel and bihemispheric infarcts

localization of the multiple lesions within the brainstem was as follows: medulla and pons, seven; medulla and mesencephalon, three; bilateral pons, ten; pons and mesencephalon, 19; bilateral pons and bilateral mesencephalon, six; bilateral mesencephalon, five; multiple lesions, eight. On the basis of clinical findings alone, multifocal brainstem abnormalities were found only in 30 patients (52%). CT and/or MRI showed multifocal lesions in only 28 patients (48%), whereas combined electrophysiological studies (auditory evoked potentials, electronystagmography, blink reflex masseter reflex) were able to show multifocal abnormalities in 37 patients (64%). All three methods were in agreement regarding multifocal ischemic brainstem lesions in 14 patients (24%). In the other 44 patients (76%), only one or two of the three methods showed definite multifocal abnormalities. The most common cause was small penetrating arteries in 55% of the patients, followed by large-artery occlusive disease with artery-to-artery embolism in 35%, and cardiogenic embolism in 15%. In a series of 39 patients with midbrain infarction from New England Medical Center (NEMC), 36 patients (92%) had multiple lesions involving neighbouring structures. The topographic localization of multiple infarcts was as follows: four patients had midbrain plus PICA territory infarction involving cerebellum or medulla, 19 patients had midbrain plus pons or AICA territory infarction, 13 patients had midbrain and thalamus or PCA or SCA territory infarction, and only three patients had isolated midbrain infarct (Martin et al.,1998). The most common stroke mechanisms were cardioembolism (28%), large-artery-toartery embolism (18%), and intrinsic branch penetrator disease (13%). In a previous study (Chaves et al., 1994), 103 patients with cerebellar infarcts were classified using the topographical classification developed by Caplan et al. (1992): proximal (posterior inferior cerebellum and medulla); middle (anterior inferior cerebellum and pons); distal (superior cerebellum, midbrain, thalamus, temporal and occipital lobes) territories. Twenty patients had proximal and distal territory infarcts, and 22 patients belonged to the middle-plus subgroup: nine patients had proximal and middle territory infarcts, seven middle and distal, and six proximal, middle, and distal. In the proximal and distal subgroup, the most probable mechanisms were intraarterial embolism, cardiac embolism, and large-artery occlusive disease with hemodynamic strokes. In the middle-plus subgroup, the most probable cause was largeartery disease with hemodynamic strokes and less frequently intraarterial embolism, cardiac embolism, both potential intraarterial embolism and cardiac embolism, and migraine.

(a )

(b)

Fig. 38.10. A 65-year-old man with confusion, apathy and amnesia. (a) Axial T2-weighted MR imaging showing a bilateral paramedian infarct. (b) Coronal T2-weighted image showing bilateral thalamic infarcts.

Fig. 38.11. T2-weighted axial MR image showing bilateral infarcts in the head of caudate nucleus and other subcortical areas.

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with or without associated larger infarcts (Barth et al., 1993). Two patients had large infarcts in the PICA and SCA territories, two had large or medium-size infarcts associated with multiple small infarcts, four had multiple bilateral small infarcts in the SCA and PICA territories, and three had bilateral medium size junctional infarcts between the medial and lateral territories of the PICA. Multiple small infarcts were associated with vertebrobasilar atherosclerosis (8 of 12; 67%). In a clinico-radiological study of 47 patients with very small (border-zone) cerebellar infarcts the lesions were bilateral in nine cases (Amarenco et al.,1993).

(a )

Multiple, multilevel infarcts and dementia (b)

Fig. 38.12. A 65-year-old man with cerebellar syndrome, internuclear ophthalmoplegia and hemianopia. (a) T2-weighted coronal MR image, 7 days after stroke onset, showed simultaneous infarcts in the brainstem and in the territory of posterior cerebral artery on the left side. (b) MR angiography revealed occlusion of the right vertebral artery. These multiple infarcts were developed probably due to artery-to-artery embolism.

There are several studies on the multiple cerebellar infarcts (Fig. 38.13). In a series of clinicopathological study of cerebellar infarcts, the lesions involved a single arterial territory in 51 patients and multiple territories in 13 patients: PICA and anterior inferior cerebellar artery (AICA) in three patients, PICA and SCA in six, PICA, SCA, and AICA in four (Amarenco & Hauw, 1989). Another series of 34 patients with cerebellar infarcts studied by MRI showed that 13 (38%) had bilateral infarcts involving mostly small areas of the deep cerebellar white-matter,

The clinical syndrome of vascular dementia may develop as a result of different types of ischemic stroke and bilateral involvement of the strategic anatomical areas, including thalamus, angular gyrus. In a prospective series of 158 consecutive patients with stroke, the cumulative risk of developing dementia was 29% within 1 year, and 34% within 3 years (Treves et al.,1997). The cumulative effects of multiple small or large infarcts due to thrombosis of large or small arteries or multifocal emboli of either cardiac or arterial origin can yield loss of cognitive, memory and higher brain functions. Dementia can occur with extensive whitematter ischemic lesions (leading to functional disconnection of critical brain areas) in the absence of large infarcts and hemorrhagic strokes (Fukuda et al.,1990; Wolfe et al., 1990). Limited damage to small subcortical structures can also result in functional brain impairment sufficient to induce neurobehavioural syndromes resembling dementia, explained by disruption of corticosubcortical pathways. Bilateral paramedian thalamic or caudate infarction may induce a characteristic clinical picture with slowness of motor, speech, mental and mood functions. The difficulties encountered in defining, diagnosing and classifying different patterns of dementia associated with stroke have been emphasized in many studies on this area. Gorelick et al. (1992) analysed CT findings among multiinfarct patients with (58 patients) and without (74 patients) dementia. Overall, multi-infarct patients with dementia had more cerebral infarcts, especially left cortical and subcortical infarcts, higher ratios of mean ventricular volume to brain volume, more extensive enlargement of the body of the lateral ventricles and cortical sulci, and a higher incidence of white-matter lucencies. Among non-CT factors, level of education and stroke severity also predicted vascular dementia. In a study by Tatemichi et al. (1993), 66 of 251 patients (26%) with acute ischemic stroke developed

Multiple, multilevel and bihemispheric infarcts

dementia after 3 months. Dementia was significantly associated with age, education, race, history of prior stroke, diabetes mellitus, left-hemisphere infarct and lacunar infarction. Multiple independent factors, including both small subcortical and large cortical infarcts, especially involving the left medial frontal and temporal regions, with additional contributions by demographic and vascular risk factors were responsible for the development of dementia. In our series of 40 patients with acute multiple infarct involving the anterior circulation, four patients who did not have history of cognitive disturbances before the onset of stroke developed acute dementia (Bogousslavsky et al., 1996).These patients had large infarcts involving the anterior and posterior circulation that spared motor, sensory, and visual areas and pathways.

Conclusion Our current knowledge of the clinical and etiological spectrum of multiple brain infarcts is considerably higher than one decade ago. In patients with simultaneous multiple, multilevel infarcts or recurrent strokes, most causes seem to be of a similar type. Simultaneous multiple, multilevel infarcts may be associated with specific neurologic–neuropsychologic dysfunction patterns in most of the patients, allowing diagnosis accuracy. Wider applications of MRI, transcranial Doppler examination and cardiac investigations, including transesophageal and contrast echocardiography will allow better understanding of the causative mechanisms of multiple brain infarction and precise localization of lesions during life.

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Fig. 38.13. A 75-year-old man with history of diabetes mellitus and hypercholesterolemia developed sudden ataxia, unsteadiness. T2-weighted axial MR images showed bilateral multiple cerebellar infarcts.

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Midbrain infarcts Marc Hommel and Gérard Besson Central University Hospital of Grenoble, France

Posteromedial choroidal artery

Anterior choroidal artery

MEDIAL THALAMUS

POSTEROLATERAL THALAMUS TGA

TPA PoCA P2

P1

PCA BA

1 2 3

Posterior cerebral artery

4

Superior cerebellar artery Collicular artery

Basilar artery

5 P3

Fig. 39.1. Right lateral view of the midbrain adapted from Tatu et al. (1996).

The midbrain is a common site for stroke lesions, and the multiplicity of the functions affected by midbrain lesions is responsible for the broad clinical spectrum of signs and symptoms observed. Moreover, the arterial blood supply to the midbrain is complex. It is reported in Fig. 39.1 and the vascular territories are reported in Fig. 39.2. There are overlaps between arterial territories, and there are individual variations. The arterial system supplying the midbrain is terminal for the midbrain. Moreover, from the bifurcation of the basilar artery, arterial branches arise for the thalamus and occipital lobes. Therefore, it can sometimes be difficult to determine that a stroke has occurred and to define the exact topography of the lesion. Nevertheless, limb movements, consciousness, cognition and oculomotor capacities are the functions mainly involved in midbrain strokes, and their combinations, which tend to be characteristic, are important for diagnosing the site of

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TEMPORAL AND OCCIPITAL LOBES Anterolateral group

Anteromedial group

Lateral group

Posterior group

Fig. 39.2. Axial diagram of the upper midbrain; BA, basilar artery; PoCA, posterior communicating artery; PCA, posterior cerebral artery; P1, P1 part of the PCA; P2, P2 part of the PCA; P3, P3 part of the PCA; TPA, thalamoperforating arteries; TGA, thalamogeniculate arteries; 1, corticospinal tract; 2, substantia nigra; 3, red nucleus; 4, medial and lateral lemniscus; 5, oculomotor nucleus.

infarction. Therefore, knowledge of the anatomy of the midbrain and its blood supply is crucial for delineation of the affected nerve areas and for determining the site of the arterial occlusion and the size of the affected artery suggesting the mechanism of the arterial occlusion, which in turn determines the most appropriate treatment (Tatu

Midbrain infarcts

(a )

(b)

Fig. 39.3. Patient of 83 years of age presenting with an infarction in the territory of the anterior choroidal artery (Fig. 39.3(a)). The midbrain vascular territory of the anterior choroidal artery is shown on the diffusion weighted trace (Fig. 39.3(b)).

et al., 1996). For example, if a patient presents with a motor deficit, the arteries of the anterolateral group may be involved. They have their origin either in the posterior cerebral artery, or in the trunk of the anterior choroidal artery (Fig. 39.3), and a large artery occlusion mechanism such as embolism or atherothrombosis may be more likely. On the other hand, if a patient presents with oculomotor or cerebellar signs attributable to a unilateral lesion in the anteromedial arteries group arising from the basilar artery in the interpeduncular fossa, a small artery disease or a branch occlusion from the basilar artery is possible. And, with the exception of the paramedian thalamosubthalamic infarction, which can be related to the occlusion of the only thalamomesencephalic artery, bilateral lesions are very likely to be related to a basilar artery lesion or to an embolic mechanism (Bogousslavsky et al., 1994). Moreover, recent improvements in imaging techniques such as magnetic resonance imaging with the diffusion, perfusion and FLAIR sequences associated with MR angiography, has largely improved the diagnosis of midbrain vascular lesions.

Clinical features of midbrain infarcts Oculomotor syndromes Oculomotor palsies are frequent in patients with midbrain infarcts, and they provide the best indication of the presence of a lesion of the midbrain, especially in cases of thirdnerve syndromes or of vertical-gaze palsies. They are

caused by occlusion of the paramedian arteries, which are branches from the upper part of the basilar artery. They can occur in isolation or can be associated with involvement of other structures (Table 39.1).

Third-nerve palsies Isolated third-nerve palsy Isolated third-nerve palsy can be due to an infarct involving the third-nerve fasciculus within the midbrain (Collard et al., 1990). Infarction of the third-nerve nucleus can be clinically distinguished from fascicular infarction because a lesion of the nucleus will affect elevation for both eyes. The superior rectus muscle is innervated by the contralateral nucleus, whose efferent fibres are affected as they pass through the ipsilateral third-nerve nucleus (Bogousslavsky & Regli, 1984; Getenet et al., 1994; Keane, 1988; PierrotDeseilligny et al., 1981). Mydriasis is frequent, but pupillary functions will sometimes be preserved (Breen et al., 1990). When the most medial part of the arterial territory is affected, ptosis and mydriasis can be bilateral. Nevertheless, isolated unilateral third-nerve infarction or infarction of the third-nerve nucleus is very rare. More often, there tend to be motor deficits or features suggesting thalamic involvement.

Isolated palsy of the superior oblique These have been observed in small infarcts involving the region of the trochlear nucleus (Thömke & Ringel, 1999).

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Table 39.1. Midbrain ischemic syndromes 1. Oculomotor syndromes Isolated third-nerve syndromes Third-nerve-nucleus or radicular palsy Third-nerve palsy plus crossed hemiplegia (Weber’s syndrome) Third-nerve palsy plus crossed cerebellar syndrome (Claude’s syndrome) Third-nerve palsy plus crossed abnormal movements (Benedikt’s syndrome) Isolated superior oblique palsy Supranuclear conjugate-vertical-gaze palsy Upward-gaze palsy Downward-gaze palsy Combined upward- and downward-gaze palsy Supranuclear disconjugate-vertical-gaze palsy Monocular-elevation palsy Vertical one-and-a-half syndrome Internuclear ophthalmoplegia Other neuro-ophthalmological features Skew deviation Ocular-tilt reactions Pretectal pseudobobbing Pseudo-sixth phenomenon Nystagmus Nystagmus retractorius Upbeat nystagmus Seesaw nystagmus Hypermetric saccades Disorders of convergence Convergence nystagmus Convergence spasm Convergence retraction nystagmus Eyelid abnormalities Horner’s syndrome Ptosis Blepharospasm Retraction and elevation of the upper eyelids (Collier sign) Pupillary abnormalities Light-near dissociation

Third-nerve palsy plus hemiplegia Herman Weber (1863) described a patient who presented with unilateral third-nerve palsy associated with a crossed hemiplegia due to a hematoma affecting the paramedian and lateral midbrain. However, that was not the first description of what has come to be called Weber’s syndrome. Marotte (1853) reported the first known case, caused by a midbrain infarct. Infarcts as causes of Weber’s syndrome are rare. Third-nerve palsy can be accompanied by supranuclear gaze palsies, and the ipsilateral

Inverse Argyll–Robertson Mydriasis Meiosis Corectopia Internuclear ophthalmoplegia Trochlear-nucleus involvement Visual-field abnormalities Sectoranopia Homonymous hemianopia Bilateral altitudinal hemianopia Cortical blindness Colour-vision abnormalities Achromatopia Metamorphopsia 2. Classic lacunar syndromes Pure motor stroke Ataxic hemiparesis Midbrain locked-in syndrome 3. Hemiplegia in PCA occlusion Pseudo-occlusion of proximal middle cerebral artery 4. Movement disorders Asterixis Chorea Tremor Cerebellar syndrome Bilateral cerebellar syndrome (Wernekink commissure syndrome) 5. Neuropsychological syndromes Peduncular hallucinosis Behavioral changes Confusion Memory disturbances Consciousness disturbances, coma Hypersomnia, insomnia 6. Associated signs Related to occipital-, internal temporal-, thalamic-, and cerebellar-associated infarctions

pupil can be mydriatic or miotic, depending on the preservation of sympathetic fibres. A sensory deficit can be present. This syndrome is likely to be related to occlusions of the posterior cerebral artery in its P1 segment. Therefore, associated thalamic and occipital-lobe signs are common.

Third-nerve palsy plus cerebellar signs The combination of third-nerve palsy associated with contralateral cerebellar signs is called Claude’s syndrome.

Midbrain infarcts

It is caused by infarction of the third-nerve nucleus or its fibres and of the cerebellothalamic connections where they pass through the red nucleus (Claude, 1912; Claude & Loyez, 1912). This rare syndrome is due to a unilateral paramedian lesion of the upper midbrain (Lefebvre et al., 1993; Mrabet et al., 1995).

Third-nerve palsy plus abnormal movements The combination of a third-nerve palsy with involuntary abnormal movements (tremor or chorea) affecting the contralateral limbs is known as Benedikt’s syndrome. It is caused by a paramedian upper-midbrain infarction of the red nucleus that also affects the third-nerve fibres.

Supranuclear conjugate-vertical-gaze palsies The supranuclear conjugate-gaze palsies are due to median or paramedian infarctions in the upper midbrain. Three types of arterial territories can be involved. Occlusion of a paramedian perforating artery or its branches can provoke a small paramedian uppermidbrain infarct that can cause gaze palsy. Occlusion of the superior cerebellar artery can give rise to an infarction in the posterior commissure or in the periaqueductal grey matter. However, the features can be more complex if the territory of the paramedian thalamic/mesencephalic artery is involved. This artery often has a trunk dividing into bilateral distal branches. Proximal occlusion of this artery can cause a butterfly-shaped infarct involving the medial thalamus and subthalamus bilaterally and the paramedian upper midbrain. Therefore, such patients often present with associated bilateral thalamic and midbrain clinical signs (Castaigne et al., 1981; Tatemichi et al., 1992).

discrete bilateral infarcts are located more caudally than the lesions that cause upward-gaze palsies (PierrotDeseilligny et al., 1982).

Combined upward- and downward-gaze palsy Combined upward- and downward-gaze palsy has been related to bilateral or unilateral midbrain infarcts (Castaigne et al., 1981). Discrete unilateral infarcts affecting the riMLF may be responsible for a conjugate-verticalgaze palsy (Ranalli et al., 1989).

Supranuclear disconjugate-vertical-gaze palsies The disconjugate-vertical-gaze palsies, monocular-elevation palsy, and vertical one-and-a-half syndrome can be related to an ipsilateral or contralateral discrete unilateral infarct affecting the upper paramedian midbrain (Hommel & Bogousslavsky, 1991; Thömke & Hopf, 1992).

Other neuro-ophthalmological features Other neuro-ophthalmological features have been reported: skew deviations, tonic ocular-tilt reactions (Halmagi et al., 1990; Ohashi et al., 1998), pretectal pseudobobbing also known as V-pattern pseudobobbing (Bogousslavsky, 1989), intermittent corectopia (eccentric pupil) (Selhorst et al., 1976), upper-eyelid retraction, ptosis associated with internuclear ophthalmoplegia and dissociated vertical nystagmus (Marshall et al., 1991), convergence retractory nystagmus (Biller et al., 1984), seesaw nystagmus, oculomotor and trochlear nuclear involvement (Growdon et al., 1974), dissociated vertical-gaze palsies, and asterixis (Bril et al., 1979).

Upward-gaze palsy Upward-gaze palsies have been related to unilateral or bilateral midbrain infarctions. Infarction of the posterior commissure, the periaqueductal region, and the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) can cause upward-gaze palsy (Bogousslavsky et al., 1986; Hommel & Bogousslavsky, 1991; Kim et al., 1993; Serdaru et al., 1982; Mehler, 1988).

Downward-gaze palsy Isolated downward-gaze palsies are very rare. In patients with downward-gaze palsy, only bilateral infarcts affecting the upper part of the midbrain have been reported. These

Associated clinical features If the territory of the thalamomesencephalic artery is involved, the various gaze palsies can be associated with other clinical features, mainly behavioural, neuropsychological, and consciousness disturbances. Often, there is an initial coma, and subsequent hypersomnia. Akinetic mutism, disorientation to time and place, memory disturbances (anterograde amnesia), motor or multimodal hemineglect, faciobrachial hypesthesia, and transcortical motor aphasia are frequent. Delayed athetoid or clonic movements may occur (Bogousslavsky et al., 1986; Castaigne et al., 1981).

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Classic lacunar syndromes due to midbrain infarcts Pure motor stroke A lacunar infarct of the lateral midbrain affecting the pyramidal tract in the cerebral peduncle can cause pure motor stroke (Gaymard et al., 1991; Ho, 1982).

Ataxic hemiparesis An association of hemiparesis, ataxia, and hypesthesia (hypesthetic ataxic hemiparesis) can be related to an infarction of the dorsolateral midbrain.

Midbrain locked-in syndrome Bilateral, isolated small infarcts in the lateral midbrain involving the corticospinal tracts have been responsible for tetraplegia and mutism, leaving conscious patients with only gaze movements as means to communicate (Chia, 1991). Midbrain hematomas have been known to cause pure sensory strokes. To our knowledge, no midbrain lacunar infarct has been the cause of pure sensory stroke. However, the dorsolateral midbrain could be the site of a pure sensory stroke due to a lacunar infarct.

Hemiplegia with posterior cerebral artery occlusion Proximal occlusion of a posterior cerebral artery (PCA) causes a spectrum of clinical manifestations related to the combination of midbrain, thalamic, and occipital infarctions. These clinical features include homonymous visual-field defects, abnormal visual perception, and neuropsychological signs and symptoms. Usually there is little or no weakness. However, occlusion at the origin of the PCA can cause a midbrain infarct affecting the lateral part of the upper midbrain, projecting to the pyramidal tract and responsible for a contralateral hemiplegia. Two cases of hemiplegia with PCA-territory infarction have been reported without benefit of imaging or autopsy (Benson & Tomlinson, 1971). Caplan et al. (1988) reported a case in which there was anatomic verification of a lateral midbrain infarct. In addition, we have reported four patients with hemiplegia associated with infarction in the territory of the PCA (Hommel et al., 1990). We stress that this association of hemiplegia and neuropsychological and visual disturbances due to the associated thalamic and occipital infarcts can mimic, in the acute phase, an occlusion of the proximal middle cerebral artery. The likely site

of arterial occlusion is the proximal part of the P2 segment of the PCA (Hommel et al., 1991; North et al., 1993).

Other syndromes Abnormal movements Subthalamic small deep infarcts can be associated with abnormal movements and asterixis (Bril et al., 1979), with unilateral or bilateral ballistic movements (Caplan, 1980; Fig. 39.4), and with blepharospasm.

Cerebellar syndrome The third nerve is not always involved by infarcts affecting the red nucleus. Chiray et al. (1923) reported on patients with isolated lateral and rostral infarcts of the red nucleus presenting with cerebellar syndromes. Unilateral ataxia of the limbs that related to a cerebellar infarct in the territory of the superior cerebellar artery can be associated with various combinations of rostral midbrain syndromes. The cerebellar ataxia is often overshadowed by upper-midbrain and thalamic–subthalamic signs. The midbrain signs can be due either to emboli in the superior cerebellar artery, also fragmenting into the rostral basilar artery, or to infarction of the midbrain territory of the superior cerebellar artery. The Wernekink commissure syndrome is very rare and is characterized by a bilateral cerebellar syndrome, sometimes associated with midbrain oculomotor signs (Lhermitte, 1958).

Peduncular hallucinosis Rarely, infarcts restricted to the upper midbrain may give rise to peduncular hallucinosis. They usually are visual and vivid, rarely auditory, and occur in patients with insomnia. They may be limited in time during the day, occurring especially at sundown. The term hallucinosis is used in order to distinguish these features from the hallucinations occurring in patients with delirium, because in peduncular hallucinosis the patients often are aware that the abnormal perceptions are hallucinations and that they have no psychiatric disorder (Caplan, 1980).

Causes of midbrain infarcts When considering the mechanisms of infarction in the territory of the vertebrobasilar arteries, it is important to

Midbrain infarcts

(a )

(b)

Fig. 39.4. 65-year-old patient presenting with an auditive peduncular hallucinosis, a bilateral third nerve palsy with mydriasis and amnesia plus apathy. The midbrain bilateral infarction in the anteromedial arteries territory is shown on the image with FLAIR sequences (a) and on diffusion weighted trace (b).

emphasize that there have been no large comprehensive studies of consecutive cases employing the most modern techniques available (Caplan et al., 1992). Therefore, many questions remain to be answered. What are the rates of large-artery and small-artery occlusions? What are the incidences and sources of emboli? How frequently are atheromatous lesions the causes of thrombosis? What are the frequencies of small-artery abnormalities, of hemodynamic mechanisms, of coagulation disorders? Numerous studies have contributed to our knowledge regarding selected aspects of these questions, but quantitative data on the roles of the different causes are still lacking, especially when considering selected parts of the nervous system such as the midbrain. In order to improve this situation, Caplan et al. (1992) reviewed the mechanisms of arterial occlusions in vertebrobasilar arteries, as compared with carotid arteries. They stressed some common myths regarding the mechanisms of posterior infarcts (carotid arteries develop ulcerations, and vertebral arteries do not; vertebrobasilar artery ischemia is hemodynamic, and carotid artery infarcts are embolic). Those myths continue to hinder our acquisition of knowledge about strokes and do a disservice to patients, denied the benefit of the most effective treatment. In a review of 187 autopsies in which there was basilar artery occlusion, Gauthier (1961) reported that the upper part of the basilar artery was occluded at the level of the bifurcation of the basilar artery in 20 patients, the upper one-third of the basilar artery was occluded in eight patients, and there was extensive thrombus of the entire basilar artery in 18 patients. Those occlu-

sions occurred at sites that can cause midbrain infarcts. There were no detailed data on the causes of the occlusions, and the status of the basilar artery was described in only 80 patients. Atherothrombosis was the mechanism in 64 of 80 patients (80%), irrespective of the topography of the occlusions. Extensive thrombosis of basilar artery fusiform aneurysms was rare. Kubik and Adams (1946) reported that, when an occlusion of the basilar artery was limited to its upper part, the mechanism of the occlusion was an embolus. Moreover, they stated that in seven of their 18 cases (36%), occlusion of the basilar artery was of embolic origin, even in its lower and middle parts. Castaigne et al. (1973), in an autopsy study, found that only three of 30 cases were caused by in situ thrombosis. Emboli arose from proximal vascular lesions in 15 cases, extended from the basilar artery in 8 cases, and had a cardiac origin in 1 case. In studying rostral basilar infarcts, Mehler (1989) reported that 23% had a cardiac embolic source, 13% had an arterial source, and 10% had unknown sources, making a total of 46% embolic sources. According to a study from the New England Medical Center, the mechanisms of vertebrobasilar infarcts were large-artery occlusive disease (43%), small-artery disease (18%), cardiac-origin emboli (19%), and intraarterial emboli (20%) (Caplan & Tettenborn, 1992). Therefore, it appears likely that there are no broad differences in the mechanisms of infarction between the carotid and the vertebrobasilar arterial systems. Because of the anatomic shape of the upper basilar artery and its branches, it seems likely that large proportions of top-of-the-basilar-artery syndromes and

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midbrain infarcts are of embolic origin (Caplan, 1980; Mehler, 1988).

Conclusions Midbrain infarcts have a wide spectrum of clinical expressions, and they are sometimes difficult to diagnose. Special clinical training and dedication are necessary if one is to delineate precisely the topography of the infarcts and the sites of arterial occlusions. Extensive cardiac and arterial examinations must be carried out in these patients, using the same techniques as in carotid-territory infarcts. These examinations are necessary, if one is to determine the mechanisms of the infarcts. Improvements in our knowledge base regarding causes and prognosis are crucial if we are to progress toward better therapeutic decisions. In the future, therapeutic trials to evaluate the efficacy of surgery, antiplatelet agents, and anticoagulants should be planned for patients with vertebrobasilar infarcts.

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Pontine infarcts and hemorrhages Chin-Sang Chung1 and Louis R. Caplan2 1 2

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Beth Israel Deaconess Medical Center, Boston, MA, USA

Neurovascular anatomy of the pons The anatomic distribution of the major pontine arteries was worked out by Duret (1873) and, later, Stopford (1915, 1916) and Foix and Hillemand (1925a,b). The arterial supply can be divided into three groups. (i) Paramedian arteries arising from the dorsal surface of the basilar artery penetrate the pons directly and are larger than the other penetrating vessels. They supply the medial portion of the basis pontis and the most ventral part of the tegmentum. (ii) Short circumferential arteries supply the lateral threefifths of the pons. And (iii) long circumferential arteries nourish the lateral tegmentum and tectum. Short penetrators course more laterally and run parallel to the median arteries. Lateral penetrators arise from the long circumferential arteries, supply the lateral tegmentum, and run perpendicular to the median penetrators (Fig. 40.1). According to a recent description of the arterial supply to the brainstem and cerebellum (Tatu et al., 1996), the pons is supplied by three groups of arteries: (i) anteromedial and anterolateral groups arising from the basilar artery, entering the foramen cecum, the basilar sulcus, and the interpeduncular fossa; (ii) lateral group arising from the AICA (entering the parenchyma in the pontomedullary sulcus and arising from the lateral pontine arteries (entering the brachium pontis); and (iii) posterior group arising from the superior cerebellar artery (medial and lateral branches).

Pontine infarcts Historical background The early reports on pontine infarction were mostly from necropsy studies of single patients or small series of patients with basilar artery occlusion (Hayem, 1868; Leyden, 1882; Foix & Hillemand, 1926; Lhermitte & Trelles,

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1934). Foix and Hillemand (1926) demonstrated the common patterns of blood supply to the brainstem and described two clinical syndromes: (i) a paramedian syndrome presenting with hemiplegia, or quadriplegia if bilateral; and (ii) a lateral tegmental syndrome presenting with ipsilateral cerebellar and contralateral motor and sensory symptoms. Lhermitte and Trelles (1934) reported cases of pontine hemiplegia or quadriplegia due to unilateral paramedian softening or basilar artery disease, as well as pontocerebellar pseudobulbar palsy due to more laterally placed bilateral lesions. In 1946 Kubik and Adams published a well-illustrated report on basilar artery occlusion and correlated the pathological findings and clinical features, which were various combinations of dizziness, altered consciousness, pupillary disturbances, ocular palsies, cranial nerve palsies, dysarthria, hemiplegia or quadriplegia, and bilateral extensor plantar reflexes. Recognition of these clinical features made antemortem diagnosis of basilar artery occlusion possible even before the CT era. In their pathological and clinical series, Fisher and Curry (1965) described so-called lacunar syndromes of hemiplegia and dysarthria caused by pontine infarcts. Pupillary, sensory, and higher-cortical-function abnormalities were not observed. Two years later, Fisher (1967a) described the dysarthria-clumsy-hand syndrome caused by a deeply situated lacune in the pons. In a review of 83 necropsies, Silverstein (1972a) divided pontine infarcts into syndromes depending on location: bilateral, unilateral paramedian, tegmental, lateral, combined unilateral paramedian and lateral, and patchy pontine syndromes. About half of the patients had a unilateral paramedian pontine syndrome. Infarcts localized to the lateral tegmental area were found only in a few patients. During the last few decades, advances in imaging techniques like CT and MRI revolutionized the clinical diagno-

Pontine infarcts and hemorrhages

(a ) (a )

(b)

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Fig. 40.2. Pontine infarct caused by occlusion of the basilar artery: (a) midbrain, (b) upper pons, (c) lower pons, and (d) medulla. (Adapted from Kubik & Adams, 1946; from Caplan, 1993, with permission.)

Fig. 40.1. (a) Artist’s drawing of arterial penetrators at the level of the inferior colliculus. A, paramedian penetrating arteries; B, penetrators from short circumferential arteries. (From Caplan & Goodwin, 1982, with permission; drawn by Harriet Greenfield.) (b) Artist’s drawing of arterial penetrators at the level of the midportion of the pons. A, paramedian penetrating arteries; B, short circumferential arteries; C, penetrators from long circumferential arteries. (From Caplan & Goodwin, 1982, with permission; drawn by Harriet Greenfield.)

sis of brainstem strokes and so many new reports on clinical syndromes of pontine stroke followed (Caplan, 1996; Hommel et al., 1989; Helgason & Wilbur, 1991; Kim, 1992; Kataoka et al., 1997).

Stroke mechanisms Large artery diseases and embolism Atherothrombosis and embolism of the large basilar artery can cause pontine infarctions. Kubik and Adams (1946) analysed the findings in 18 patients with basilar artery occlusion (11 due to basilar artery thrombosis and seven due to embolism) and illustrated the basilar artery and

brainstem lesions at various levels. Figure 40.2 is a drawing of one of their diagrams, showing the lesions in a patient. The infarcts were located in the medulla, pons, and midbrain and correlated well with the levels of occlusion. In all the patients with basilar thrombosis, there was luminal narrowing, with extensive basilar artery atheromatosis. In patients with embolism, the embolus usually was lodged in the distal portion of the basilar artery.

Small artery diseases and microembolism Various kinds of penetrating artery diseases can also cause pontine infarcts. The representative vascular lesions are lipohyalinosis and branch atheromatous diseases. Fisher and Curry (1965) reported three pathologically verified cases of pure motor hemiplegia due to pontine infarction. The infarcts were located on one side of the pons, not crossing the midline, and were situated at any level. The basilar artery was patent in all patients. The patients had either hypertension or diabetes, but no atrial fibrillation. Fisher (1967a) described a pathological case of a deeply situated lacune in the pons as shown in Fig. 40.3, almost reaching the medial lemniscus. The branch supplying the pontine infarct was not occluded. Fisher and Caplan (1971) suggested basilar branch atheromatous disease at the origin of the penetrating

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Fig. 40.3. An MRI picture showing a deep pontine lacunar infarct.

arteries as a cause of pontine infarction on the basis of pathological examination of the brainstem (Fig. 40.4). They described two patients who showed severe occlusive lesions at the mouths of arteries originating from the basilar artery lumen. In one patient an atheromatous plaque within the basilar artery obstructed the intramural portion of the basilar branch. In the other patient a plaque arising in the lumen of the basilar artery extended into the mouth of the branch and formed an occlusive ‘junctional plaque’ (Fig. 40.5). In pontine infarcts due to bilateral occlusion of basilar artery branches reported by Fisher (1977), a microdissection created a crevice in a plaque located at the orifice of a branch in one artery while a bead of atheroma, with superimposed microthrombosis, obliterated the other basilar branch. Infarcts in the midline extending from the base of the pons posteriorly into the tegmentum suggest basilar branch occlusion, while infarcts involving only part of the tegmentum probably result from small penetrator branch occlusion.

Clinical features Unilateral paramedian infarcts (Fig. 40.6) Occlusion of the paramedian branches usually causes damage to the corticospinal, corticopontocerebellar, and corticobulbar tracts, the cranial nuclei or their outgoing

Fig. 40.4. Basilar branch occlusion. The diagram at the bottom is a close-up of the artery shown within the cube above; A, atheroma; P, plaque. A plaque is seen extending into the branch. (From Fisher & Caplan, 1971; with permission.)

fascicles, and the medial longitudinal fasciculus (Kim et al., 1995). Thus, a variety of lacunar syndromes may follow paramedian pontine infarcts. The neurological manifestations depend on how severely the tegmentum is involved. Motor abnormalities are common and sometimes are accompanied by transient dizziness, diplopia, gaze abnormalities, nystagmus, dysarthria, and dysphagia. Lacunar syndromes, such as dysarthria-clumsy-hand syndrome, pure motor hemiplegia, pure sensory stroke, and ataxic hemiparesis, are often found in patients with paramedian infarcts (Fisher & Curry, 1965; Rascol et al., 1982; Huang et al., 1988; Kim et al., 1995; Caplan, 1996; Kim & Bae, 1997).

Dysarthria–clumsy hand syndrome Glass et al. (1990), studied six patients with the dysarthria–clumsy hand (DA–CH) syndrome. All were found to have pontine base infarctions contralateral to the symptomatic side. Clinically, these patients had dysarthria; ‘clumsiness’ characterized by dysmetria, dysrhythmia,

Pontine infarcts and hemorrhages

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(b)

(c )

Fig. 40.5. Cartoons showing mechanism of atheromatous branch occlusive disease. The topmost figure shows the location (stippled) of a paramedian pontine infarct. In the figures below, the figures to the left illustrate plaque within the basilar artery blocking the branch. The central figures show plaque from the basilar artery extending into the branch. The figures to the right show a small microatheroma forming at the mouth of the branch. (From Caplan, 2000, with permission.)

Fig. 40.6. An MRI showing a paramedian pontine infarct.

reported 17 patients with PMH that were caused by paramedian pontine infarcts. Large lesions involving the paramedian caudal or middle pons correlate with severe PMH whereas lesions of similar size located in the paramedian rostral pons tend to produce DA–CH syndrome (Kim et al., 1995).

Ataxic hemiparesis dysdiadochokinesia, and sometimes truncal and gait ataxia; and mild ipsilateral weakness. In their series and in a review of the literature, the DA–CH syndrome was caused by pontine infarcts in the majority of cases. Kim et al. (1995) also reported DA–CH syndrome in six patients with pontine base infarcts and a variant form, dysarthria-facial syndrome.

Pure motor hemiparesis Pure motor hemiparesis (PMH) can develop in patients with capsular infarcts or paramedian pontine infarcts. Nighoghossian et al. (1993) prospectively studied 21 patients with PMH. In their series pontine paramedian infarcts caused PMH in six patients (29%). Clinical findings cannot definitely distinguish between capsular and pontine PMH, but the combination of dysarthria and a history of previous transient gait abnormality or vertigo more strongly suggests a pontine location. Kim et al. (1995)

Ataxic hemiparesis (AH) can develop as a result of paramedian pontine infarction, particularly when the pyramidal tracts are spared. Variants of AH like dysarthria–hemiataxia and quadrataxic hemiparesis can also develop (Kim et al., 1995).

Ocular movement abnormality When voluntary and reflex-like eye movements are measured in a patient with a basal pontine infarct, ipsilateral smooth-pursuit eye movements are predominantly impaired and interrupted by saccades. This profound smooth-pursuit deficit contrasts with only minor abnormalities of visually guided saccades and the vestibuloocular reflex (Thier et al., 1991). With basal-tegmental infarcts the patients may present various gaze abnormalities in addition to hemiparesis and sensory dysfunction. They include abducens nerve palsy, internuclear ophthalmoplegia (INO), horizontal gaze palsy, and one-and-a-half syndrome (Kataoka et al., 1997).

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Fig. 40.7. MRI pictures showing a small unilateral paramedian tegmental infarct ((a) arrow) and a relatively large unilateral tegmental infarct caused by occlusion of the left superior cerebellar artery ((b) curved arrow).

Other neurological signs A brainstem lacunar infarction may be associated with involuntary tonic limb spasms clinically similar to those reported as paroxysmal symptoms of multiple sclerosis. Involuntary tonic spasm of a paretic limb was reported in the acute phase of a lacunar infarct in the ventral pons that presented with PMH initially. The abnormal movements responded well to treatment with oral diazepam (Kaufman et al., 1994). Among 27 patients with basal pontine infarcts reported by Kataoka et al. (1997), pathological laughing was observed in three patients.

Unilateral tegmental infarcts (Fig. 40.7) Isolated infarcts in the lateral tegmentum are rare (Fig. 40.7(a)). Occlusion of the penetrating vessels supplying the lateral tegmentum results in infarction of the cerebellar projections, the fifth and eighth cranial nuclei, descending sympathetic tracts, and part of the sensory lemniscus. Occlusion of the anterior inferior cerebellar artery (AICA) or superior cerebellar artery (SCA) is occasionally responsible for pontine tegmental infarcts (Fig. 40.7(b)). The clinical findings include paralysis of ipsilateral conjugate gaze, abducens or facial paralysis, trigeminal

sensory involvement, contralateral hemiplegia, or pure sensory syndromes (pins-and-needles sensations in contralateral side of the body and decreased position and vibration senses)(Hommel et al., 1989).

Cranial nerve palsies In pontine tegmental infarcts, isolated or multiple cranial nerve palsies often develop. Ocular abnormalities are relatively common. They include isolated sixth-nerve palsy causing horizontal diplopia (Donaldson & Rosenberg, 1988; Fukutake & Hirayama, 1992; Kim et al., 1993) and various combinations of ocular motor disturbances like vertical gaze paresis of the opposite eye (Kim et al., 1993). Brainstem imaging abnormalities correlate well with the ocular signs. Infarction in the lateral inferior pons can cause non-ocular cranial nerve signs that include weakness of masticatory muscles, trigeminal sensory changes, facial weakness of lower-motor-neuron type and decreased palatal movement (Bergeron et al., 1979). Ocular and non-ocular dysfunctions generally improve within several months.

Sensory symptoms Various sensory symptoms are associated with ataxia or loss of balance, slurred speech, diplopia, and tinnitus in

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pontine tegmental infarcts. Numbness or tingling sensations in the arm and leg, in the head, or in the hand and face are the most common sensory symptoms (Helgason & Wilbur, 1991). Some patients with infarcts of the medial or lateral pontine tegmentum present with pure sensory symptoms. Sensory complaints may be localized to the hand and mouth or hemi-body referable to medial lemniscal or spinothalamic tract dysfunction and are occasionally localized to one limb, to an arm and leg, or to the face, characteristic of stroke localized to the cerebral hemisphere (Kim & Bae, 1997). Pure or predominant pontine sensory stroke is most often produced by small infarcts in the paramedian dorsal pontine area. Pontine pure sensory stroke (PSS) can be differentiated from thalamic PSS by the following characteristics: frequent association of dizziness/gait ataxia, predominant lemniscal sensory symptoms, occasional leg dominance or cheiro-oral pattern, and frequent bilateral perioral involvement (Kim & Bae, 1997). In addition, pontine PSS but not thalamic PSS selectively affects vibration and position sense, leaving pinprick and temperature perceptions intact while thalamic lesions but not pontine tend to spare the trunk. Dyesthesias from pontine lesions are more severe than those from thalamic lesions (Shintani, 1998).

Bilateral pontine infarcts Large acute bilateral infarcts in the pons are usually caused by basilar artery occlusion (Fig. 40.8). The clinical findings are quite similar to those of pontine hemorrhages. Disturbance of consciousness, pupillary and eye-movement abnormalities, hemiplegia or quadriplegia, cranial nerve abnormalities, and reflex changes are common. Vertigo, headache of dull, steady, aching nature, diplopia, blurred vision, ataxic gait, and altered consciousness are the common presenting symptoms in patients with basilar artery thrombosis. Dysarthria, pseudobulbar symptoms (such as dysphagia), emotional lability, hemiplegia or quadriplegia, abducens nerve palsies, pupillary abnormalities, facial palsies, paralysis of the tongue, paresthesias, hyperreflexia, and bilateral Babinski signs are also common. Some patients show midbrain signs due to concomitant involvement of the midbrain (Kubik & Adams, 1946; Silverstein, 1972a). Sometimes basilar artery thrombosis may present only with mild hemiparesis or other mild neurological symptoms initially for several days. With progression of the thrombosis patients may become stuporous or comatose, quadriplegic, ophthalmoplegic, aphonic, and dysphagic (Fisher, 1988; Kim et al., 1996). Fisher (1988) emphasized

Fig. 40.8. An MRI showing an acute bilateral pontine infarct caused by occlusion of the basilar artery. Note a high signal lesion in the basilar artery lumen.

the significance of possible initial progression of pontine infarction. He called the initial neurological deficit ‘herald hemiparesis.’ Occasionally, patients with marked basilar artery stenosis can develop a unilateral pontine infarct followed by another in the contralateral side after some interval, causing bilateral pontine infarcts (Fig. 40.9).

Prognosis In patients with pontine infarcts, an understanding of the underlying vascular lesion is not only important for therapeutic decisions but also necessary for prognosis. Management of risk factors, limitation of infarct size, and prevention of further strokes are the main goals of treatment. Decisions of the use of anticoagulants or antiplatelet agents must be based on knowledge of the underlying vascular pathologies and pathogenetic mechanisms. Thus, early evaluation of the vertebrobasilar arterial system is critical. CT and MR angiography and transcranial Doppler (TCD) ultrasonography can assess the structural and hemodynamic status of the vertebrobasilar system noninvasively and can provide the details of the system without difficulty (Brandt et al., 1999). Basilar artery occlusion was once considered invariably

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Fig. 40.9. MRI pictures that show a unilateral pontine infarct (a) followed by another infarct in the contralateral side after 3 months (b) that were caused by marked basilar artery stenosis seen on MR angiography (c).

fatal; recently, however, patients with no deficits or minor deficits following basilar artery occlusions have been reported (Caplan & Rosenbaum, 1975; Caplan, 1979). The extent of the deficit depends on the presence of collateral circulation and the occurrence of distal embolization. Patients with sudden-onset signs or gradual evolution usually have more severe deficits than patients who have had prior transient ischemic attacks (Caplan, 1979). Lacunes in the pons are tiny infarcts caused by lipohyalinosis, microemboli, or occlusion of penetrating branches from the basilar artery. Recovery from neurological deficits in lacunar syndromes is usually excellent, but occasionally, in patients with previous damage, the prognosis can vary (Fisher, 1982). Some patients with bilateral occlusions of basilar artery branches, with infarctions of different ages in the pons, have had progressive clinical deterioration and a fatal outcome (Fisher, 1977). The patients with upper pontine lesions are significantly less disabled than those with lower pontine lesions. Patients with basal tegmental infarcts in the upper pons are significantly better than those with infarcts in the lower pons. The favourable outcome seems to be related to the level of the pontine lesion, which influences the effect on the corticospinal tract. Pontine base infarction producing AH tends to spare the pyramidal tracts. Thus, the prognosis of these patients is relatively good (Kim et al., 1995). Patients presenting with PMH from pontine paramedian infarcts have worse prognosis than those with PMH from the internal capsule (Nighoghossian et al., 1993). Recovery is better in the patients with isolated small ventral or tegmental lacunar infarcts of small artery disease than in those with basilar artery branch disease associated with large ventral infarcts (Bassetti et al., 1996). Ocular and monocular dysfunctions generally improve

within several months (Kim et al., 1993). Videofluoroscopic modified barium-swallowing examination is an important tool for assessment of swallowing functions of brainstem stroke and provides important information on prognosis. Despite initial severity, recovery is usually good. Following an aggressive program of aspiration prevention, over 80% of patients ultimately resume full oral nutrition in the end (Horner et al., 1991).

Treatment of vascular lesions that cause pontine ischemia In patients with penetrating branch artery territory ischemia, the major therapeutic strategy is to maximize blood flow. Blood pressure should not be lowered unless it is very high (⬎180/110). Fluid volume should be maintained by liberal intravenous fluids or oral fluids when there is no swallowing problem. Patients are often nursed flat in bed during the acute period of ischemia. It is unlikely that either agents that modify platelet functions (such as aspirin, clopidogrel, or dipyridamole) or standard anticoagulants (heparin, heparinoids, low-molecular-weight heparin or coumarin) are effective since the major problem is hypoperfusion in the territory of the branch. Neither white platelet-fibrin or red erythrocyte-fibrin thrombi are thought to play an important role in the pathogenesis of the luminal narrowing. When pontine ischemia is due to thrombosis of an atherosclerotic basilar artery or caused by an embolus to the basilar artery, thrombolytic agents are used when the patient is seen early in the course and the brainstem is not already extensively infarcted. Intra-arterial administration of thrombolytic agents is probably more effective than

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intravenous use. In some patients with basilar artery thrombosis engrafted upon severe atherosclerotic narrowing, angioplasty may be necessary to keep the artery open after thrombolysis. Heparin (or low-molecular-weight heparin or heparinoids) is given after thrombolysis followed by coumarin. In patients with basilar artery thrombosis who are not given thrombolytic drugs, heparin and then coumarin are given. When the basilar artery is completely occluded we suggest using coumarin only for a period of 4–6 weeks and then switching to a drug that modifies platelet functions. When pontine ischemia is due to severe basilar artery stenosis, we advise longer term coumarin while monitoring periodically (using MRA, CTA, and/or TCD) the status of the basilar artery. Maintenance of blood flow is also important during the acute period so that we also try to maximize blood flow, utilizing the same strategies used for patients with penetrating artery disease.

Pontine hemorrhages About 10% of all brain hemorrhages occur in the pons (Silverstein, 1972b). Before the development of CT scan, pontine hemorrhages were considered a uniformly fatal disease characterized by horizontal-gaze paresis, pinpoint pupils, quadriparesis, and rapid onset of coma. The advent of CT and MRI has allowed detection of small hematomas, and we now know that the spectra of clinical findings and outcomes are rather broad and definitely not homogeneous. Hypertension is the most common cause, especially in the older age groups (Chung & Park, 1992). Cryptic vascular malformations constitute another important cause, particularly in young patients (Holtzman et al., 1987). Pontine hemorrhages are highly fatal with an overall case mortality rate of over 55–60% in most cases except in cases of small pontine hemorrhages (Chung & Park, 1992; Wijdicks & St. Louis, 1997).

Classification and clinical features Various classifications of primary pontine hemorrhages (PPH) were proposed, particularly after the CT scan was introduced. The most recent one was proposed by Chung & Park (1992). They classified PPH into four types based on the clinical and CT scan findings: massive, basaltegmental, bilateral tegmental, and small unilateral tegmental (Figs. 40.10 to 40.13) (Chung & Park, 1992). They characterized the clinical presentations and outcomes with CT parameters (like hematoma size, midline crossing, midbrain involvement, and rupture into the fourth ventricle) for individual types.

Fig. 40.10. A CT picture showing primary pontine hemorrhage of massive type.

Massive or large paramedian type (Fig. 40.10) This massive type presents with the neurological deficits that were described by Gowers(1892) and Osler(1903). This type results from rupture of intraparenchymal midpontine branches originating from the basilar artery. The bleeding vessel is probably a paramedian perforator in its distal portion and forms initial hematoma at the junction of the tegmentum and the basis pontis, where the hematoma grows into its final round or oval shape and replaces most of both subdivisions of the pons (Silverstein, 1972b; Kase & Caplan, 1986). They often extend rostrally to the midbrain and rarely caudally to the medulla. Rupture of blood into the fourth ventricle is very common (Dinsdale, 1964; Silverstein, 1972b; Chung & Park, 1992).

Level of consciousness A decrease in the level of alertness is the most prominent neurological sign. Most of the patients become comatose or stuporous (Goto et al., 1980; Chung & Park, 1992; Kushner & Bressman, 1985). All comatose patients die (Kushner & Bressman, 1985).

Respiratory abnormalities Abnormal respiratory patterns are often described as ‘inspiratory gasps of apneustic respiration,’ Cheyne–Stokes patterns, slow and labored respirations, gasping and apnea (Steegman, 1951).

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Among Nakajima’s 43 patients with fatal pontine hematomas, 86% had respiratory abnormalities on admission (Nakajima, 1983).

Hallucinations Hallucinations were described by eight patients in Nakajima’s series (1983). Hallucinations occurred between 3 and 50 days after the onset of hemorrhage and disappeared in several days. Some of the descriptions were vivid and colourful and included visions of a ‘green coach,’ ‘coloured kettle and bucket,’ ‘landscape of my neighbourhood,’ and ‘two white dogs.’ Others were bizarre illusions: ‘white and black serpents moving on the wall of the building,’ and ‘woman in a black dress standing in a grave.’ The mechanism of the hallucinatory experience probably relates to dysfunction of the reticular formation in the pontine tegmentum.

Motor abnormalities Quadriplegia, with stiffness of all limbs, is the commonest of all neurological deficits. A hemiplegic onset has occasionally been described. In the series of Goto et al. (1980), four of 15 patients had hemiplegia, but only three of 28 of Silverstein’s patients (1972b) with central hemorrhages had hemiplegia. Even when hemiplegia is present, the limbs on the opposite side will have exaggerated reflexes and a Babinski sign. Other spontaneous movements, such as shaking tremors, violent shivering, and dystonic postures, occur and can be misinterpreted as seizures. Decerebrate movements occur spontaneously or after painful stimuli. Decerebrate posturing was noted in 12 of 15 patients in the series of Goto et al. (1980). Five of the six patients with large tegmentobasal hematomas in the Kushner and Bressman (1985) series showed ‘decerebrate and decorticate posturing.’

Cranial nerve palsies Weaknesses of the face, pharynx, palate, and tongue are nearly invariable in patients with large central pontine hemorrhages. Even those hemorrhages that remain entirely tegmental destroy the corticobulbar fibers to these bulbar cranial nerve motor nuclei. Formal testing is difficult in comatose patients. Puffing of the cheeks with expiration, decreased eyelid tone, and pooling of secretions in the oropharynx are usually found. Deafness or sudden hearing impairment, dizziness, vertigo, and numbness of the face are also common findings. Goto et al. (1983) reported gustatory abnormalities in patients who survived pontine hemorrhages. They found decreased numbers of neurons and fibers in the solitary tract on the side of the lesion.

Ocular and eye-movement abnormalities Small, reactive, pinpoint pupils, due to interruption of descending sympathetic tracts, are characteristic of pontine hemorrhages, but anisocoria and skew deviation are also sometimes found. In the 44 fatal cases reported by Nakajima (1983), pinpoint pupils were noted in 11 patients, anisocoria in 13, and skew deviation in four. Bilateral horizontal conjugate-gaze paresis is often present because of involvement of the paramedian pontine reticular formation (PPRF). Voluntary and reflex horizontal eye movements induced by head turning or ice-water stimulation are lost. In some patients in whom the lesion is predominantly in the basis pontis, reflex eye movements are preserved (Kase & Caplan, 1986). Patients with asymmetric tegmental hemorrhages can have a unilateral horizontal-gaze palsy, usually to the side of the lesion, or more often can have a one-and-a-half syndrome, also called ‘paralytic pontine exotropia’ (Fisher, 1967b; Sharpe et al., 1974). Ocular bobbing, a term introduced by Fisher to describe sudden brisk conjugate ocular depression, followed a few seconds later by a slower return to midposition, is also found (Fisher, 1964). Bobbing can be explained on the basis of preservation of vertical-gaze centres in the midbrain and diencephalon while horizontal-gaze centres are damaged.

Autonomic dysfunction Signs of autonomic dysfunction, such as abnormal sweating and neurogenic bladder, have also been described. Hyperthermia has been common in the fatal cases; rarely, hypothermia has been noted (Nakajima, 1983; Chung & Park, 1992; Wijdicks & St. Louis, 1997).

Prognosis The prognosis of this massive type of PPH is worst among all pontine hemorrhage types. More than 90% of the patients die within a few weeks. Even survivors remain vegetative or are locked-in (Chung & Park, 1992).

Bilateral tegmental and basal-tegmental types (Figs. 40.11 and 40.12) Although Chung & Park (1992) separated the basaltegmental and bilateral tegmental types according to the involvement of the basis pontis that carries the pyramidal tracts, both have quite similar clinical findings and outcomes. In addition, the bleeding vessels of both types are considered to be same. The hematomas develop in the bilateral pontine tegmentum or in the junction between the basis pontis and tegmentum. Only the degree and direction of extension of hematomas differ.

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The patients become suddenly somnolent, stuporous, or sometimes comatose and present with bilateral, oculomotor paralysis and other multiple cranial nerve palsies, hemiparesis or quadriparesis. The prognosis is slightly better than in the massive subtype but is still quite poor. The survival rates were 14.3% for the bilateral tegmental type and 25.1% for the basis-tegmental type in Chung & Park’s series (1992). If the fibres of the reticular formation are spared, the patient can remain alert and survive despite the presence of complete horizontal ophthalmoplegia and bobbing (Payne et al., 1978). Only occasionally basal-tegmental hematomas remain unilateral. The most important and consistent clinical signs in these cases are crossed cranial nerve abnormalities and hemiplegia in reported cases (Kushner & Bressman, 1985; Kase et al., 1980).

Small unilateral tegmental type (Fig. 40.13) Small hematomas may develop in the unilateral tegmental region and can remain confined to the region without crossing the midline or invading the basis pontis (Goto et al., 1980; Chung & Park, 1992). They present clinically with findings similar to the classic lacunar syndromes. Thus, it seems that they used to be diagnosed as lacunar infarction during the pre-CT era. They are usually caused by rupture of penetrators from long circumferential arteries which enter the tegmentum laterally and run medially and perpendicularly to the paramedian branches (Kase & Caplan, 1986) or occasionally from the distal portion of a paramedian artery penetrating from the base (Kase & Caplan, 1986). The major clinical features are ocular and other cranial nerve abnormalities, which are: (i) pupillary abnormalities like anisocoria, with the ipsilateral pupil smaller, and normal pupillary reactivity and (ii) defects in ocular motility including paralysis of ipsilateral conjugate gaze, internuclear ophthalmoplegia, one-and-a-half syndrome, ipsilateral sixth-nerve palsy, reduced upward gaze, and ocular bobbing. Hemisensory loss is another invariable finding in patients with lateral tegmental hemorrhage and is related to involvement of the sensory lemniscus. Rarely trigeminal sensory symptoms or pure selective loss of touch, vibration and position senses can develop (Veerapin, 1989; Kim & Jo, 1992; Kim & Bae, 1997). The motor deficits are usually minor and transient. The initial motor deficit may be bilateral. In such case it is more severe contralateral to the hematoma and the ipsilateral hemiparesis frequently clears. Other brainstem signs, such as decreased hearing, dysarthria, dysphagia, decreased ipsilateral facial sensation, absence of ipsilateral corneal

Fig. 40.11. A CT picture showing primary pontine hemorrhage of bilateral tegmental type.

Fig. 40.12. A CT picture showing primary pontine hemorrhage of basal-tegmental type.

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rarely. The only distinguishing features in these patients with hematomas and lacunar infarcts are the presence of headache or ‘heaviness’ and nausea or vomiting. Patients with unilateral hemorrhages in the basis pontis invariably survive, often with minor residual hemiparesis.

Clinical courses and prognostic assessment

Fig. 40.13. An MRI CT picture showing primary pontine hemorrhage of unilateral tegmental type.

reflex, and bilateral ptosis, may be also associated (Caplan & Goodwin, 1982; Bogousslavsky & Regli, 1984). Ataxia may be present in the unilateral limbs or bilaterally. The clinical features vary depending on the specific locations of the hematomas in the tegmentum. For example, if the hematoma is localized in the paramedian basaltegmental junction and involves the medial lemniscus, it may cause ataxia, dystonic posture, hypesthesia, and abnormalities of stereognosis, two-point discrimination, and ability to localize tactile stimuli in the contralateral side with preserved temperature sensibility (Graveleau et al., 1986). If located in the unilateral dorsal tegmentum involving the paramedian pontine reticular formation (PPRF), one-and-a-half syndrome may develop (Hitchings et al., 1988). The patients with unilateral lateral tegmental hemorrhages often survive without disabling handicaps and have a case survival rate of 94.1% in Chung & Park’s series (1992).

Small unilateral basal type (Fig. 40.14) This type of PPH is uncommon (Silverstein, 1972b) and the clinical features resemble the lacunar syndromes: pure motor hemiplegia with or without dysarthria (Gobernado et al., 1980; Kobatake & Shinohara, 1983; Kameyama et al., 1989) and ataxic hemiparesis or dysarthria–clumsy-hand syndrome (Schnapper, 1982; Tuhrim et al., 1982; Ambrosetto, 1987). Ipsilateral hypesthesia may occur very

Although the survival rate among patients with pontine hemorrhages has improved in general because of improved medical treatment and an increased rate of detection of small benign pontine hemorrhages by CT or MRI. An accurate assessment of clinical courses is critical to establish a reasonable therapeutic approach and to avoid unnecessary interventions. The clinical courses of patients with PPH vary greatly, depending on the initial level of consciousness, the size, location, and extrapontine extent of hematomas, and the development of systemic complications (Caplan & Goodwin, 1982; Masiyama et al., 1985; Kase & Caplan, 1986; Del-Brutto et al., 1987; Chung, 1988; Jeon et al., 1989; Oiwa et al., 1990; Weisberg, 1986; Caplan, 1996). With respect to hematoma size, authors have proposed that the volume, the cross-sectional diameter, and the transverse or vertical length of hematoma are the most critical factors, but the sizes cited have varied (Goto et al., 1980; Chung, 1988; Masiyama et al., 1985; Ochiai et al., 1979). As for extrapontine extension of hematomas, Oiwa et al (1990) found that extension of the hematomas into the cerebellum, the midbrain, or the fourth ventricle, or combined involvement of these structures, correlated with a poor prognosis. In Chung and Park’s study (1992), midbrain involvement and midline crossing of hematoma correlated significantly to the prognosis. Recently Wijdicks and St. Louis (1997) proposed that adverse prognostic factors included: history of hypertension, coma on admission, absent motor response, absent oculocephalic reflexes, absent corneal reflexes, hyperthermia (⬎39 °C), hypertension (MAP ⬎130 mm Hg), tachycardia (⬎110 beats per minute), extension into the midbrain and thalamus, acute hydrocephalus and intraventricular hemorrhage (Wijdicks & St. Louis, 1997).

Treatment Management of PPH is not different from that for other hypertensive intracerebral hemorrhages. Provision of adequate airway clearance and oxygenation, control of intra-

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Fig. 40.14. Axial (a) and sagittal (b) T1 MRI pictures showing primary pontine hemorrhage in the unilateral region of the pons.

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Fig. 40.15. A series of CT pictures showing a primary pontine hemorrhage of basis-tegmental type that were successfully aspirated using stereotactic surgery. (a) Before surgery, (b) immediately after surgery, and (c) 2 weeks after surgery.

cranial pressure by hyperventilation and hyperosmotic agents, control of blood pressure, and prevention of complications are the general rules for medical management. Microneurosurgery and stereotactic procedures have allowed a direct approach to draining deep-seated hemorrhages. There have been case reports discussing successful drainage of pontine hematomas (Murphy, 1972; Cioffi et al., 1981), particularly using stereotactic methods (Fig.

40.15). However surgical management should be reserved only for selected patients. There are reports advocating surgical interventions for selected cases (Koos et al., 1969; Kowada et al., 1972; Viale et al., 1979) but medical management has been as effective in similar cases (Kase et al., 1980; Caplan & Goodwin, 1982; Tuhrim et al., 1982; Masiyama et al., 1985; Kushner & Bressman, 1985; Payne et al., 1978).

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Medullary infarcts and hemorrhages Bo Norrving Department of Neurology, University Hospital, Lund, Sweden

Lateral medullary infarction (LMI) is one of the best-recognized vascular syndromes of the vertebrobasilar territory, comprising about 2% of all admissions for acute stroke (Norrving & Cronqvist, 1991). Medial medullary infarcts (MMI) were previously thought to be very rare, but because they are difficult to diagnose without brain MRI their frequency has likely been underestimated before this technique became available (Kim et al., 1995; Toyoda et al, 1996; Bassetti et al., 1997). Combined medial and lateral infarcts, as well as medullary hemorrhages, are rare types of stroke, reported only as single cases or small patient series (Kase, 1994; Caplan, 1996).

Lateral medullary infarcts (Wallenberg’s syndrome) Mode of onset The onset of a lateral medullary infarction (LMI) is sudden in only about 40% of cases. More often is the course progressive, gradually or stepwise, over a 24–48 h period. Preceeding transient ischemic attacks (TIAs), usually with components of the lateral medullary syndrome, are recorded in about 25% of patients.

Symptoms

Arterial supply of the medulla The main arterial supply to the lateral medullary area is through a number of direct penetrating arteries that originate from the distal vertebral artery (Fig. 41.1). The area is also variably supplied by small branches arising from the the posterior inferior cerebellar artery (PICA), the anterior inferior cerebellar artery (AICA) or the basilar artery (Fisher et al., 1961). A lateral medullary infarct can be caused by occlusion of one or more of these penetrating arteries, most often secondary to occlusion of the vertebral artery. In cases with involvement of the PICA or AICA, a cerebellar infarction in the territory of these arteries may be coexisting, if not spared by means of collateral flow. The dorsal medulla is supplied only by branches from the PICA; a lesion in this area is nearly always accompanied by cerebellar infarction (Escourolle et al., 1976; Hauw et al., 1976). The medial medullary territory is supplied by penetrating arterioles arising from the anterior spinal artery (to the caudal medulla), and the anteromedial arteries from the distal vertebral artery (to the rostral medulla) (Bassetti et al., 1997).

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The frequencies of the main symptoms are shown in Table 41.1, based on data from five large clinical series (Peterman & Siekert, 1960; Currier et al., 1961; Fisher et al., 1961; Norrving & Cronqvist, 1991; Sacco et al., 1993). Ataxia of gait was the most frequent symptom at onset. Clumsiness of ipsilateral limbs is usually noted by the patient, and may be described as ‘weakness’ although no pyramidal-tract signs are detected. The ataxia is usually accompanied by dizziness more often described as ‘swaying’ or feeling ‘sea sick’ than as a ‘spinning’ feeling (Fisher, 1967). Nausea and vomiting are frequently reported, but rarely persist for more than 1–3 days after the onset. Hematemesis can sometimes occur in the acute phase. Visual disturbances are also common, and may be described as difficulty in focusing, blurred vision, diplopia (vertical, horizontal, or oblique), or oscillopsia (a sense of moving objects). More rare, but characteristic for LMI, are episodes of momentary vertical inversion or tilting of images (Bogousslavsky & Meienberg, 1987; Waespe & Wichmann, 1990; Dietrich & Brandt, 1992). Numbness confined to the contralateral limbs, ipsilateral face, or both, may be reported by the patient, who may

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Table 41.1. Frequencies of neurologic symptoms and findings in patients with LMS: mean of five published series Frequency, %

Fig. 41.1. Axial diagram of the medulla: 1: nerve XII nucleus; 2: dorsal vagal nucleus; 3: medial vestibular nucleus; 4: nucleus of the solitary tract; 5: accessory cuneate nucleus; 6: spinal trigeminal nucleus; 7: spinal trigeminal tract; 8: inferior cerebellar peduncle; 9: spinothalamic tract; 10: inferior olivary nucleus; 11: medial lemniscus; 12: corticospinal tract; A: anteromedial arterial territory; B: lateral arterial territory; C: posterior arterial territory; ASA: anterior spinal artery; PICA: posterior inferior cerebellar artery; VA: vertebral artery.

also notice diminished sensation for pain and temperature. However, the sensory disturbance in LMI is heterogenous, and several other patterns have also been observed (see ‘Neurologic findings’, below). Hoarseness of the voice, dysarthria, and dysphagia are common initial symptoms. Dysphagia appears to be more severe in rostral lesions of the lateral medulla (Kim et al., 1994). Hiccups is a significant problem in about 25% of patients, usually developing some time after the onset, and most often resolving within a few days. However, cases with hiccups of longer duration, refractory to therapies used, have been reported. Headache most often is of moderate intensity and is continuous, nonthrobbing, and unilateral. Prominent unilateral occipital headache, especially if preceeding the stroke, should suggest vertebral artery dissection as the underlying arterial lesion (as discussed later). Facial pain, as distinguished from headache, is a most characteristic feature of LMI, when present. The facial pain may be constant or may occur only in brief episodes, and it is usually associated with numbness of the ipsilateral side of the face. Localization of the pain is to the half of the face ipsilateral to the lesion, usually maximum around the eye.

Neurologic symptoms Ataxia Numbness Dysphagia Vertigo Nausea-emesis Dysarthria Headache Diplopia or blurred vision Hoarseness Facial pain Hiccups

84 78 69 60 58 49 44 34 30 25 23

Neurologic findings Pain and temperature hypesthesia Horner’s syndromea Gait and limb ataxiaa Facial hypesthesia Nystagmus Pharyngeal and vocal cord paresisa Facial paresisa

92 89 87 82 78 72 46

Note: a Ipsilateral to the side of the lesion. Source: Peterman & Siekert (1960), Currier et al. (1961), Fisher et al. (1961), Norrving & Cronqvist (1991), Sacco et al. (1993).

Neurologic findings The main findings from the neurologic examination are shown in Table 41.1. Of the seven main signs, Horner’s syndrome, ataxia, and contralateral hypalgesia are the most frequent. However, it needs to be pointed out that, unless paresis of the vocal cord or ipsilateral pharynx (due to involvement of the nucleus ambiguus) is present, the other findings do not unequivocally localize the lesion to the lateral medullary region. Most features of LMI are shared with the lateral inferior pontine syndrome, usually caused by occlusion of small arteries from the AICA or short circumferential arteries. Features characteristic of the lateral inferior pontine, but not of the lateral medullary, syndrome are deafness, tinnitus, massive facial paresis, and multimodal trigeminal sensory involvement. In patients without the latter features, the AICA syndrome, thought to be rare, may be misdiagnosed as ‘atypical’ or partial LMI (Amarenco & Hauw, 1990). Horner’s syndrome ipsilateral to the lesion is due to

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involment of sympathetic fibres which pass through the medullary tegmentum. Nystagmus can vary in amplitude, is usually horizontal and rotatory, and may increase either on ipsilateral or (less commonly) contralateral gaze. Other neuro-ophthalmologic findings are also common in LMI, but can well be overlooked. Skew deviation, with the ipsilateral eye lower, may be related to damage of the otolithic-occulomotor pathways. Hypermetric saccades toward the affected side and hypometric saccades towards the opposite side are common (Bogousslavsky & Meienberg, 1987). The ipsilateral bias of ocular movements helps to explain the findings of ocular lateropulsion, most often seen when the visual fixation is eliminated (Waespe & Wichmann, 1990). Lateropulsion, deviation of the visual vertical, and cyclorotation of the eyes have been attributed to involvement of the vestibulo-ocular reflex pathways (Dietrich & Brandt, 1992). Gait and limb ataxia, with axial lateropulsion and dysmetria ipsilateral to the side of the lesion, can be produced by involvement of the cerebellar pathways or the restiform body or by an associated cerebellar infarction. The latter is present in about 20–25% of patients with LMI, and usually involves the territory of the medial branch of the PICA (Fisher et al., 1961; Amarenco et al., 1990; Norrving & Cronqvist, 1991; Caplan, 1996). It is not possible solely on the basis of the clinical examination to predict whether or not there is an associated cerebellar infarction. Facial hypalgesia ipsilateral to the lesion is due to involvement of the descending tract of the fifth nerve and its nucleus. Most often, sensation is decreased for pain and temperature, but touch may also be diminished. The corneal reflex is lost or severely reduced. LMI extending medially can also affect the ventral trigeminothalamic tract, which contains the crossed fibers from the contralateral spinal trigeminal tract and nucleus, causing facial hypalgesia contralateral to the lesion. A larger lesion involving both far-lateral and medio-lateral medulla may produce bilateral facial hypalgesia (Matsumoto et al., 1988). Pharyngeal paresis and vocal-cord paresis are due to involvement of the nucleus ambiguus in the medullary tegmentum and may be absent from patients with farlateral lesions not extending medially to the nucleus. These signs are of importance because, when present, they unequivocally localize the lesion to the lateral medullary region. Although persistent signs of pharyngeal and vocal cord are common, the symptoms usually resolve (Nelles et al., 1998). Facial weakness is usually mild to moderate. The presence of facial weakness is not easily explained by infarc-

tions of the lateral medullary region, but has been attributed to involvement of an aberrant corticobulbar tract, of corticobulbar fibres being interrupted while they ascend contralaterally after decussating, or of descending extrapyramidal fibres (Caplan, 1996; Terao et al., 1997). Although severe facial weakness may suggest a lateral inferior pontine infarction, slight to moderate facial paresis has been documented in lesions restricted to the lateral medullary region only (Fisher et al., 1961; Sacco et al., 1993; Kim et al., 1994). Decreased pain and temperature sensations in the contralateral trunk and limbs, due to involvement of the lateral spinothalamic tract, are frequent findings, even in those patients who do not report any numbness. Because of a somatotopic arrangement of the spinothalamic tract in the caudal brainstem, other patterns of sensory loss can also be seen, including a sensory level on the trunk, and ipsilateral and crossed patterns (Matsumoto et al., 1988; Kim et al., 1997; Vuadens & Bogousslavsky, 1998). A farlateral lesion can produce a crossed sensory pattern (ispilateral face plus contralateral trunk and lower limb), whereas a mediolateral lesion can produce unilateral sensory loss (contralateral face, trunk, and upper limb) (Matsumoto et al., 1988; Kim et al., 1997). The sensory deficit is one of the most common persisting signs after a LMI, and in some patients central poststroke pain occurs (Leijon, 1988; MacGowan et al., 1997). Not included in Table 41.1 are autonomic and respiratory dysfunctions, because the frequencies of those signs in patients with LMI have not been precisely determined. Case reports have documented the occurrences of dysfunction of the autonomic system (heart rate, blood pressure control) and respiratory regulation (failure of automatic respiration, sleep apnea) in patients with LMI, and such abnormalities may well be more common than is clinically recognized (Caplan et al., 1986; Bogousslavsky et al., 1990; Norrving & Cronqvist, 1991). Hemiparesis ipsilateral to the lesion (Opalski’s syndrome) is very rare and has been attributed to extension of the ischemia into the rostral spinal cord, with involvement of corticospinal fibres caudal to the pyramidal decussation (Dhamoon et al., 1984). The occurrence of hemiplegia contralateral to the lesion indicates a combined lateral and medial medullary syndrome (as discussed later).

Neuroimaging of LMI Computerized tomography (CT) usually fails to identify medullary vascular lesions, but may visualize a coexisting cerebellar infarction. MRI has become the preferred

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method to study LMI, permitting clinico-anatomic correlations (Bogousslavsky et al., 1986; Ross et al., 1986; Sacco et al., 1993; Kim et al., 1994, 1998). Also, MRI helps to localize the infarction to the lateral medullary region, as opposed to the lateral inferior pontine region, which is of importance in cases of partial lateral medullary syndromes (Sacco et al., 1993).

Arterial lesions underlying LMI The most frequent arterial lesion underlying LMIs is occlusion of the vertebral artery (VA), being present in about 75 % of cases (Fisher et al., 1961; Escourolle et al., 1976; Norrving & Cronqvist, 1991; Sacco et al., 1993; Kim et al., 1998). Three-fourths of the VA occlusions are thrombotic, and the remainder are due to cardiac embolism. The VA occlusion extends to block the PICA orifice in about half of the cases, but only rarely is the lesion confined only to the PICA (Fisher et al., 1961). In younger patients, the association of severe headache or neck pain with LMI, especially if the headache precedes other symptoms, should suggest the presence of VA dissection affecting the distal extracranial or intracranial segments (Caplan & Tettenborn, 1992; Kim et al., 1998).

Complications after LMI Although LMI has often been regarded as a benign condition, the outcomes are not uniformly favourable. Possible reasons for poor outcome include a mass effect from a coexisting cerebellar infarction, cardiovascular and respiratory dysfunctions, clot propagation/embolization, and bilateral VA disease (Caplan et al., 1986). In one clinical series, five out of 43 patients (11.6 %) died from respiratory and cardiovascular complications in the acute phase, suggesting that dysfunction of the autonomic system may be more common than is clinically recognized (Norrving & Cronqvist, 1991). Cerebellar infarctions causing brainstem compression, acute hydrocephalus, or herniation may occur (Sypert & Alvord, 1975; Caplan, 1996), but are rare in the setting of a classical LMI, presumably because most often only a small part of the cerebellar hemisphere (corresponding to the medial branch of the PICA) is infarcted (Amarenco et al., 1990; Norrving & Cronqvist, 1991; Caplan, 1996). Artery-to-artery embolism from the VA is a recognized cause of brainstem and occipital lobe infarctions, but in most cases the initial clinical presentation has not been LMI. There have been only four well-documented cases from two series in which LMI due to VA stenosis/occlusion

was later followed by embolism to the territory of the superior cerebellar or posterior cerebral artery (Fisher et al., 1961; Koroshetz & Ropper, 1987). Propagation of a clot from a VA occlusion distally into the basilar artery has been well described in autopsy series, but not clinically. This complication is usually associated with compromised flow in the contralateral VA, in which case the clinical features are rarely confined to the lateral medullary region, but also involve the pons and rostral brain-stem (Caplan, 1996). In clinical series of patients with LMI, the VA disease has been almost exclusively unilateral.

Medial, combined medial and lateral, and bilateral medullary infarcts Before the advent of brain MRI, infarcts of the medial medulla were only verifiable by autopsy, and less than 30 cases were reported in the litterature (Davidson, 1944; Escourolle et al., 1976; Hauw et al., 1976; Sawada et al., 1990). Several recent clinico-anatomical reports using MRI have expanded the knowledge of the associated clinical syndromes, and have shown that the frequency of MMI, although still low, was previously underestimated (Kim et al., 1995; Toyoda et al, 1996; Bassetti et al., 1997). The ‘classical’ triad of MMI (Dejerine’s syndrome) consists of hemiplegia and loss of posterior column sensation on the contralateral side and involvement of the tongue on the ipsilateral side (Ho & Meyer, 1981), due to involvement of the corticospinal tract at the medullary pyramid, the medial lemniscus, and the hypoglossal nucleus or nerve, respectively. However, the clinical picture is not confined to the classical triad but much more heterogenous. The involvement of the tongue or sensory pathways may be lacking, and cases may present with a pure motor hemiparesis (Chokroverty et al., 1975; Roppler et al., 1979) or sensori-motor stroke (Kim et al., 1995; Toyoda et al., 1996; Bassetti et al., 1997), mimicking lacunar infarction from capsular or pontine involvement. In the largest clinical series reported (Kim et al., 1995) a benign sensorimotor syndrome was the most common presentation of MMI. The hemiparesis may be associated with a mild central facial palsy (contralateral to the lesion) in up to half of the cases. Several types of eye movement disturbances (most often upbeat nystagmus) have been reported in MMI, as well as somnolence, dysarthria and truncal lateropulsion. A medullospinal form of MMI, with ipsilateral hemiparesis due to a caudal lesion disrupting the pyramidal tract below the decussation, has also been reported (Kim et al., 1995;

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Toyoda et al., 1996; Bassetti et al., 1997). The clinical features usually evolve gradually, sometimes over several days (Bassetti et al., 1997). Unilateral MMI is due to an occlusion of penetrating branches of the vertebral artery or the anterior spinal artery. The underlying arterial lesion is usually ipsilateral vertebral artery disease, most often atherothrombotic occlusion, whereas dissection, dolichoectasia, embolism, or occlusion of single penetrating branches are less common etiologies (Escourolle et al., 1976; Kim et al., 1995; Toyoda et al., 1996; Bassetti et al., 1997). The medial medullary infarcts may occur combined with the lateral medullary syndrome, simultaneously or consequently, producing the hemimedullary syndrome of Babinski–Nageotte. The combined syndrome is almost invariably caused by vertebral artery occlusion (Fisher et al., 1961). Presumably, the usual origin of the anterior spinal artery from both vertebral arteries explains why features of the medial medullary syndrome are not more frequently seen in cases of LMI (which is most often due to unilateral vertebral artery occlusion). Bilateral infarction of the medial medullary may produce quadriplegia, either isolated (pure motor quadriplegia), or associated with impairment of posterior column sensation and involvement of the tongue (Mizutani et al., 1980; Jagiella & Sung, 1989; Takizawa et al., 1996). Bilateral infarction may be due to occlusion of an anomalous anterior spinal artery arising from one vertebral artery only, or from involvement of the anterior spinal artery after the junction into a single vessel supplying the caudal medulla. The clinical course has included a stepwise progression over several days, and risk of death due to respiratory and circulatory disturbances. In surviving patients, an initially flaccid paresis subsequently becomes spastic, and, as for patients with a unilateral medial medullary infarction, a dense paresis usually remains.

Medullary hemorrhages Medulla oblongata is one of the rarest sites of intracranial hemorrhages. Some of the cases reported have been due to an arteriovenous malformation (Kase, 1994), but spontaneous hemorrhages, with and without hypertension, and bleedings associated with anticoagulant therapy have also been reported (Neumann et al., 1985; Biller et al., 1986; Weisberg et al., 1989; Shuaib, 1991; Barinagarrementeria & Cantú, 1994). Clinical presentation generally results from a combination of the features of the lateral and medial medullary syndromes, with survival and a favourable outcome in most cases.

iReferencesi Amarenco, P. & Hauw, J-J. (1990). Cerebellar infarction in the territory of the anterior and inferior cerebellar artery. A clinicopathological study of 20 cases. Brain, 113, 139–55. Amarenco, P., Roullet, E., Hommel, M., Chaine, P. & Marteau, R. (1990). Infarction in the territory of the medial branch of the posterior inferior cerebellar artery. Journal of Neurology, Neurosurgery and Psychiatry, 53, 731–5. Barinagarrementeria, F. & Cantú, C. (1994). Primary medullary hemorrhage. Report of four cases and review of the literature. Stroke, 25, 1684–7. Bassetti, C., Bogousslavsky, J., Mattle, H. & Bernasconi, A. (1997). Medial medullary stroke: report of seven patients and review of the literature. Neurology, 48, 882–90. Biller, J., Gentry, L.R., Adams Jr, H.P. & Morris, D.C. (1986). Spontaneous hemorrhage in the medulla oblongata: clinical MR correlations. Journal of Computerized Assisted Tomography, 10, 303–6. Bogousslavsky, J. & Meienberg, J. (1987). Eye-movement disorders in brain-stem and cerebellar stroke. Archives of Neurology, 44, 141–7. Bogousslavsky, J., Fox, A.J., Barnett, H.J.M., Hachinski, V.C., Vinitski, S. & Carey, L.S. (1986). Clinico-topographic correlation of small vertebrobasilar infarct using magnetic resonance imaging. Stroke, 17, 929–38. Bogousslavsky, J., Khurana, R., Deruaz, J.P., Hornung, J.P., Regli, F., Janzer, R. & Perret, C. (1990). Respiratory failure and unilateral caudal brainstem infarction. Annals of Neurology, 28, 668–3. Caplan, L.R. (1996). Intracranial vertebral arteries and proximal intracranial territory infarcts. In Posterior Circulation Disease. Clinical Findings, Diagnosis, and Management, ed. L.R. Caplan, pp. 263–323. Cambridge, MA: Blackwell Science. Caplan, L.R & Tettenborn, B. (1992). Vertebrobasilar occlusive disease: review of selected aspects. 1. Spontaneous dissection of extracranial and intracranial posterior circulation arteries. Cerebrovascular Diseases, 2, 256–265. Caplan, L.R., Pessin, M.S., Scott, R.M. & Yarnell, P. (1986). Poor outcome after lateral medullary infarcts. Neurology, 36, 1510–13. Chockroverty, S., Rubino, F.A. & Haller, C. (1975). Pure motor hemiplegia due to pyramidal infarction. Archives of Neurology, 32, 647–8. Currier, R.D., Giles, C.L. & DeJong, R.N. (1961). Some comments on Wallenberg’s lateral medullary syndrome. Neurology, 11, 778–90. Davidson, C (1944). Syndrome of the anterior spinal artery of the medulla oblongata. Journal of Neuropathology and Experimental Neurology, 3, 73–80. Dhamoon, S.K., Iqbal, J. & Collins, G.H. (1984). Ipsilateral hemiplegia and the Wallenberg syndrome. Archives of Neurology, 41, 179–80. Dietrich, D.M. & Brandt, T. (1992). Wallenberg’s syndrome: lateropulsion, cyclorotation, and subjective visual vertical in thirty-six patients. Annals of Neurology, 31, 399–408.

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Escourolle, R., Hauw, J-J., Der Agopian, P. & Trelles, L. (1976). Les infarctus bulbaires. Etude des lésions vasculaires dans 26 observations. Journal of the Neurological Sciences, 28, 103–13. Fisher, C.M. (1967). Vertigo in cerebrovascular disease. Acta Otolaryngologica, 85, 529–34. Fisher, C.M., Karnes, W.E. & Kubik, C.S. (1961). Lateral medullary infarction – the pattern of vascular occlusion. Journal of Neuropathology and Experimental Neurology, 20, 323–79. Hauw, J.J., Der Agopian, P., Trelles, L. & Escourolle, R. (1976). Les infarctus bulbaires: étude systématique de la topographie lésionelle dans 49 cas. Journal of the Neurological Sciences, 82, 83–102. Ho, K.L. & Meyer, K.R. (1981). The medial medullary syndrome. Archives of Neurology, 38, 385–7. Jagiella, W.M. & Sung, J.H. (1989). Bilateral infarction of the medullary pyramids in humans. Neurology, 39, 21–4. Kase, C.S. (1994). Midbrain and medullary hemorrhage. In Intracerebral Hemorrhage, ed. C.S. Kase & L.R. Caplan, pp. 445–63. Boston: Butterworth-Heinemann. Kim, J.S, Lee, J.H., Suh, D.C. & Lee, M.C. (1994). Spectrum of lateral medullary syndrome. Correlation between clinical findings and magnetic resonance imaging in 33 subjects. Stroke, 25, 1405–10. Kim, J.S., Kim, H.G. & Chung, C.S. (1995). Medial medullary syndrome. Report of 18 new patients and a review of the literature. Stroke, 26, 1548–52. Kim, J.S., Lee, J.H. & Lee, M.C. (1997). Patterns of sensory dysfunction in lateral medullary infarction. Clinical–MRI correlation. Neurology, 49, 1557–63. Kim, J.S., Lee, J.H. & Choi, C.G. (1998). Patterns of lateral medullary infarction. Vascular lesion-magnetic resonance imaging correlation of 34 cases. Stroke, 29, 645–52. Koroshetz, W.J. & Ropper, A.H. (1987). Artery-to-artery embolism causing stroke in the posterior circulation. Neurology, 37, 292–6. Leijon, G. (1988). Central post-stroke pain – clinical characteristics, mechanisms and treatment. Linköping University Medical Dissertations, No 281. MacGowan, D.J.L., Janal, M.N., Clark, W.C. et al. (1997). Central poststroke pain and Wallenberg’s lateral medullary infarction: frequency, character, and determinants in 63 patients. Neurology, 49, 120–125. Matsumoto, S., Okuda, B., Imai, T. & Kameyama, M. (1988). A sensory level on the trunk in lower lateral brainstem lesions. Neurology, 38, 1515–19. Mizutani, T., Lewis, R.A. & Gonatas, N.K. (1980). Medial medullary syndrome in a drug abuser. Archives of Neurology, 37, 425–8.

Nelles, G., Contois, K.A., Valente, S.L. et al. (1998). Recovery following lateral medullary infarction. Neurology, 50, 1418–22. Neumann, P.E., Mehler, M.F. & Horoupian, D.S. (1985). Primary medullary hypertensive hemorrhage. Neurology, 35, 925–8. Norrving, B. & Cronqvist, S. (1991). Lateral medullary infarction: prognosis in an unselected series. Neurology, 41, 244–8. Peterman, A.F. & Siekert, R.G. (1960). The lateral medullary (Wallenberg) syndrome: clinical features and prognosis. Medical Clinics of North America, 44, 887–95. Roppler, A.H., Fisher, C.M. & Kleinman, G.M. (1979). Pyramidal infarction in the medulla: A cause of pure motor hemiplegia sparing the face. Neurology, 29, 91–5. Ross, M.A., Biller, J., Adams, H.P. & Dunn, V. (1986). Magnetic resonance imaging of Wallenberg’s lateral medullary syndrome. Stroke, 17, 542–5. Sacco, R.L., Freddo, L., Bello, J.A., Odel, J.G., Onesti, S.T. & Mohr, J.P. (1993). Wallenberg’s lateral medullary syndrome. Clinical-magnetic resonance imaging correlations. Archives of Neurology, 50, 609–14. Shuaib, A. (1991). Benign brainstem hemorrhage. Canadian Journal of the Neurological Sciences, 18, 356–7. Sypert, G. & Alvord, E. (1975). Cerebellar infarction: a clinicopathological study. Archives of Neurology, 32, 357–63. Takizawa, S., Akiyama, K., Takagi, S. & Shinohara, Y. (1996). Bilateral medial medullary infarction: a case report and review of the literature. Cerebrovasc Diseases, 6, 308–12. Terao, S., Takatsu, S., Izumi, M., Mitsuma, T., Takahashi, A., Takeda, A. & Sobue, G. (1997). Central facial weakness due to medial medullary infarction: the course of facial corticobulbar fibres. Journal of Neurology, Neurosurgery and Psychiatry, 63, 391–3. Toyoda, K., Imamura, T., Saku, Y., Oita, J., Ibayashi, S., Minematsu, K., Yamaguchi, T. & Fujishima, M. (1996). Medial medullary infarction: Analyses of eleven patients. Neurology, 47, 1141–7. Vuadens, P. & Bogousslavsky, J. (1998). Face–arm–trunk–leg sensory loss limited to the contralateral side in lateral medullary infarction: a new variant. Journal of Neurology, Neurosurgery and Psychiatry, 65, 255–7. Waespe, W. & Wichmann, W. (1990). Oculomotor disturbances during visual-vestibular interaction in Wallenberg’s lateral medullary syndrome. Brain, 113, 821–46. Weisberg, L.A., Trufant, S., Carballosa, R. & Szanto, E. (1989). Primary medullary hemorrhage. Computerized Medical Imaging and Graphics, 13, 487–90.

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Cerebellar stroke syndromes Pierre Amarenco Neurology Services, Saint-Antoine Hospital, Paris, France

Introduction Early recognition of ischemia in the posterior circulation is important in an era of new therapeutic approaches such as thrombolysis therapy. For a long time, study of the territory of cerebellar infarcts and their related stroke syndromes has been neglected because neuroimaging most often failed to show the infarct and because the sensitivity and specificity of clinical symptoms and signs in diagnosing cerebellar strokes were low. Large cerebellar strokes mimicking posterior fossa tumours have been only diagnosed at surgery by Fairburn and Oliver and Lindgren, then recognized as a clinical entity: the cardinal signs of vertigo, headache, vomiting and gait ataxia became better known to neurologists (Fairburn & Oliver, 1956; Lindgren, 1956; Fisher et al., 1965; Lerich et al., 1970). These reports also emphasized the possibility of pressure effects leading to brainstem compression, hydrocephalus, cardiorespiratory complications and death due to either hemorrhage or edematous infarction (Fisher et al., 1965; Lerich et al., 1970). Later, Duncan et al. reported patients with PICA territory infarcts with mostly vestibular signs (Duncan, et al., 1975), and Sypert and Alvord, in a necropsy study, examined the vascular mechanisms associated with edematous pure cerebellar infarcts sparing the brainstem found at autopsy (Sypert & Alvord, 1975). However, this pseudotumoural form is rare (less than 20% of cases) and, even with CT scan, smaller cerebellar strokes have not been diagnosed. This is in constrast to other posterior circulation strokes presenting with well-defined brainstem and occipital and temporal lobes stroke syndromes. Likewise, diagrams representing the territories of cerebral arteries in anterior and posterior circulation never showed territories of the cerebellum because they simply remained unknown.

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Fig. 42.1. Lateral view of cerebellar arteries. 1: superior cerebellar artery (SCA); 2: medial branch of the SCA; 3: lateral branch of the SCA; 4: anterior inferior cerebellar artery; 5: posterior inferior cerebellar artery (PICA); 6: medial branch of the PICA; 7: lateral branch of the PICA; 8: basilar artery; 9: vertebral artery.

During the last three decades, anatomical studies have described the course and variations of cerebellar arteries and their branches (Lazorthes et al. (1978); Atkinson, 1949; Takahashi et al., 1968; Greitz & Sjögren, 1963). The neuropathological examination of 64 cerebellar infarcts has allowed the description of the territory of the cerebellar arteries and of their main branches (Figs. 42.1, 42.2; Amarenco & Hauw, 1989). The advent of MRI gives us the opportunity to show precisely even small cerebellar strokes (Amarenco et al., 1993), and to define precisely the territory of cerebellar arteries (Amarenco, 1991a,b,c). Newer techniques such as diffusion weighted imaging (Fig. 42.3) show the cerebellar ischemic tissue as early as within 1 hour of

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Fig. 42.2. Anatomical drawings of the territory of branches of the cerebellar arteries as it appears on CT and MRI (modified from Amarenco et al., 1993b).

symptom onset. This has prompted several attempts to better define the cerebellar stroke syndromes (Amarenco, 1991; Kase et al., 1993; Barth et al., 1993; Amarenco et al., 1994; Min et al., 1999; Barinagarrementeria et al., 1997; Tohgi et al., 1993; Canaple & Bogousslavsky, 1999; Chaves et al., 1994). Several large prospective evaluations have now been published (Amarenco et al., 1994; Min et al., 1999; Barinagarrementaria et al., 1997; Tohgi et al. 1993). In this review I will present our current understanding of the territories, related clinical syndromes and causes of PICA, SCA and AICA occlusions and hemorrhages (Table 42.1). Cerebellar infarcts are much more frequent than cerebellar hemorrhages in an autopsy series (85% vs. 15% (Amarenco et al., 1990a); 75% vs. 25% (Duncan et al., 1975)) as well as in a CT series (80% vs. 20%) (Shenkin & Zavala, 1982). They accounted for 1.9% of 1000 consecutive initial strokes in the Lausanne stroke registry, and for 1.5% (Amarenco & Hauw, 1990a,b,c) and 4.2% (Amarenco et al., 1989) in autopsy series. Their prevalence was likely overestimated in earlier CT series, in which cerebellar infarcts accounted for 15% of all cerebral infarcts (Shenkin &

Zavala, 1982; Amarenco et al., 1989). However, they may still be underdiagnosed since, during the CT era, cerebellar infarcts, not detected on clinical grounds, were increasingly demonstrated with CT imaging. A series using DWI is now needed to determine the true prevalence. MRI improves our sensitivity even more in diagnosing these infarcts and hemorrhages (Simmons et al., 1986). Cerebellar infarcts and hemorrhages have clinical features in common. They share the same cardinal symptoms and signs and usually only a CT or MRI scan can make the diagnosis.

Superior cerebellar artery infarcts SCA infarcts are among the most frequent: 33/64 in an autopsy series (Amarenco & Hauw, 1990a), 65% in a CT series (Hinshaw et al., 1980), 30/66 in a clinicoradiologic series (Kase et al., 1993), 35/115 in a clinical MRI series (Amarenco et al., 1994). They are characterized by the rarity of clinical involvement of the brainstem territory of the SCA (i.e. the classic SCA syndrome) (Kase et al., 1993;

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(a )

Fig. 42.3. Diffusion weighted imaging demonstrating a typical mPICA cerebellar infarct (a) and (b) with dorsomedullary involvement (b) 2 hours after the symptoms onset.

Amarenco & Hauw, 1990a), partial cerebellar involvement, and by a benign outcome and cardioembolic cause (Kase et al., 1993; Amarenco et al., 1990a, 1991a,b, 1994; Chaves et al., 1994).

Clinical features Involved territories Infarcts in the full territory of the SCA are usually accompanied by other infarcts in the rostral territory of the basilar artery, involving uni- or bilaterally occipitotemporal lobes, thalamic and subthalamic areas, and the mesencephalon (73% of autopsy cases) (Amarenco & Hauw, 1990a). Some infarcts also involve the ventral aspect of the pons. Some SCA infarcts occur together with PICA and AICA infarcts (one-third of autopsy cases) (Amarenco & Hauw, 1990a). They are frequently edematous infarctions with brainstem compression and tonsillar herniation (Amarenco & Hauw,

1990a,b). Finally, some SCA infarcts occur together with embolic middle cerebral artery infarcts. Although partial territory SCA infarcts can also be associated with other rostral basilar artery infarcts (Amarenco & Hauw, 1990a), they most frequently involve the rostral cerebellum in isolation (Kase et al., 1993; Amarenco et al., 1991b, 1994; Chaves et al., 1994; Struck et al., 1991). The brainstem territory is usually unaffected in these patients. Partial territory infarcts are undoubtedly the most frequent and strikingly differ from infarcts of the full territory by a constant benign outcome (Kase et al., 1993; Amarenco et al., 1991b).

Clinical pictures Six different clinical patterns can be distinguished. (a) The classic SCA syndrome, first described by Mills and Guillain, Bertrand and Péron is exceptional (Kase et al., 1993; Amarenco & Hauw, 1990a) (3% of autopsy cases

Cerebellar stroke syndromes

(b )

Fig. 42.3 (cont.)

(Amarenco & Hauw, 1990a)). It is due to the involvement of the brainstem territory of the SCA. The signs include ipsilateral limb dysmetria, ipsilateral Horner’s syndrome, contralateral temperature and pain sensory loss, and contralateral IVth nerve palsy. Other signs are less frequently reported, such as ipsilateral loss of emotional expression of the face, uni- or bilateral hearing loss (possibly due to involvement of the lateral lemniscus), and sleep disorders (due to locus ceruleus involvement). Ipsilateral abnormal limb movements are a more unusual occurrence. Movements are described as choreiform or athetotic, and consist of slow undulatory movements of large amplitude, appearing with effort, emotion or at rest, being postural and continuous for others. Guillain et al. also noted some unsteadiness of the head. Sometimes, there are coarse tremors. Usually, movement disorders are felt to be due to the involvement of the dentate nucleus or superior cerebellar peduncle. The reason why such a

movement disorder is not found more constantly, despite almost constant superior cerebellar peduncle involvement in SCA infarcts, could be explained by the results of experimental selective sectioning of the superior cerebellar peduncle. When ascending output (upward) projections of the dentate nucleus are cut, tremor results; when descending (downward) projections are sectioned, appendicular ataxia develops. Total section of the superior cerebellar peduncle in the monkey results in hypotonia, ataxia and tremor (for review see Gilman et al., 1981). A few weeks later, palatal myoclonus may occur in the case of dentate nucleus involvement together with contralateral hypertrophy of the inferior olivary nucleus. Palatal myoclonus is sometimes associated with synchronous myoclonic movements of the jaw and face, of the tongue and ipsilateral vocal cord giving voice disorders. One patient with no palatal myoclonus and with myoclonus of the jaw and coarse tremor of the right hand has been reported.

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Table 42.1. Cerebellar stroke syndromes Location of Cerebellar Infarct

Associated Infarcts

Clinical Syndrome

Rostral (SCA)

Mesencephallum, subthalamic area, thalamus, occipitotemporal lobes

Rostral basilar artery syndrome or coma from onset⫾tetraplegia

Laterotegmental area of the upper pons

Dysmetria and Horner’s syndrome (ipsilateral), temperature and pain sensory loss and IVth nerve palsy (contralateral) Dysarthria, headache, dizziness, vomiting, ataxia and delayed coma (pseudotumoural form)

dorsomedial (mSCA)

Dysarthria ataxia

ventrolateral (lSCA)

Dysmetria, axial lateropulsion (ipsilateral), ataxia and dysarthria

Medial (AICA)

Lateral area of the lower pons

VII, V, VIII, Horner’s syndrome, dysmetria (ipsilateral), temperature and pain sensory loss (contralateral) Pure vestibular syndrome Vertigo, headache, vomiting, ataxia, and delayed coma (pseudotumoural form)

Caudal (PICA) dorsomedial (mPICA)

Dorsolateromedullary area

Wallenberg’s syndrome Isolated vertigo or vertigo with dysmetria and axial lateropulsion (ipsilateral) and ataxia

Ventrolateral (lPICA) Caudal and medial

Vertigo, ipsilateral limb dysmetria AICA syndrome⫾delayed coma (pseudotumoural form) Lateral area of the lower pons and/or lateromedullary area

Vertigo, vomiting, headache, ataxia, dysarthria and delayed coma (pseudotumoural form) Coma from onset⫾tetraplegia

Rostrocaudal Brainstem, thalamus, occipitotemporal lobes

(b) The rostral basilar artery syndrome is the most striking clinical presentation in autopsy series (25% of cases) as well as in clinical practice (Amarenco & Hauw, 1990a). The presenting signs are visual field defects, vomiting, dizziness, diplopia, paresthesia, clumsiness of limbs, motor weakness, and drowsiness. The signs indicate occipitotemporal lobe involvement (cortical blindness or hemianopia, memory loss or confusion, Balint’s syndrome), thalamomesencephalic involvement (multimodal sensory loss, contralateral Horner’s syndrome, ipsilateral hemianopia, appendicular ataxia or pendular reflexes, including the Dejerine Roussy syndrome; behavioural changes, abulia, unilateral spatial neglect, memory loss, transcortical

motor aphasia; vertical gaze palsy) subthalamic involvement (hemiballism), mesencephalic involvement (third nerve palsy isolated or plus contralateral movement disorders of limbs (Benedikt’s syndrome), or plus contralateral dysmetria of limbs (Claude’s syndrome), or plus contralateral motor weakness (Weber’s syndrome); vertical gaze paresis (Parinaud’s syndrome); pseudo-sixth nerve palsy; tonic deviation of gaze; palpebral retraction; pupil disorders; drowsiness, hallucinosis, confusion). Other signs include ipsilateral Horner’s syndrome, dysmetria of limbs, hemiplegia, contralateral temperature and pain sensory loss, internuclear ophthalmoplegia. Usually, only a combination of two or three of these signs of the rostral basilar

Cerebellar stroke syndromes

artery syndrome are present. In these circumstances, the SCA involvement is frequently difficult to recognize or is unexpectedly discovered on CT (Amarenco & Hauw, 1990a). (c) Coma from onset, together with tetraplegia and oculomotor palsy, is another frequent clinical finding in autopsy series (33% of cases). It is due to sudden embolic occlusion of the rostral end of the basilar artery (Amarenco & Hauw, 1990a). (d) SCA involvement can be absolutely hidden by simultaneous embolic infarction in the internal carotid artery territory with brachiofacial sensory motor hemiplegia and aphasia. This occurred in 9% of autopsy cases (Amarenco & Hauw, 1990a) in association with a cardiac source of embolism. Occasionally, this also occurs in occlusions of the inominate artery with intra-arterial embolism to the right MCA and embolism through the vertebral artery to the SCA. (e) Cerebellovestibular signs are the prominent clinical presentation in clinical series (Kase et al., 1993; Amarenco et al., 1991b, 1994; Chaves et al., 1994; Struck et al., 1991), due to partial SCA territory involvement (Fig. 42.2a, b, c). Symptoms are mainly headache and gait ataxia and, in about 35% of cases, dizziness and vomiting (Kase et al., 1993; Struck et al., 1991). The patients most often presented with appendicular (73%) and gait ataxia (67%), nystagmus (50%), and brainstem signs (30%) in a series of 30 unilateral isolated infarct of the SCA documented by CT (Kase et al., 1993). Nystagmus is horizontal and ipsilateral in 20% of cases, horizontal and contralateral in 3% of cases, horizontal bilateral in 20%, and vertical in 7% (Kase et al., 1993). In a non-selected CT series of 17 SCA infarcts, there were 15/17 with limb ataxia, 12/17 had truncal ataxia and dysarthria (Struck et al., 1991). Dysarthria is one of the main symptoms in SCA infarcts and seems to be the counterpart of vertigo for PICA infarcts (Amarenco et al., 1991a,b). Hemiparesis occurred in almost a quarter of cases (Struck et al., 1991). (f) The LSCA syndrome has been described recently (Amarenco et al., 1991a,b). It is due to anterior rostral cerebellar involvement (Fig. 42.2), includes dysmetria of arm and leg and ipsilateral axial lateropulsion, dysarthria, and unsteadiness (Amarenco et al., 1991b). The findings can mimic the dysarthria-clumsy-hand lacunar syndrome, present with isolated axial lateropulsion, and be characterized by dysmetria, nystagmus, or contrapulsion of saccades. Since our description of nine cases (Amarenco & Hauw, 1990a), we further observed ten new cases of lSCA infarct (Amarenco et al., 1994). Nine had the same presentation as previously described. The remaining patient had no clinical signs.

(g) Clinical syndromes due to dorso-medial infarct of the rostral cerebellum, in the territory of the mSCA, have not been fully analysed, although some single cases have been reported. When the most medial branches were involved, isolated unsteadiness of gait was found (Kase et al., 1985). When the anterior cerebellar lobe (i.e. the lingula, central, culmen lobules of the vermis and the anterior lobule of the hemisphere) are involved, slight appendicular ataxia and spontaneous posturing of the neck, trunk and all four extremities are found (Ringer & Culberson, 1989). When more lateral branches are involved, in the paravermal territory, isolated dysarthria is found (Amarenco et al., 1991a). Lechtenberg and Gilman showed that the paravermal zone of the left rostral cerebellum was the most frequently damaged in 31 cases with cerebellar dysarthria and nondegenerative cerebellar disease. However, there was no case of pure dysarthria and a cerebellar infarct. The report of a lone infarct of this area (Amarenco et al., 1991a) shows that this paravermal zone is involved in the control of the tone of the voice, and that dysarthria should be one of the main features of mSCA infarcts. In our six consecutive patients with mSCA infarcts (Table 42.1), two had pure dysarthria, one had dysarthria and ipsilateral limb clumsiness, one had dysarthria and other supratentorial signs, one had pure dysmetria and the sixth had dysmetria together with a classic SCA syndrome.

Course SCA infarcts may have a pseudotumoural presentation (see below), a finding in 21% of autopsy cases (Amarenco & Hauw, 1990a). Since clinicoanatomical correlations from autopsy studies are based on the most severe cases, the course and outcome of SCA infarcts are best evaluated by CT and MRI series. When the CT lesion is limited to the SCA territory, 93% of patients have partial SCA involvement. They have a benign outcome and are minimally disabled or neurologically intact (93% of the cases) (Kase et al., 1993). Only 7% of patients (2/30) had the pseudotumoural clinical pattern leading to coma and one patient died. A similar benign course is observed in lSCA infarcts as well as in mSCA infarcts.

Causes Arterial occlusions, when found, mainly involve the distal basilar artery, the intracranial vertebral artery, and less frequently the SCA, in autopsy as well as in clinical series (Kase et al., 1993; Amarenco et al., 1990a,b,c; Amarenco & Hauw, 1990a; Struck et al., 1991). However, in most patients in these series no arterial occlusion is found since it has

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moved on or lysed by the time of the angiography or postmortem examination. Thus, the frequency of occlusion of the SCA could be underestimated. Every autopsy and clinical series emphasizes cardiac embolism as the most common cause of SCA infarcts, whatever the extent of the infarct (Kase et al., 1993; Amarenco et al., 1990a, 1991b; Amarenco & Hauw, 1990a; Struck et al., 1991). Cardiac sources of emboli are observed in 35% (Struck et al., 1991), 40% (Amarenco et al., 1994), 61% (Kase et al., 1993), and 70% of cases (Amarenco & Hauw, 1990a). Sometimes the responsible stroke mechanism is artery-to-artery embolism either atherosclerotic, from vertebral artery occlusion, or ulcerated plaques in the aortic arch (Kase et al., 1993; Amarenco et al., 1990a, 1994; Struck et al., 1991), or from vertebral artery dissection. Atherosclerotic occlusion occurs in 17% (Amarenco et al., 1994) to 30% of the cases (Kase et al., 1993; Amarenco & Hauw, 1990a). In the young, rare causes are superior cerebellar artery dissection and fibromuscular dysplasia, migraine and transcardiac embolism via a patent foramen ovale at the time of Valsalva’s maneuver.

Anterior inferior cerebellar artery infarcts These are considered exceedingly rare infarcts, but may be underdiagnosed (Amarenco & Hauw, 1990c). MRI reveals a higher frequency than is usually believed (Fig. 42.2c, d, e, f ) (Amarenco et al., 1993a,b,c). This pontocerebellar infarct strikingly differs from SCA and PICA infarcts by the almost constant brainstem signs that feature the clinical presentation. This complex syndrome also frequently heralds a dramatic basilar artery occlusion and extensive brainstem infarct, therefore its recognition is important to the clinician to urgently plan intra-arterial thrombolysis in that circumstance.

Clinical features Involved territories (Amarenco & Hauw, 1990c) Most AICA infarcts involve a small territory usually restricted to the lateral region of the caudal pons and, in the cerebellum, to the middle cerebellar peduncle (100% of cases) and flocculus (69% of cases). Involvement of these regions explains the usual clinical signs. Infarcts often also affect other cerebellar lobules (75% of cases) but usually remain limited (small). Infarcts often involve a small part of the cerebellum comprising the central white-matter, the flocculus and a thin rim of cerebellar cortex located at the junction of the territories of the three cerebellar arteries but this involvement does not modify the clinical presen-

tation. When the AICA is larger (and the PICA is hypoplastic) the AICA territory encompasses the whole anterior inferior cerebellum, and there are yet no significant clinical differences from smaller infarcts, even in those cases where AICA and PICA arise from a common trunk from the vertebral or basilar arteries. In most infarcts, the inferolateral pontine territory is involved, the infarction sometimes extending up to the middle third of the lateral pons and down to the superior part of the lateral medulla. It involves neither the upper third of the lateral pons (which is supplied by the superior lateral pontine artery, a branch of the basilar artery or of the mSCA), nor the ventral aspect of the pons. AICA territory infarcts are sometimes associated with PICA and SCA infarcts (35% of autopsy cases), and, in this circumstance, there is frequently massive ventromedian pontine infarction and tonsillar herniation. Other partial AICA infarcts involve at least the middle cerebellar peduncle which is the core of the AICA territory.

Clinical pictures (Amarenco & Hauw, 1990c; Amarenco et al., 1993a,b,c) Four different clinical pictures can be distinguished. (a) The classic syndrome of the AICA, first reported by Adams in 1943 in one case and in detail by Amarenco and Hauw (1990c) in 20 clinicopathologic cases, is by far the most frequent. Symptoms are vertigo, vomiting, tinnitus and dysarthria. The signs include ipsilateral facial palsy, hearing loss, trigeminal sensory loss, Horner’s syndrome, appendicular dysmetria, and, on the opposite side, temperature and pain sensory loss of limbs and trunk. Finally, the AICA syndrome can include ipsilateral conjugate lateral gaze palsy (due to the floccular involvement rather than that of abducens nucleus), dysphagia (due to extension of the infarct to the superior part of the lateral medulla), and ipsilateral limb motor weakness (due to contralateral involvement of the corticospinal tract in the pons or mesencephalon). Because the signs are crossed, the lesion is often misdiagnosed as lateral medullary infarction (Wallenberg’s syndrome) because of some similar signs. However, signs unusual in Wallenberg’s syndrome such as severe facial palsy, deafness, tinnitus and multimodal sensory impairment of the face allow accurate clinicotopographic diagnosis. A complete AICA syndrome is observed in 30% of autopsy cases, an almost complete syndrome in 35%, and an incomplete syndrome in 10%. Motor weakness of the limbs is found in half the cases. (b) Coma from onset with tetraplegia occurs in 20% of autopsy cases. It is due to massive ventromedial involvement of the basis pontis together with cerebellar infarction in the territory of the three cerebellar arteries.

Cerebellar stroke syndromes

(c) Isolated vertigo, mimicking a labyrinthitis, may occasionally occur in partial AICA territory infarcts (Amarenco et al., 1990b). (d) AICA territory infarcts can also cause isolated cerebellar signs, as was demonstrated by a clinico-MRI report in a child (Philips et al., 1988).

Course Although the majority of cases were autopsy reports, AICA infarcts may have a better outcome than can be predicted from the literature. Most of the reported cases died from remote complications such as pulmonary embolism and infections, and clinical-MRI patients had benign outcomes with minimal residual neurological signs (Amarenco et al., 1993c). However, in some cases, AICA territory infarcts may herald massive basilar artery thrombosis (Amarenco et al., 1993a).

Cause The arterial occlusion usually involves the lower basilar artery and less frequently the end of the vertebral artery above the PICA ostium at postmortem examination. In many cases, there have been associated anomalies of the vertebrobasilar system such as a hypoplastic vertebral artery, dolichoectatic basilar artery, or patent trigeminal artery. The mechanism is mostly atherosclerotic occlusion. Only one case of presumed embolic occlusion from mitral stenosis and atrial fibrillation was reported. Pure AICA infarcts are usually due to basilar branch occlusion. Plaques in the main basilar artery extent into AICA or microatheromata block the AICA origin. Some of these patients have been diabetic. Patients with AICA plus infarcts mainly have proximal basilar artery occlusion. Cases associated with migraine have been reported.

Posterior inferior cerebellar artery infarcts These infarcts have been the most studied and reported, by far, to be the most frequent of cerebellar infarcts. Nevertheless, recent clinicopathologic and clinicoradiological series showed they are as frequent as SCA infarcts (Kase et al., 1993; Barth et al., 1993; Amarenco et al., 1989, 1994; Hinshaw et al., 1980). In 64 autopsy cases, 10 of which involved both PICA and SCA territories, there were 28 PICA vs. 33 SCA infarcts (Amarenco et al., 1989)). In 66 isolated unilateral cerebellar infarcts there were 36 PICA vs. 30 SCA infarcts (Kase et al., 1993). Macdonell et al. (1987) found 7 PICA infarcts in 19 autopsy cases of cerebellar infarcts, and

Hinshaw et al. (1980) 29% in 42 radiological cases of cerebellar infarcts. In our prospective series, they accounted for 35% of cases (Amarenco et al., 1994). PICA infarcts were historically, and partly erroneously, linked to lateral medullary infarcts (i.e. Wallenberg’s syndrome). After the anatomical descriptions of Duret in 1873 where only PICA supplied the lateral region of the medulla, and after Wallenberg’s description of a case of lateral medullary infarct due to PICA occlusion, every lateral medullary infarct was assumed to be due to PICA occlusion even when the occlusion was not demonstrated. Subsequently lateral medullary syndrome was confused with the PICA syndrome (for review see Amarenco et al., 1993a). However, further studies, mainly by Miller Fisher and his colleagues, showed that the lateral region of the medulla is mainly supplied by three or four small direct branches arising from the termination of the vertebral artery between the PICA ostium and origin of the basilar artery, and less frequently by small branches arising from the PICA. Krayenbull and Yasargil estimated that PICA participated in the supply of this region in up to 22% of individuals. Consequently, PICA infarcts sparing the lateral medullary territory are the most frequent and, paradoxically, syndromes featuring these infarcts were only described during the last 15 years since Duncan, Parker, and Fisher’s paper which emphasized the frequency of vertigo as the prominent presenting symptom (Duncan et al., 1975).

Clinical aspects Involved territories Two different clinical situations occur depending on whether the medulla is involved or not. In an autopsy series, the medulla was involved in its dorsolateral aspects in one-third of cases (Amarenco et al., 1989). No lateral medullary infarction was seen without associated infarction in the dorsal medullary territory. PICA infarcts are much less frequently associated with other vertebrobasilar (pontine, mesencephalic, thalamic or occipitotemporal) infarcts than AICA or SCA infarcts. The full PICA territory is involved in isolation in only 7% of autopsy cases and is much more frequently associated with SCA, AICA infarcts, or both (46%), being then frequently edematous infarcts with brainstem compression. Partial PICA territory infarcts (Fig. 42.2) are very frequent in autopsy series (46%), involving mainly the dorsomedial area of the caudal cerebellum, that is, the territory of the mPICA (32%), and less frequently the lateral area, that is, the territory of the lPICA (18%) (Amarenco et al., 1989). They represent 75% of PICA infarcts in a clinical series (Kase et al., 1993). These partial

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infarcts (Fig. 42.2 (d)(e)(f ) are never edematous. Thus, when restricted to the PICA territory, they are often small in size and benign in course (Kase et al., 1993). In a clinical series only one-quarter of 36 patients had signs of brainstem compression (all of these had full PICA territory infarct), one-fifth had obstructive hydrocephalus, and one-ninth died from cerebellar swelling (Kase et al., 1993). There are no clinically significant differences between full PICA and mPICA territory lesions (Amarenco et al., 1990c).

Clinical features Several clinical syndromes can be distinguished. (a) The dorsal lateral medullary syndrome occurred in 25% of autopsy cases of PICA territory infarcts (Amarenco et al., 1989) and in one-third of patients in a clinical series of 36 PICA infarcts (Kase et al., 1993). Conversely, since dorsal medullary infarcts are almost constantly associated with PICA infarcts and since 13% of lateral medullary infarcts occur together with dorsal medullary infarcts, it is estimated that there is a PICA territory cerebellar infarct in 13% of cases of lateromedullary infarcts (Amarenco et al., 1989). Wallenberg’s syndrome can be complete or not, including vertigo, nystagmus, Vth, IXth, Xth cranial nerve palsies, ipsilateral Horner’s syndrome, appendicular ataxia and contralateral temperature and pain sensory loss. (b) When PICA territory infarcts spare the medulla, they mainly present with vertigo, headache, gait ataxia, appendicular ataxia, and horizontal nystagmus (Kase et al., 1993; Ho et al., 1981; Tomaszek & Rosner, 1985). Headache is cervical, occipital, or both plus occasional periauricular or hemifacial-ocular radiation. Unilateral headaches are ipsilateral to the cerebellar infarction (Kase et al., 1993). Nystagmus is the most frequent sign (75%) either horizontal (ipsilateral in 47% of patients, contralateral in 5%, bilateral in 11%) or vertical (11% of patients) (Kase et al., 1993). In addition to vertigo, one of the most striking findings in PICA infarcts is ipsilateral axial lateropulsion (Amarenco, 1991) as if there was a lateral projection of the central representation of the centre of gravity. This sign is totally different from lateral deviation of the limbs (i.e. past-pointing) and gait veering. We found this sign in 26% of our 115 patients in which data were prospectively collected (Amarenco et al., 1994), in 53% of the 38 isolated PICA infarcts, and in 65% of the 20 mPICA infarcts (Table 42.1, the series includes now 126 patients). Kase et al also frequently noted that attempts at standing or walking led to falling towards the side of the cerebellar infarction (Kase et al., 1993). In one-quarter of patients, there were signs of brainstem compression such as drowsiness, lateral gaze palsy, followed by progressive coma (Kase et al, 1993).

(c) the isolated acute vertigo form, mimicking labyrinthitis, was first clinicopathologically described by Duncan, Parker and Fisher in a patient who died from an acute myocardial infarction 3 weeks after the onset of vertigo (Duncan et al., 1975). The autopsy showed a recent medial and caudal cerebellar infarct with no other brain lesions. Subsequently, several convincing clinical cases were reported (Guiang & Ellington, 1977; Freely, 1979; Huang & Yu, 1985). We and others added a second autopsy case (Amarenco et al., 1989). MRI has shown the high frequency of such infarcts (Amarenco et al., 1994), which should be sought when there are vascular risk factors in patients older than 50, or in circumstances supporting a vascular mechanism in the young. Normal caloric responses and direction-changing nystagmus on gaze to each side, or after changing of head posture, or lying down, are two other signs which can suggest a ‘pure’ vestibular syndrome in a patient with a PICA territory infarct (Amarenco et al., 1989). Vertigo is explained by involvement of the uvulonodular complex of the vermis, which is part of the vestibular portion of the cerebellum. Since the nodulus is supplied by the PICA and the flocculus by the AICA, these infarcts should not be called ‘flocculo-nodular infarcts’. (d) PICA territory infarcts in association with AICA or SCA infarcts are much more severe in clinical presentation (Amarenco et al., 1989), and they often present with a pseudotumoural pattern or deep coma with tetraplegia. (e) Syndromes of the mPICA (Amarenco et al., 1990c). MRI now often shows this type of infarction. As we have shown on pathologic sections of the cerebellum (Amarenco & Hauw, 1989; Amarenco, 1991; Amarenco et al., 1989), mPICA infarcts appear on T2-weighted MRI axial sections as an increased signal in a triangular zone, dorsomedial, with dorsal base and ventral top directed toward the fourth ventricle. Infarcts of the medial branch may be clinically silent (Amarenco et al., 1989, 1990c) or present with three main patterns: (i) isolated vertigo, often misdiagnosed as labyrinthitis; (ii) vertigo together with ipsilateral axial lateropulsion of the trunk and gaze (Amarenco et al., 1994), and dysmetria or unsteadiness; (iii) Wallenberg’s syndrome when the medulla is also involved. By contrast with lPICA, only the mPICA may give rise to rami to the dorsolateral aspect of the medulla. (f) Up to now, infarcts in the territory of the lateral branch of the PICA have been chance autopsy findings with no available clinical information (Amarenco et al., 1989). Clinical manifestations of infarcts of the lateral branch of the PICA have been recently described (Amarenco et al., 1993a; Barth et al., 1994). In our series of five patients, it presented mainly with vertigo and ipsilateral dysmetria (Amarenco et al., 1994).

Cerebellar stroke syndromes

Course Recent clinical series showed that PICA infarcts have a much more benign outcome than is usually believed (Kase et al., 1993; Chaves et al., 1994). Sypert and Alvord’s autopsy series emphasized the high incidence of brainstem compression and tonsillar herniation in acute PICA infarcts (Sypert & Alvord, 1975). However, 46% of cerebellar infarcts in this series were not acute cases and were separately analysed: they were all clinically undiagnosed (Sypert & Alvord, 1975). Kase et al. found signs of brainstem compression in one-quarter of patients (all of whom had full PICA territory infarcts), acute hydrocephalus in one-fifth, and only oneninth patients died from cerebellar swelling (Kase et al., 1993). The majority of PICA territory infarcts are partial territory infarcts and have a benign course (Kase et al., 1993).

Cause The arterial occlusion mainly involves the intracranial portion of the vertebral artery facing the PICA ostium and the origin of the PICA. The mechanisms of occlusion are equally divided into cardioembolic and atherosclerotic causes (Amarenco et al., 1989; Kase et al., 1993). Other mechanisms are vertebral artery dissection (Kase et al., 1993), ulcerated plaques in the aortic arch (Amarenco et al., 1990a), and occlusion of the mPICA by tonsillar herniation due to raised posterior fossa pressure (Amarenco & Hauw, 1990b).

Multiple posterior circulation infarcts Basilar artery occlusion often accompanies intracranial vertebral artery occlusion either on one or both sides with PICA, AICA, SCA or PCA occlusion due to blockage of their origin by the occlusive thrombus in the parental artery or due to artery-to-artery embolism. Patients with occlusion of the intracranial vertebral arteries (ICVAs) and basilar artery and patients with large emboli often have infarcts in multiple cerebellar artery territories. Penetrator branches at various levels, i.e. pontine, midbrain or thalamosubthalamic level, may also be occluded. Massive multiple infarction may occur when there is no collateral anastomosis involving mainly the cerebellum, ventromedial pons and midbrain, thalamus and occipitotemporal lobes. In our pathological series of 64 patients with cerebellar infarction, 13 had cerebellar infarction extended to the territory of more than one artery. These large infarcts all involved the PICA territory (four bilaterally) together with the SCA territory in ten cases (three bilaterally) and AICA

territory in seven cases (one bilaterally). The full territory of these arteries was usually affected giving rise to mass effect on the brainstem and tonsillar herniation. They were associated with massive bilateral paramedian pontine infarction in half the patients and were due to basilar artery occlusion in three patients involving either the entire BA or the upper BA with vertebral artery occlusion facing the PICA ostium or below it in the three patients; four patients had unilateral vertebral artery occlusion at the PICA ostium, one of whom had a vertebral artery occlusion blocking a common trunk of PICA and AICA; two patients had bilateral vertebral artery occlusions, below the PICA ostia, one of whom had artery-to-artery emboli in one PICA and one PCA; five patients had no occlusion at postmortem examination, two of whom had postangiographic dissection without occlusion and three others had a cardiac source of embolism. These patients all had signs of massive brainstem infarction, and of edematous cerebellar infarction in 70% of cases (Amarenco et al., 1989; Amarenco & Hauw, 1990c; Caplan, 1996). In a clinical series of patients with territorial and small non-territorial infarcts diagnosed with MRI in most cases, Amarenco and colleagues included four patients with PICA ⫹SCA infarcts; one was attributed to cardiac embolism, one to ECVA dissection, one to ICVA occlusive disease and one had no recognized cause.16 They also included in this series one patient with PICA⫹AICA⫹SCA infarction who had severe basilar artery disease. Among the clinical series of Tohgi et al. (1993), there were eight patients with PICA⫹ AICA⫹SCA infarcts who had angiography; seven severe vertebral artery occlusive lesions and four basilar artery occlusive lesions were found at angiography among these eight patients. In the NEMC registry, 37 of the 84 patients (44%) had multiple territory cerebellar infarcts (Caplan, 1996). Others had cerebellar infarcts in one territory but brainstem infarcts in other intracranial territories. The clinical findings can best be thought of as an addition of the findings in each territory. The additional mass of cerebellar infarction has the potential to cause more mass effect than cerebellar infarcts limited to one territory, especially if the full PICA and/or SCA territory is included in the lesion. The multiple territory cerebellar infarcts in the NEMC registry seemed to fall into two groups: those that involved proximal and distal intracranial territories (PICA and SCA), and those that included the middle intracranial territory (PICA and AICA, AICA and SCA, and PICA, AICA, and SCA). The latter group we referred to as middle⫹ territory infarcts. The stroke mechanisms underlying the middle⫹ territory infarcts seemed to be very similar no matter what the configuration of lesions (Prox⫹Mid, Mid⫹Dist, Prox⫹

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Mid⫹Dist). Embolism was the predominant stroke mechanism in patients with proximal and distal territory cerebellar infarction. At times, the infarcts were limited to PICA and SCA cerebellum. The vascular lesion when present was always on the side of the PICA territory infarct since the ECVA and ICVA supply only the ipsilateral PICA but can be the source of embolism to both SCA territories. One patient with severe bilateral ICVA and basilar artery stenosis had bilateral PICA and SCA territory cerebellar infarcts. In most patients, the infarcts also included other non-cerebellar structures within the proximal or distal intracranial territories, for example, the medulla, midbrain, thalamus, and PCA hemispheral regions. Within the proximal⫹distal group intra-arterial emboli arose from the ECVA in eight patients. Five had VAO disease (three severe atherostenosis, two VAO occlusions), two had ECVA dissections, and one patient had an angiographic complication. Cardiac sources of emboli were cardiomyopathy in two patients, and atrial fibrillation, valvular disease, and PFO in one patient each. All of the patients with large artery intracranial occlusive disease had severe ICVA disease, bilateral in four patients and at the ICVA/basilar artery junction in the other patient. The pattern in which ICVA lesions caused local proximal territory (medullary and/or PICA cerebellar) ischemia by hypoperfusion and in addition served as a donor source of embolism to the distal intracranial territory has been discussed in the section on occlusion of the intracranial vertebral artery. In patients with emboli that arose from the heart or ECVAs, the emboli presumably first stopped at the ICVA and then traveled distally, or a part of the embolus broke off and reached the SCA-distal basilar artery region. In contrast to the proximal⫹distal territory group of patients with multiple territory infarcts, when the middle territory was involved, the most common cause was large artery intracranial occlusive disease. Ten of the 12 patients with intracranial occlusive disease had severe basilar artery occlusive disease, accompanied by ICVA disease in seven patients. Embolism was a less common cause occurring in about one-third of patients. Two patients had only potential cardiac sources of embolism in the form of atrial fibrillation; two had only intra-arterial sources (ECVA dissection and angiographic complication), and two patients had both potential cardiac and arterial sources – atrial fibrillation and VAO occlusion in one patient, and ECVA dissection and a PFO in the other patient. One patient had severe, presumably migraine-related vasospasm of both ICVAs and the basilar artery. Basilar artery lesions are more often due to in-situ occlusive disease of the basilar artery itself or to propagation of

thrombus from the ICVA. ICVA and basilar artery occlusive disease often coexist. Since middle territory⫹infarcts, by definition, must have at some time been related to decreased basilar artery perfusion, the mechanisms of infarction are very similar to those found in patients with basilar artery territory ischemia. In contrast, proximal and distal territory infarcts spare the basilar artery but involve the ICVA supply zone. Their etiology is similar to that found in patients with ICVA disease.

Border-zone cerebellar infarcts Defined as infarcts involving only border-zone territories, watershed cerebellar infarcts were believed rare (Macdonell et al., 1987; Rodda, 1971; Savoiardo et al., 1989). Border zone infarcts, which are small infarcts ⬍2 cm in diameter (Amarenco et al., 1990a, 1993a,b,c, 1994), might have been underestimated by pathologic studies which selected only cerebellar infarcts ⬎2 cm. Modern neuroimaging shows very small ischemic lesions in the cerebellum (Amarenco et al., 1993b, 1994). They are located in boundary zones between the SCA and PICA or between left and right SCAs on the cortex (Macdonell et al., 1987; Rodda, 1971, Amarenco et al., 1993b, 1994), and between SCA and PICA in the deep cerebellar white-matter (Savoiardo et al., 1989). In a recent large clinical series, 57% of these lesions were due to a focal hypoperfusion resulting from a severe occlusive disease of the vertebral or basilar arteries, either atherosclerotic (34%) or cardioembolic (23%), 19% were due to end (pial) artery disease (intracranial atheroma, hypercoagulable state or arteritis), 4% were due to global hypoperfusion resulting from a cardiac arrest, and 19% were of unknown mechanism (Amarenco et al., 1993).

Clinical aspects Involved territory (Amarenco et al., 1993b) The location of very small cerebellar infarcts can be divided into three groups. Cortical border-zone infarcts are in a parallel direction with the penetrator branches which are perpendicular to the cortex. According to Duvernoy, these branches have no anastomoses between each other. These cortical infarcts are the most frequent and located at the boundary zones between SCA and PICA territories, corresponding to the AICA-PICA, mPICA-lPICA, mPICA-SCA, and mSCA-lSCA border-zones. Other border-zone infarcts involved the medial rostral cerebellum between the right and left SCA territories.

Cerebellar stroke syndromes

Very small deep infarcts are in the deep watershed territory as defined by Savoiardo et al. (1987), but in a more restricted area, usually limited to a small hole outside the dentate nucleus. The infarcts involve usually the caudal cerebellum, and are located at the deep boundary zones of the AICA, lPICA, mPICA, lSCA, and mSCA territories. SCA branches that reach the deep territory of the cerebellum are long branches arising from mSCA or lSCA. They follow the superior cerebellar peduncle reaching the dentate nucleus. These arteries supply the dentate nucleus area and they anastomose with superficial branches penetrating the cortex perpendicularly. Few cortical dorsal border-zone infarcts between PICA and SCA differ from other borderzone infarcts which are perpendicular to the cortex by their strict cortical and superficial location along the boundary zone between cortical superficial branches of the SCA and PICA. They were rarely found, probably because of the abundance of anastomoses in this area. On the other hand, the lack of anastomoses between perpendicular penetrator arteries directed from the cortex to the deep white-matter allows for the more frequent observation of borderzone infarcts perpendicular to the cortex.

Clinical picture (Amarenco et al., 1993b, 1994) Clinically, border-zone infarcts do not differ from territorial infarcts, but some of these patients have transient loss of consciousness, postural trunk or head position-related symptoms for days, weeks, months or years before or after the infarct. These consisted of lightheadedness, pitching sensations, vertigo, disequilibrium, resulting from a low flow state in the posterior circulation, that is a true vertebrobasilar insufficiency.

Course Total recovery is the rule, except for some cases with recurrent transient symptoms. Forty percent of patients have no sign at the time of neurological examination.

Causes Small non-territorial cerebellar infarcts have the same high rate of embolic mechanism as territorial infarcts (47% of cases): same frequency of cardiac source of embolism (42%), and of large artery occlusive disease (19%). They differ by the presence of more frequent low flow states distal to bilateral vertebral artery occlusion (14% in nonterritorial infarcts vs. 0% in territorial infarcts), and by the presence of more frequent hypercoagulable states resulting in end artery disease (17% in non-territorial infarcts vs.

1.25% in territorial infarcts) (Amarenco et al., 1994). Thus, except for the few cases due to an angiographically proven hemodynamic mechanism, non-territorial very small cerebellar infarcts are essentially the same as territorial infarcts; their extent and site simply more likely depend on the size of the emboli causing the infarct. The smaller the embolus is, the smaller the recipient artery, and therefore the more distal is the ‘end zone’ infarct (Amarenco et al., 1994). This has been recently confirmed in another independent series (Canaple & Bogousslavsky, 1999). Three circumstances can be distinguished. (a) Focal hypoperfusion distal to large artery occlusion. This mechanism is the most frequent (more than half the cases) (Amarenco et al., 1993b). The arterial occlusions often involve the proximal basilar artery, including or not the anterior inferior cerebellar artery ostium, and sometimes associated with a distal vertebral artery occlusion ipsilateral to the border-zone cerebellar infarct. Angiography may show a low flow state with direct or retrograde filling of the three cerebellar arteries (superior, anterior inferior and posterior inferior cerebellar artery) via cortical hemispheric and vermal anastomoses. The rostral basilar artery can be supplied by retrograde filling from the superior cerebellar arteries or posterior communicating arteries. In this case, the occipito-temporal areas can be protected by either a posterior cerebral artery arising from the carotid artery via the posterior communicating artery with a hypoplastic P1 segment or a good functional posterior communicating artery. Arterial occlusions can also involve only the vertebral artery, ipsilateral to the infarct, either at the termination or the origin. Some of them are associated with a fetal posterior cerebral artery or a severe intracranial atheroma of the contralateral vertebral artery or of the basilar artery as well, explaining a significant reduction in the total vertebrobasilar blood flow. However, in some other cases, the vertebral artery occlusion is isolated, and the reduction in blood flow in the infarcted watershed area results in a small embolus occluding a very distal artery. Other cases are due to bilateral vertebral artery occlusion, either distal, or proximal on one side and distal on the other. In those cases, the lack of anastomoses causes the infarct in a border-zone area. The flow in the basilar artery comes from either a single posterior inferior cerebellar artery (if the occlusion is distal to its ostium) via hemispheric and vermal pial anastomoses, or the posterior communicating arteries (i.e. the carotid arteries), or both. Some cases are associated with a severe carotid stenosis. Whether the symptoms and signs in these cases are due to carotid disease is still debated. (b) Small or end (pial) artery diseases are associated with

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primary or secondary hypercoagulable states which are known to give, in the carotid territory, the same pattern of border-zone infarct: thrombocythemia, polycythemia, hypereosinophilia, disseminated intravascular coagulation. Arteritis and cholesterol emboli are occasionally encountered. Other patients have severe intracranial distal atheroma with MRI showing multiple small cortical and deep infarcts of the cerebral hemispheres and angiography demonstrating multiple intracranial arterial stenoses and no extracranial atheroma. (c) Systemic hypotension due to cardiac arrest is seldom the cause of border-zone cerebellar infarcts. Romanul et al. reported in 1964 five bilateral cases, together with supratentorial bilateral border zone infarcts. The other two reported cases involved only the cerebellum unilaterally and had underlying severe vertebrobasilar occlusive disease (Amarenco et al., 1993b). The cerebellum seems to be relatively protected from deep systemic hypotension, since in postmortem series border-zone infarcts involved watershed area of anterior, middle and posterior cerebral arteries and not the cerebellum. Only microscopic examination disclosed mild lesions in the cerebellar whitematter.

superficial branches that penetrate perpendicularly the cortex reaching the white matter. Thus there is a possibility for internal deep border-zone infarct at the watershed area of the SCA, AICA and PICA outside and below the dentate nucleus. However, small emboli may also be the main mechanism.

Lacunar infarction

Involved territories and mechanisms

Lacunar strokes due to lipohyalinosis, although well known by neuropathologists, have never been reported in the cerebellum in association with a stroke syndrome. The arterial anatomic disposition with progressively tapered arteries reaching the deep cerebellar white-matter does not favor lacunar stroke as Fisher observed in his early descriptions. In contrast, the ventral pons and capsulolenticulostriate areas are supplied by small arteries arising directly from large vessels. In the literature, there is only one case of a ‘giant lacuna’ in the cerebellum, which is pathologically quite different from the usual lacunar stroke. Small deep infarcts that we analysed in a series of 47 very small cerebellar infarcts presented with small round lesions, i.e. had the CT or MRI appearance of ‘lacunae’. They were located in the watershed area between the SCA, PICA and AICA. They were associated with large artery occlusive disease in 60% of cases, cardiac source of embolism in 13% of cases, and end-artery disease in 13% of cases: one due to cholesterol emboli from the aortic arch, the other in a patient with intracranial atheroma (the remaining 13% were of unknown cause). AICA and PICA have a less extended deep territory than those of the SCA. Branches which supply their deep territory arise from the

Pseudotumoural cerebellar infarcts Although benign forms of cerebellar infarcts are much more frequent, the possibility of rapidly progressive cerebellar swelling with acute hydrocephalus and death needs to be kept in mind since surgery in this situation may be life saving. This form was first described by Menzies in 1893. Over 40 years ago it was shown that a total recovery could be obtained with surgical treatment (Fairburn & Oliver, 1956; Lindgren, 1956). Edema leads to cerebellar swelling, raised pressure in the posterior fossa, and brainstem compression. Aqueductal or IVth ventricle displacement or occlusion leads to obstructive hydrocephalus and acute intracranial hypertension. Cerebellar swelling may also cause tonsillar herniation through the foramen magnum.

In autopsy series, these infarcts involved the PICA territory (Sypert & Alvord, 1975), SCA territory or both (Amarenco & Hauw, 1990b). In clinical series, PICA territory is more frequently involved than SCA territory (Kase et al., 1993). Swelling of the cerebellum seems to be related to at least four factors: (i) mainly the large size of the infarcts (Sypert & Alvord, 1975) (involvement of more than a third of the cerebellar hemisphere); (ii) the site of embolic occlusion (rostral end of the basilar artery affecting the SCA ostia or bilateral vertebral artery occlusion affecting the PICA ostia) together with the failure of anastomotic collateral supply; (iii) the increase in vasogenic edema in case of reperfusion after the migration of an embolus; (iv) the presence of a massive SCA infarct whose particular location seems to statistically favour hydrocephalus. The clinical presentation is similar to that of cerebellar hemorrhage (Fisher et al., 1965; Heros, 1982; Ott et al., 1974) but unenhanced CT readily allows distinction between the two conditions.

Clinical pictures (a) Delayed alteration of consciousness clinically characterizes 90% of these infarcts. It appears from a few hours to 10 days after the onset of symptoms (mean 5 days) (Lerich et al., 1970) either in isolation or together with worsening

Cerebellar stroke syndromes

of other neurologic signs. It can be rapidly (over a few hours) or slowly (over a few days) progressive. Isolated supratentorial hydrocephalus, disappearance of the IVth ventricle, or both on CT suggest an edematous cerebellar infarct despite the occasional lack of cerebellar hypodensity. MRI is positive in such cases. Surgery is needed when deterioration of consciousness appears. Total recovery is obtained in 63% of published cases after ventricular drainage or opening of the dura mater by suboccipital craniectomy. The prognosis, however, depends on whether there is an associated brainstem infarct or not since there is a strong correlation between hemi- or tetraplegia and the presence of a massive pontine infarction at autopsy (Amarenco & Hauw, 1990b). Thus, surgery should be avoided when there is severe motor weakness. Absence of paramedian pontine hyperintensity on axial MRI section should aid in the decision regarding surgery. (b) Cerebellar infarcts with deep coma at onset. The sudden onset of deep coma of unknown cause together with isolated supratentorial hydrocephalus on CT should suggest an edematous cerebellar infarction requiring emergency surgery. Ventricular drainage may be life saving and the early release of brainstem compression allows a good or a total functional recovery even for deeply comatose patients.

The size of hemorrhage is variable. Some are ⱕ3 cm and have a minimal brainstem compression and minor hydrocephalus. Those ⬎3 cm usually have a life-threatening mass effect on the brainstem and large hydrocephalus with increased intracranial pressure. Hypertension is by far the leading cause (80%) of cerebellar hemorrhages. Other frequent causes are arteriovenous malformation, cavernoma, metastatic tumour, anticoagulation or coagulopathy, and trauma.

Clinical pictures (Heros, 1982; Ott et al., 1974; Norris et al., 1969; Labauge et al., 1983) The main symptoms are acute posterior headaches and gait ataxia. Drowsiness, vertigo, vomiting and dysarthria come next. Signs are cerebellar ataxia, limb dysmetria, dysarthria, nystagmus and coma. Therefore, there is no significant difference with cerebellar infarction and cranial CT is always required. It is becoming obvious that many small cerebellar hemorrhages detected by CT result in only mild symptomatology and have a relatively benign natural history, but once a cerebellar hemorrhage leads to stupor and signs of brainstem compression the fatality rate approaches 100% (Heros, 1982). Some patients may present in deep coma and quickly die. Other awake patients gradually worsen. Finally many patients seem to be stable during the first hours or days and suddenly deteriorate becoming apneic and then die (Heros, 1982; Ott et al., 1974).

Cerebellar hemorrhage There is approximately one cerebellar hemorrhage for every nine cerebellar infarcts. However, they have the same clinical presentation and usually only non-contrast CT or MRI can make the diagnosis. They usually have the same evolution as pseudotumoural cerebellar infarcts.

Involved territory (Heros, 1982; Ott et al., 1974; Norris et al., 1969; Labauge et al., 1983) Cerebellar hemorrhages usually involve the deep territory near the dentate nucleus which is supplied by early long perforating branches of the SCA that follow the superior cerebellar peduncle. These arteries anastomose with cerebellar cortical arteries which supplied the subcortical area after penetrating the cortex perpendicularly. This area of anastomosis could be particularly fragile. From this site they can involve most of the ipsilateral hemisphere and occasionally can cross the midline. Other hemorrhages extend internally to the vermis. Rarely, they also involve the brainstem, but not infrequently the cerebellar peduncles with rupture in the fourth ventricle.

Treatment Surgical treatment Surgical treatment is recommended during the first week in all patients with cerebellar hemorrhage (Heros, 1982). Others recommend not to evacuate the hematoma if the patient is awake, stable and cerebellar hematoma ⬍3 cm. Among brain infarcts, the possibility of life-saving surgery is unique to cerebellar infarcts when they present as a space occupying lesion with obstructive hydrocephalus (Fairburn & Oliver, 1956; Lindgren, 1956). Before the CT era, there was a consensus towards suboccipital craniectomy and aspiration of necrotic tissue (Lerich et al., 1970; Feely, 1979; Norris et al., 1969; Wood & Murphey, 1969). With CT monitoring, recovery has been reported after ventricular drainage without surgical resection of the infarcted tissue (Shenkin & Zavala, 1982; Hinshaw et al., 1980; Khan et al., 1983). The best approach is probably individualized taking into account, in each case, the severity of the neurological state, particularly impairment of

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consciousness (Cioffi et al., 1985; Jauss et al., 1999). If the patient is alert and clinically stable, medical treatment alone is needed. If the patient is alert but CT shows hydrocephalus or mass effect on the IVth ventricle, medical treatment is also indicated. In such a case, some authors suggest monitoring the intracranial pressure and performing surgery when pressure is above 350 mmHg. When deterioration of consciousness appears, ventricular drainage becomes necessary, and if it is not rapidly effective, a surgical decompression is urgently required. Some authors advocate routine surgical resection because of the theoretical risk of upward transtentorial herniation after ventricular drainage. The main difficulty in the decision-making regarding surgery is encountered when brainstem signs are present, making it sometimes impossible to determine whether the deterioration of neurological state is due to direct compression by the swollen cerebellum or to an associated extensive brainstem infarction. It seems reasonable to avoid surgery in the presence of a massive brainstem infarct, particularly if severe hemi- or tetraplegia is present. MRI is very helpful in this situation in imaging the brainstem.

Medical treatment Medical treatment, as for other brain infarcts, consists primarily of general symptomatic treatment. No specific treatment has been well studied. It might be appropriate, in the case of a critical cerebral hemodynamic situation, to maintain strict recumbency. Intravenous thrombolysis with rt-PA may be beneficial if the patient is seen within 3 hours of symptoms onset (Albers et al., 2000). The use of an antithrombotic agent (heparin or aspirin) remains empirical. We now use heparin and warfarin for short term (3–6 weeks) in patients with recent occlusion of the vertebral artery in the neck or intracranially or of the basilar artery. When the causative lesion is a severe stenosis, we use these drugs for a longer time, at least until the vascular lesion becomes complete or the artery recanalizes. Aspirin is used for non-stenotic irregular lesions. In the case of basilar artery occlusion with severe neurological deficit, intra-arterial thrombolysis may be considered if the patient is seen within 6 hours of symptoms onset. Preventive treatment consists of detection of major cardiac sources of emboli and their treatment with oral anticoagulants. In atherothrombotic cerebellar infarcts, there is no place for prophylactic surgery because of the intracranial location of the causal atheromatous lesion (Amarenco et al., 1990a). Despite the lack of specific randomized studies, it seems reasonable to institute prophylactic antiplatelet therapy, together with the treatment of vascular risk factors, in patients who are not studied fully.

iReferencesi Albers, G.W., Amarenco, P., Easton, J.D., Sacco, R.L. & Teal, P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest, 2000, in press Amarenco, P. (1991). The spectrum of cerebellar infarctions. Neurology, 41, 973–9. Amarenco, P. & Hauw, J-J. (1989). Anatomie des artères cérébelleuses. Revue Neurologique (Paris), 145, 267–76 Amarenco, P. & Hauw, J-J. (1990a). Cerebellar infarction in the territory of the superior cerebellar artery: a clinicopathologic study of 33 cases. Neurology, 40, 1383–90. Amarenco, P. & Hauw, J-J. (1990b). Infarctus cérébelleux œdémateux. Etude clinico-pathologique de 16 cas. Neurochirurgie, 36, 234–41. Amarenco, P. & Hauw, J-J. (1990c). Cerebellar infarction in the territory of the anterior and inferior cerebellar artery. A clinicopathological study of 20 cases. Brain, 113, 139–55. Amarenco, P., Hauw, J-J., Hénin, D., et al. (1989). Infarctus du territoire de l’artère cérébelleuse postéro inférieure. Etude clinicopathologique de 28 cas. Revue Neurologique (Paris), 145, 277–86. Amarenco, P., Hauw, J-J. & Gautier, J-C. (1990a). Arterial pathology in cerebellar infarction. Stroke, 21, 1299–305. Amarenco, P., Roullet, E., Chemouilli, Ph. & Marteau, R. (1990b). Infarctus pontin inféro-latéral. Deux aspects cliniques. Revue Neurologie (Paris), 146, 433–7. Amarenco, P., Roullet, E., Hommel, M., Chaine, P. & Marteau, R. (1990c). Infarction in the territory of the medial branch of the posterior inferior cerebellar artery. Journal of Neurology, Neurosurgery and Psychiatry, 53, 731–5. Amarenco, P., Chevrie-Muller, M.C., Roullet, E. & Bousser, M-G. (1991a). Paravermal infarct and isolated cerebellar dysarthria. Annals of Neurology, 30, 211–13. Amarenco, P., Roullet, E., Goujon, C., Chéron, F., Hauw, J-J. & Bousser, M-G. (1991b). Infarction of the anterior part of the rostral cerebellum. Neurology, 41, 253–8. Amarenco, P., Hauw, J-J. & Caplan, L.R. (1993a). Cerebellar infarctions. In Handbook of Cerebellar Diseases, ed. R. Lechtenberg, Chapter 16, pp. 251–90. New York: Marcel Dekker. Amarenco, P., Kase, C.S., Rosengart, A., Pessin, M.S., Bousser, M-G. & Caplan, L.R. (1993b). Very small (border zone) cerebellar infarcts: distribution, mechanisms, causes and clinical features. Brain, 116, 161–86. Amarenco, P., Rosengart, A., DeWitt, L.D., Pessin, M.S. & Caplan, L.R. (1993c). Anterior inferior cerebellar artery territory infarcts: mechanisms and clinical features. Archives of Neurology, 50, 154–61. Amarenco, P., Lévy, C., Cohen, A., Touboul, P-J., Roullet, E. & Bousser, M-G. (1994). Causes and mechanisms of territorial and nonterritorial cerebellar infarcts in 115 consecutive cases. Stroke, 25, 105–12. Atkinson, W.J. (1949). The AICA. Its variations, pontine distribution, and significance in the surgery of cerebello pontine angle tumors. Journal of Neurology, Neurosurgery and Psychiatry, 12, 137–51.

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Barinagarrementeria, F., Amaya, L.E. & Cantú, C. (1997). Causes and mechanisms of cerebellar infarction in young patients. Stroke, 28, 2400–4. Barth, A., Bogousslavsky, J. & Régli, F. (1993). The clinical and topographic spectrum of cerebellar infarcts: a clinical-magnetic resonance imaging correlation study. Annals of Neurology, 33, 451–6 Barth, A., Bogousslavsky, J. & Régli, F. (1994). Infarcts in the territory of the lateral branch of the posterior inferior cerebellar artery. Journal of Neurology, Neurosurgery and Psychiatry, 57, 1073–6. Canaple, S. & Bogousslavsky, J. (1999). Multiple large and small cerebellar infarcts. Journal of Neurology, Neurosurgery and Psychiatry, 66, 739–45. Caplan, L.R. (1996). Posterior Circulation Disease. Cambridge: Blackwell Science. Chaves, C.J., Caplan, L.R., Chung, C-S. et al. (1994). Cerebellar infarcts in the New England Medical Center Posterior Circulation Stroke Registry. Neurology, 44, 1385–90. Cioffi, F.A., Bernini, F.P., Punzo, A. & D’Avanzo, R. (1985). Surgical management of acute cerebellar infarction. Acta Neurochirurgica, 74, 105–12. Duncan, G.W., Parker, S.W. & Fisher, C.M. (1975). Acute cerebellar infarction in the PICA territory. Archives of Neurology, 32, 364–8. Fairburn, B. & Oliver, L.C. (1956). Cerebellar softening, a surgical emergency. British Medical Journal, 1, 1335–6. Feely, M.P. (1979). Cerebellar infarction. Neurosurgery, 4, 7–11. Fisher, C.M., Picard, E. & Polak, A. (1965). Acute hypertensive cerebellar hemorrhage: diagnosis and surgical treatment. Journal of Nervous Mental Diseases, 140, 38–57. Gilman, S., Bloedel, J. & Lechtenberg, R. (1981). Disorders of Cerebellum. Philadelphia: Davis. Greitz, T. & Sjögren, S. (1963). The posterior inferior cerebellar artery. Acta Radiologica, 1, 284. Guiang, R.L. & Ellington, O.B. (1977). Acute pure vertiginous disequilibrium in cerebellar infarction. European Neurology, 116, 11–15. Heros, R.C. (1982). Cerebellar hemorrhage and infarction. Stroke, 13, 106–9. Hinshaw, D.B., Thompson, J.R., Hasso, A.N. & Casselman, E.S. (1980). Infarctions of the brainstem and cerebellum: a correlation of computed tomography and angiography. Radiology, 137, 105–12. Ho, S.U., Kim, K.S., Berenberg, R.A. & Ho, H.T. (1981). Cerebellar infarction: a clinical and CT study. Surgical Neurology, 16, 350–2. Huang, C.Y. & Yu, Y.L. (1985). Small cerebellar strokes may mimic labyrinthine lesions. Journal of Neurology, Neurosurgery and Psychiatry, 48, 263–5. Jauss, M., Krieger, D., Hornig, C., Schramm, J. & Busse, O. (1999). Surgical and medical management of patients with massive cerebellar infarctions: results of the German–Austrian Cerebellar Infarction Study. Journal of Neurology, 246, 257–64. Kase, C.S., White, J.L., Joslyn, J.N., Williams, J.P. & Mohr, J.P. (1985). Cerebellar infarction in the superior cerebellar artery distribution. Neurology, 35, 705–11.

Kase, C.S., Norrving, B., Levine, S.R. et al. (1993). Cerebellar infarction. Clinico-anatomic correlations. Stroke, 24, 76–83. Khan, M., Polyzoidis, K.S., Adegbite, A.B.O. & McQueen, J.D. (1983). Massive cerebellar infarction: conservative management. Stroke, 14, 745–51. Labauge, R., Boukobza, M., Zinszner, J., Blard, J.M., Pages, M. & Salvaing, P. (1983). Hématomes spontanés du cervelet. Vingthuit observations personnelles. Revue Neurologie (Paris), 139, 193–204. Lazorthes, G., Gouazé, A., Salamon, G., Poulhes, J. & Espagno, J. (1978). La vascularisation artérielle du cervelet. In La vascularisation cérébrale, ed. G. Lazorthes, A. Gouazé & G. Salamon, pp. 205–19. Paris: Masson. Lerich, J., Winkler, G. & Ojemann, R. (1970). Cerebellar infarction with brainstem compression: diagnosis and surgical treatment. Archives of Neurology, 22, 490–8. Levine, S.R. & Welch, K.M.A. (1988). Superior cerebellar artery infarction and vertebral artery dissection. Stroke, 19, 1431–4. Lindgren, S.O. (1956). Infarctions simulating brain tumors in posterior fossa. Journal of Neurosurgery, 13, 575–81. Macdonell, R.A.L., Kalnins, R.M. & Donnan, G.A. (1987). Cerebellar infarction: natural history, prognosis and pathology. Stroke, 18, 849–55. Min, W.K., Kim, Y.S., Kim, J.Y., Park, S.P. & Suh, C.K. (1999). Atherothrombotic cerebellar infarction. Vascular lesion – MRI correlation of 31 cases. Stroke, 30, 2376–81. Norris, J.W., Eisen, A.A. & Branch, C.L. (1969). Problems in cerebellar hemorrhage and infarction. Neurology, 19, 1043–50. Ott, K.H., Kase, C.S., Ojemann, R.G. & Mohr, J.P. (1974). Cerebellar hemorrhage: diagnosis and treatment. A review of 56 cases. Archives of Neurology, 31, 160–7. Philips, P.C., Lorentsen, K.J., Shropshire, L.C. & Ahn, H.S. (1988). Congenital odontoid aplasia and posterior circulation stroke in childhood. Annals of Neurology, 23, 410–13. Ringer, R.A. & Culberson, J.L. (1989). Extensor tone disinhibition from an infarction within the midline anterior cerebellar lobe. Journal of Neurology, Neurosurgery and Psychiatry, 52, 1597–9. Rodda, R. (1971). The vascular lesions associated with cerebellar infarcts. Proceedings of the Australian Association of Neurologists, 8, 101–10. Savoiardo, M., Bracchi, M., Passerini, A. & Visciani, A. (1989). The vascular territories in the cerebellum and brainstem: CT and MR study. American Journal of Neuroradiology, 8, 199–209. Shenkin, H.A. & Zavala, M. (1982). Cerebellar strokes: mortality, surgical indications, and results of ventricular drainage. Lancet, 11, 429–31. Simmons, Z., Biller, J., Adams, H.P., Dunn, V. & Jacoby, C.G. (1986). Cerebellar infarction: comparison of computed tomography and magnetic resonance imaging. Annals of Neurology, 19, 291–3. Struck, L.K., Biller, J., Bruno, A. et al. (1991). Superior cerebellar artery territory infarction. Cerebrovascular Diseases, 1, 71–5. Sypert, G.W. & Alvord, E.C. (1975). Cerebellar infarction – a clinicopathologic study. Archives of Neurology, 32, 357–63. Takahashi, M., Wilson, G. & Hanafee, W. (1968). The anterior infe-

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rior cerebellar artery: its radiographic anatomy and significance in the diagnostic of extraaxial tumors of the posterior fossa. Radiology, 90, 281–7. Tohgi, H., Takahashi, S., Chiba, K. & Hirata, Y. (1993). Cerebellar infarction. Clinical and neuroimaging analysis in 293 patients. The Tohoku Cerebellar Infarction Study Group. Stroke, 24, 1697–701.

Tomaszek, D.E. & Rosner, M.J. (1985). Cerebellar infarction: analysis of twenty-one cases. Surgical Neurology, 24, 223–6. Wood, M.W. & Murphey, F. (1969). Obstructive hydrocephalus due to infarction of a cerebellar hemisphere. Journal of Neurosurgery, 30, 260–3.

43

Extended infarcts in the posterior circulation (brainstem/cerebellum) Barbara E. Tettenborn Kantonsspital St Gallen, Switzerland

Introduction Clinical symptoms and signs as well as management of patients with ischemia in t¥he posterior circulation are far less well defined than of patients with ischemia in the anterior circulation. Several studies have addressed the issue of extended, space-occupying infarcts in the cerebellum and their management, but there exist only few data on extended or multiple infarcts in the brainstem and their prognosis. Only few attempts have been made to correlate extended infarcts in the brainstem and the cerebellum with the underlying causes and mechanisms. The following sections will review the clinically important factors on the frequency and causes of extended and multiple infarcts in the brainstem and cerebellum with special attention to particular topographic patterns and etiological mechanisms as well as existing data on management and prognosis of these types of infarcts.

Extended or multiple infarcts in the brainstem Clinical features Patients with extended brainstem ischemia of sudden onset have often very severe to life-threatening neurological symptoms and signs depending on the localization of the lesion. The neurological symptoms of isolated mesencephalic, pontine or medullary ischemia have been presented in the last chapters. Infarctions involving several brainstem levels are likely to be caused by either basilar artery thrombosis or occlusion of both intracranial vertebral arteries. Basilar artery occlusion can give rise to a variety of clinical pictures. Many years ago it was thought that basilar artery thrombosis was a life-threatening disease in all

patients but now it is known that, if it occurs slowly over time, basilar artery thrombosis can be survived without major disability in some patients (Caplan, 1979; Bogousslavsky et al., 1986; Berlit et al., 1994). Nevertheless, in the case of acute onset of basilar artery occlusion, most patients will suffer extended brainstem infarctions of primarily pontine localization. Extensive destruction of the basis pontis gives rise to the very severe ‘locked-in’ syndrome. This term describes a state in which severe paralysis prevents gestural and vocal communication despite normal consciousness and neuropsychological functions. Neurological examination reveals tetraplegia, decerebrate response, bilateral extensor plantar responses, facial diplegia, lingual and pharyngeal palsy, horizontal gaze palsy and sometimes ocular bobbing. The patient is fully alert, and communication is possible by vertical eye movements. In most patients, death occurs within weeks or months but some survive for several years. In extended pontine infarctions many symptoms and signs can develop in various combinations as described in Chapter 40. If a patient has clinical symptoms and signs of sudden onset considered to be due to brainstem ischemia, physicians usually try to correlate all clinical findings to a single lesion. But, even within the anatomically very complex brainstem, a unifocal lesion might not explain all symptoms. Instead, several smaller lesions in the distribution of either one artery or one branch of an artery supplying the brainstem, i.e. the vertebral arteries, the basilar artery, and the long circumferential arteries (posterior inferior cerebellar artery, anterior inferior cerebellar artery, superior cerebellar artery), or in different arteries can give rise to the clinical picture of an extended brainstem infarct. In a personal study on 238 consecutive patients with clinical brainstem symptoms of sudden onset, the diagnostic methods including clinical examination, electrophysiological studies, and imaging techniques revealed

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20

32.8%

18 16 14 Patients (n = 58)

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12 17.2% 10 8

13.8% 12.1% 10.3%

6

8.6%

4

5.2%

2 0

Medulla + pons

Medulla + mesenc.

Pons bilat.

Pons + mesenc.

Pons bilat. + mes. bilat.

Mesenc. bilat.

Multiple lesions

Fig. 43.1. Multilocular brainstem infarctions (n ⫽ 58 patients).

multifocal brainstem lesions in 58 patients (24%). All 238 consecutive patients had a careful work-up including neurological examination, neuroimaging with CCT in all and MRI in most patients, electrophysiological testing including auditory evoked potentials, blink reflex, masseter reflex and electronystagmography. In all patients control examinations were done to document the shortand long-term follow-up parallel to the clinical course. Imaging techniques including MRI in most patients showed multifocal lesions in only 28 patients, whereas combined clinical, electrophysiological and imaging results demonstrated multifocal ischemia in 58 patients (24%). In the New England Medical Center Stroke Registry the percentage of multifocal brainstem strokes was 23% (Caplan, 1996). Bernasconi et al. (1996) found multilocular lesions in 11% of patients with brainstem strokes, but they included only the morphological results and did not perform any electrophysiological testing. In the majority of the 58 patients with multilocular brainstem ischemia, the pontine region was involved together with accompanying lesions of other brainstem locations (Fig. 43.1) This primarily pontine localization is in accordance with results of other studies regarding posterior circulation ischemia (Bogousslavsky et al., 1988; Caplan, 1993; Regli et al., 1993; Bernasconi et al., 1996). Patients with multifocal brainstem lesions had a higher grade of neurological disability than patients with unifocal lesions (P⫽0.001). Patients with involvement of the

pontine region had more severe neurological symptoms and signs than patients with medullary and mesencephalic involvement sparing the pontine region, the group of patients with bilateral pontine lesions or pontine plus mesencephalic lesions being the worst.

Electrophysiological testing Imaging techniques like CCT or MRI are able to demonstrate morphological lesions. A normal CCT or MRI does not necessarily exclude functionally relevant lesions. But, in the small area of the brainstem with its high complexity of functionally important structures it might be even more valuable to examine functional disturbances. The topographic yield of functional imaging techniques like SPECT and PET is not high enough to reliably show lesions within the brainstem. Electrophysiological testing including brainstem reflexes and evoked potentials can be most valuable to demonstrate functional disturbances (Tettenborn et al., 1992; Hopf, 1994; Tettenborn, 1994; Thömke et al., 1994). The methods most commonly used are auditory evoked potentials, somatosensory evoked potentials, electronystagmography, blink reflex, and masseter reflex.

Auditory evoked potentials Short-latency auditory evoked potentials (AEPs) are a series of positive and negative waves recorded within the first 10 ms after an abrupt auditory stimulus. Data about

Extended infarcts in the posterior circulation

the generator sites have been derived from intracranial recordings and from an analysis of the effect of lesions. The generator site of wave I of the AEPs is the eighth nerve. The origin of wave II is controversial; possible generators are the proximal part of the eighth nerve or the intra-axial infranuclear cochlear nerve. Data from studies on patients with defined brainstem lesions localize the major generators of wave III to the superior olivary complex in the caudal pontine tegmentum. Waves IV and V are generated in the lateral lemniscus within the upper pons and the inferior colliculus within the lower midbrain, respectively. In view of this anatomical basis, AEP abnormalities are expected in patients with pontine and mesencephalic lesions.

Somatosensory evoked potentials Somatosensory evoked potentials (SEP) can be generated by electrical stimuli to a peripheral nerve and are recorded at different levels from the spine and the scalp. Common sites of stimulation include the median or ulnar nerve at the wrist, the tibial nerve at the ankle, and the peroneal nerve at the knee. Data regarding the anatomic origins of the different components were obtained from direct recordings in patients undergoing surgery or from studies in patients with a localized lesion on CCT or MRI. The different waves are generated in the dorsal columns, the dorsal column nuclei, the medial lemniscus, the thalamus, and the parietal sensory cortex. The ability to localize circumscript brainstem lesions with SEP is limited because the anatomy of the pathways delays the cortical responses in patients with brainstem lesions at all levels.

Electronystagmography Electronystagmography (ENG) is used for monitoring eye movements. Gaze is investigated for the presence of spontaneous, gaze-provoked, or positional nystagmus. Tests for vestibular ocular reflex function use caloric testing and visual ocular control regarding saccades and pursuit eye movements. Different structures in the brainstem and cerebellum are part of the oculomotor system. Certain eye movements and ENG findings permit discrimination between a peripheral lesion within the labyrinth or eighth nerve and a central nervous system lesion, which provides additional information about localization within the brainstem and cerebellum.

Blink reflex Electrical stimulation of the supraorbital nerve elicits two separate responses of the orbicularis oculi muscle: the early R1 component via pontine pathway and the late ipsiand contralateral R2 and R2c components relayed through

a more complex route involving the pons and the lateral medulla. Blink reflex latencies reflect conduction along the entire length of the supraorbital and facial nerves: therefore, pathological alterations of latencies do not necessarly indicate a pathological process within the brainstem. Isolated R1 changes occur in pontine lesions (Buchner et al., 1996).

Masseter reflex The masseter or jaw reflex is elicited by a mechanical tap to the patient’s jaw with a triggered hammer. The reflex is mediated by trigeminal fibres ascending to the mesencephalic nucleus and descending to the pontine motor nucleus. Electrophysiologic evaluation depends on absolute normal values as well as side-to-side comparison of the reflex responses recorded simultaneously from both masseter muscles. Differencies in latencies of more than 0.5 ms indicate unilateral abnormality of the reflex arc suggesting a pontomesencephalic lesion.

Mechanisms of infarction So far, very few studies exist in the literature regarding etiology of posterior circulation infarcts (Caplan & Tettenborn, 1992a b; Bogousslavsky et al., 1993; Amarenco et al., 1994; Vuilleumier et al., 1995; Bassetti et al., 1996), even less is known about mechanisms of multiple or extended vertebrobasilar strokes. Among the 58 patients with multilocular lesions, diabetes (29%) and cardioembolic sources (17%) were more common than in the unifocal group (17% and 6%, respectively). Large artery occlusive disease was thought to be the underlying cause in 27% of the unifocal and 35% of the multifocal lesions. Penetrating artery disease was considered most likely in 43% of the unifocal and 31% of the multifocal lesions. Out of all patients, those with large artery occlusive disease had the most severe neurological disability. The group of patients with large artery occlusive disease includes intraarterial embolization as stroke etiology.

Treatment In patients with extended brainstem infarcts and major neurological disability including impairment of consciousness and necessity of artificial ventilation general medical measurements have priority. This includes intensive care unit management. In patients with proven basilar artery thrombosis, local thrombolysis can be tried. Due to the bad prognosis, the time window can be expanded as compared to anterior circulation strokes beyond the very narrow time window of 3

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hours, sometimes even beyond 6 hours. Long-term prognosis seems to depend on the efficacy of the initial thrombolytic therapy (Berlit et al., 1994). In patients with brainstem infarcts and less severe neurological impairment, especially without impairment of consciousness, medical treatment does not differ from conservative treatment of infarctions in the anterior circulation and consists primarily of general symptomatic measurements. No specific treatment has well been studied. The use of an antithrombotic agent (heparin or aspirin) in the acute vertebrobasilar stroke phase remains empirical. We now use heparin and warfarin for short terms (3–6 weeks) in patients with recent occlusions of the vertebral artery in the neck or intracranially or recent occlusions of the basilar artery (Caplan, 1996). Preventive treatment consists in detection of major cardiac sources of emboli and their treatment with oral anticoagulants. In atherothrombotic cerebellar infarcts, there is usually no place for prophylactic surgery, because of the mostly intracranial location of the causal atheromatous lesion (Amarenco et al., 1990). Despite the lack of specific randomized studies, it seems reasonable to institute prophylactic antiplatelet therapy, together with treatment of vascular risk factors as in patients with anterior circulation ischemia.

Prognosis Prognosis of multiple or extended brainstem infarcts depends mainly on the localization and the extent of the lesion as well as on the etiology of the infarction. The age of the patient is also an important prognostic factor with increasing mortality in the higher age groups and comparatively better prognosis in young patients (Hornig et al., 1992a, b). In our own study, patients with an initially high disability degree had a worse prognosis than patients with a better neurological score at the beginning. Parallel existence of several vascular risk factors is leading to a greater neurological disability at the beginning as well as to a worse long-term prognosis. Patients with cardiac origin embolism as the suggested etiology were less disabled at the time of control examination after 2.3 years of follow-up as compared to patients with large vessel or small vessel arterial disease. In contrast to the neuroimaging studies the results of the electrophysiological studies correlated with the clinical course giving good information regarding the functional improvement or deterioration. In the literature very few comparable studies regarding brainstem infarcts are available (Bogousslavsky et al., 1986, 1991). Patients who do not survive a brainstem ischemia often have a basilar artery thrombosis. Bogousslavsky et al.

(1986) found, in patients with bilateral occlusion of the vertebral artery, a mortality of 4.5% per year and a yearly stroke rate of 1.8%. Severe neurological disability was present in 16.7% of these patients in long-term follow-up. Caplan described (1979) ten patients with occlusion of intracranial vertebral or basilar artery and an initial TIA or minor stroke. All ten patients had a favourable outcome without any ischmia recurrence over the next 2.75 years, four patients were symptom-free. On the other hand, Moufarrij et al. reported (1986) on 44 patients with more than 50% stenosis of the distal vertebral artery or the basilar artery. After a follow-up of 6.1 years 18% had suffered a stroke, more than half of them in the posterior circulation. But there is enough evidence that, even in severe basilar artery thrombosis, a long-term course can be relatively favourable, possibly dependent on the effect of the initial thrombolytic therapy. The prognosis depends on several factors, one major factor being the age of the patient. We have seen a 25-yearold female patient with acute onset of dizziness, one-anda-half syndrome, up-beat-nystagmus, ptosis on the right, bilateral facial paresis, dysarthria and marked hemiparesis on the left. Initial MRI showed an extended right-sided pontine infarction (Fig. 43.2). Follow-up after 26 months revealed almost complete recovery of neurological findings with only minor impairment of the coordinative movements of the left hand. Corresponding to this marked clinical improvement all electrophysiological brainstem examinations which initially gave markedly pathological results returned to normal. Repeat MRI still showed the almost unchanged extended morphological pontine lesion (Fig. 43.3). The functional relevance of pathological electrophysiological results is obvious with the very good correlation between the patient’s clinical course and the results of the repeated electrophysiological testing. In conclusion, stroke etiology, initial neurological impairment and age seem to have a major impact on the long-term prognosis of patients with multiple or extended brainstem infarcts.

Combined cerebellar and brainstem infarcts In the past, only few studies have been done regarding cerebellar infarctions and their vascular etiology considering morphological lesions exclusively (Amarenco, 1991; Amarenco et al., 1993; Toghi et al., 1993; Amarenco et al., 1994; Chaves et al., 1994; Canaple & Bogousslavsky, 1999). In a personal study on 43 patients with non-spaceoccupying cerebellar infarcts, 35 patients (81%) had clinical signs or electrophysiological findings of brainstem

Extended infarcts in the posterior circulation

Fig. 43.2. Initial MRI of a 25-year-old female patient with extended right pontine infarction.

involvement. The majority of lesions were located in the proximal or distal vascular territory, the posterior inferior cerebellar artery or superior cerebellar artery territory, respectively. These findings are in accordance with the results of other studies regarding the location of cerebellar infarcts (Toghi et al., 1993, Chaves et al., 1994). In these studies accompanying brainstem lesions excluding compression of the brainstem were found in 15 to 20% of patients, but only morphological lesions were taken into account. Amarenco et al. (1990) described a series of 16 patients with anterior inferior cerebellar artery (AICA) infarcts accompanying pontine infarcts in 81% of patients. The cause for the high percentage of accompanying brainstem lesions in non-space-occupying cerebellar infarctions is on the one hand arterial distribution and on the other hand might the phenomenon of diaschisis play a role. In the majority of patients large artery occlusive disease was the most likely cause of the ischemia. The management of patients with combined non-spaceoccupying cerebellar and brainstem infarctions is the same as for patients with multifocal or extended brainstem infarcts. The prognosis mainly depends on the location and extent of the brainstem lesion.

Space-occupying cerebellar infarction Space-occupying cerebellar infarction was first described by Menzies in 1893. Cerebellar edema leads to swelling

Fig. 43.3. MRI after 26 months showed more or less unchanged morphological pontine lesion but neurological findings had almost completely recovered in that time.

with resulting increased pressure in the posterior fossa and finally brainstem compression. Displacement or occlusion of the fourth ventricle will lead to obstructive hydrocephalus and acute intracranial hypertension. Tonsillar herniation through the foramen magnum can occur and lead to death. When a cerebellar infarct presents as a spaceoccupying lesion with obstructive hydrocephalus surgical treatment can be life-saving. But patient selection and timing of surgery still remain controversial. There exist only few data on clinical signs in the early phase that are predictive for outcome which could help in the decision process when to operate. Recently, the results of the German–Austrian Cerebellar Infarction Study were published (Jauss et al., 1999). The clinical course and neuroradiological features of 84 patients with space-occupying cerebellar infarction confirmed by computed tomography were prospectively observed for 21 days after admission and at 3-month follow-up using a standardized protocol. The patients were assigned to three treatment groups: 34 underwent craniotomy and evacuation, 14 received ventriculostomy, and 36 were treated medically. Deterioration of consciousness typically occurred between days 2 and 4 with a maximum on day 3. The overall risk for poor outcome depended on the level of consciousness after clinical deterioration, subgroup analysis revealed no relationship to treatment, the vascular territory involved did not affect outcome. In another recently published study of Mohsenipour et al. (1999) 100 consecutive patients with

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cerebellar infarction were evaluated retrospectively regarding different therapeutic modalities including decompressive suboccipital craniectomy. Outcome was significantly influenced by age, size of the lesion, progressive appearance of brainstem dysfunction, and reduction of the level of consciousness as measured by the Glasgow Coma Scale (GCS). In patients with a GCS ⬍12 a reduction of mortality by 15% was obtained by surgical intervention and the outcome was significantly improved. These recent studies support earlier hypothesis that the level of consciousness is the most powerful predictor of outcome, superior to any other clinical sign. If a patient with cerebellar infarction is alert and clinically stable, medical treatment alone can be sufficient. If the patient is alert but CCT shows hydrocephalus or mass effect on the fourth ventricle surgical intervention is indicated. If the patient’s level of consciousness deteriorates and CCT shows mass effect on the fourth ventricle and compression of the brainstem decompressive surgery should be performed immediately. Most authors recommend operative excision of the infarcted area as the surgical method because of the theoretical risk of upward transtentorial herniation after ventricular drainage. The outcome after decompressive surgery is comparatively good with up to 63% total recovery of published cases after survival of the acute phase. Sometimes it can be difficult to decide if clinical deterioration is due to direct compression of the brainstem by the swollen cerebellum or due to accompanying extended brainstem infarct. In these cases MRI is needed for treatment decisions.

Conclusions At the present time, the knowledge of the clinical and etiological spectrum of extended and multiple brainstem infarcts is limited. Wider applications of MRI including the newer methods of diffusion-weighted imaging and noninvasive vascular and cardiac investigations will allow more precise topographic analysis and definition of brainstem lesions leading to a better understanding of the causative mechanisms of extended and multiple brainstem infarction. Extended infarcts in the cerebellum are life-threatening if they become space-occupying. Even smaller infarcts in the cerebellum are often accompanied by ischemic brainstem lesions due to the anatomical aspects of perfusion of brainstem and cerebellum with most arteries of the posterior circulation supplying parts of both regions. In patients with infarcts in the cerebellum and the brainstem, the brainstem lesions often cause the leading clinical symp-

toms. If a cerebellar infarct is extended and becomes space-occupying, the patient rapidly deteriorates. Emergency management is necessary and only extremely rapid decisions can save the patient’s life. Several studies came to the conclusion that, in patients with spaceoccupying cerebellar infarcts, immediate operative intervention with excision of the infarcted cerebellar hemisphere accompanied by implantation of a spinal fluid drain is the only adaequate method of treatment. The outcome after the operative excision of the cerebellar hemisphere is comparatively good after survival of the acute phase. Most patients adapt to normal movement abilities within several months.

iReferencesi Amarenco, P. (1991). The spectrum of cerebellar infarctions. Neurology, 41, 973–9. Amarenco, P., Hauw, J.J. & Gautier, J.C. (1990). Arterial pathology in cerebellar infarction. Stroke, 21, 1299–305. Amarenco, P., Hauw, J-J. & Caplan, L.R. (1993). Cerebellar infarctions. In Handbook of Cerebellar Diseases, ed. R. Lechtenberg, pp. 251–90. New York: Marcel Dekker. Amarenco, P., Levy, C., Cohen, A., Touboul, P.J., Roullet, E. & Bousser, M.G. (1994). Causes and mechanisms of territorial and nonterritorial cerebellar infarcts in 115 consecutive patients. Stroke, 25, 105–12. Bassetti, C., Bogousslavsky, J., Barth, A. & Regli, F (1996). Isolated infarcts of the pons. Neurology, 46, 165–75. Berlit, P., Jaschke, W., Möbius, E. & Berg-Dammer, E. (1994). Prognose vertebrobasilärer Ischämien. Nervenheilkunde, 13, 22–5. Bernasconi, A., Bogousslavsky, J., Bassetti, C. & Regli, F. (1996). Multiple acute infarcts in the posterior circulation. Journal of Neurology, Neurosurgery and Psychiatry, 60, 289–96. Bogousslavsky, J., Gates, P.C., Fox, A.J. & Barnett, H.J.M. (1986). Bilateral occlusion of vertebral artery: Clinical patterns and long-term prognosis. Neurology, 36, 1309–15. Bogousslavsky, J., Melle, G.V. & Regli, F. (1988). The Lausanne stroke registry: analysis of 1000 patients with first-ever stroke. Stroke, 19, 1083–92. Bogousslavsky, J., Cachin, C., Regli, F., Despland, P.A., van Melle, G. & Kappenberger, L. (1991). Cardiac sources of embolism and cerebral infarction – clinical consequences and vascular concomitants: the Lausanne Stroke Registry. Neurology, 41, 855–9. Bogousslavsky, J., Regli, F., Maeder, P., Meuli, R. & Nader, J. (1993). The etiology of posterior circulation infarcts: a prospective study using magnetic resonance imaging and magnetic resonance angiography. Neurology, 43, 1528–33. Buchner, H., Hacke, W. & Ferbert, A. (1996). Der Orbicularis-oculiReflex als Routineuntersuchung auf neurologischen Intensivstationen. In Hirnstammreflexe, Methodik und klinische

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Anwendung, ed. K. Lowitzsch (Hrsg.), pp. 211–17. Stuttgart, New York: Thieme. Canaple, S. & Bogousslavsky, J.(1999). Multiple large and small cerebellar infarcts. Journal of Neurology, Neurosurgery and Psychiatry, 66, 739–45. Caplan, L.R. (1979). Occlusion of the vertebral basilar artery: follow up analysis of some patients with benign outcome. Stroke, 10, 277–82. Caplan, L.R. (1993). Rules for correlating posterior circulation brain and vascular lesions. In Brain-stem Localization and Function, ed. L.R. Caplan & H.C. Hopf, pp. 3–15. Berlin, Heidelberg: Springer Verlag. Caplan, L.R. (1996). Vertebrobasilar territory ischemia: an overview. In Posterior Circulation Disease – Clinical Findings, Diagnosis, and Management, ed. L.R. Caplan, pp. 179–97. Cambridge: Blackwell Science. Caplan, L.R. & Tettenborn, B. (1992a). Vertebrobasilar occlusive disease: review of selected aspects. I. Spontaneous dissection of extracranial and intracranial posterior circulation arteries. Cerebrovascular Disease, 2, 256–65. Caplan, L.R. & Tettenborn, B. (1992b). Vertebrobasilar occlusive disease: review of selected aspects. II. Posterior circulation embolism. Cerebrovascular Diseases, 2, 320–6. Chaves, C.J., Caplan, L.R., Chung, S. et al. (1994). Cerebellar infarcts in the New England Medical Center Posterior Circulation Stroke Registry. Neurology, 44, 1385–90. Hopf, H.C. (1994). Topodiagnostic value of brainstem reflexes. Muscle and Nerve, 17, 475–84. Hornig, C.R., Büttner, T., Hoffmann, O. & Dorndorf, W. (1992a). Short term prognosis of vertebrobasilar ischemic stroke. Cerebrovascular Diseases, 2, 273–81. Hornig, C.R., Lammers, C., Büttner, T., Hoffmann, O. & Dorndorf, W. (1992b). Long-term prognosis of infratentorial transient ischemic attacks and minor strokes. Stroke, 23, 199–204.

Jauss, M., Krieger, D., Hornig, C., Schramm, J. & Busse, O. (1999). Surgical and medical management of patients with massive cerebellar infarctions: results of the German–Austrian Cerebellar Infarction Study. Journal of Neurology, 246, 257–64. Menzies, W.F. (1893). Thrombosis of the inferior cerebellar artery. Brain, 15, 436–9. Mohsenipour, I., Gabl, M., Schutzhard, E. & Twardy, K. (1999) Suboccipital decompressive surgery in cerebellar infarction. Zentralblatt Neurochirurgie, 60, 68–73. Moufarrij, N.A., Little, J.R., Furlan, A.J., Leatherman, J.R. & Williams, G.W. (1986). Basilar and distal vertebral artery stenosis: long-term follow-up. Stroke, 17, 938–42. Regli, F., Barth, A. & Bogousslavsky, J. (1993). Contribution of magnetic resonance imaging to the diagnosis of brain-stem and cerebellar infarcts. In Brain-stem Localization and Function, ed. L.R. Caplan & H.C. Hopf, pp. 17–22. Berlin, Heidelberg: Springer Verlag. Tettenborn, B. (1994). Diagnostik multitopischer ischämischer Läsionen im vertebrobasilären Stromgebiet. Nervenheilkunde, 13, 26–30. Tettenborn, B., Caplan, L.R., Krämer, G. & Hopf, H.C. (1992). Electrophysiology in ischemic brainstem disease. In Vertebrobasilar Arterial Disease, ed. R. Berguer & L.R. Caplan, pp. 124–9. St. Louis: Quality Medical Publishing. Thömke, F., Tettenborn, B. & Hopf, H.C. (1994). Elektrophysiologische Methoden sind der Magnetresonanztomographie beim Nachweis von Hirnstammläsionen überlegen. Zeitschrift EEG–EMG, 25, 259–66. Tohgi, H., Takahashi, S., Ciba, K. & Hirata, Y. (1993). Cerebellar infarction. Clinical and neuroimaging analysis in 293 patients. Stroke, 24, 1697–701. Vuilleumier, P., Bogousslavsky, J. & Regli, F. (1995). Infarction of the lower brainstem: clinical, aetiological and MRI–topographical correlations. Brain, 118, 1013–25.

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Border zone infarcts E. Bernd Ringelstein and Florian Stögbauer Neurology Clinic, Westfälische Wilhelms-University, Münster, Germany

Historical background and terminology Low-flow infarctions, also called ‘border zone infarctions’, are the result of a critically reduced cerebral perfusion pressure in far-downstream brain arteries that leads to a critically reduced cerebral blood flow and oxygen supply in certain vulnerable brain areas. These areas are defined by the specific angioarchitecture of the cerebrum. The term watershed infarction should be reserved for the cortical infarcts located in-between the territories of the major cerebral arteries, and should not be extended to the more common, subcortical type of low-flow infarction. The latter is located within the affected vascular distribution but in a zone of marginal irrigation (i.e. border zone) comparable to the ‘last field’ in a unidirectional (i.e. non-collateralized) agricultural watering system (Zülch & Behrend, 1961). The more general terms ‘low-flow infarction’, or ‘hemodynamically induced infarction’, are preferred, whereas terms like ‘deep watershed territory’-infarct (Angeloni et al., 1990) or ‘internal border zone territory’-infarct ((Angeloni et al., 1990) or ‘internal watershed infarctions’ (Bladin & Chambers, 1993) are misleading. In a wider sense, all ischemic brain infarcts are the consequence of a critically reduced blood flow. The concept underlying low-flow infarctions, however, emphasizes a difference between them and thromboembolically caused infarcts. In the thromboembolically induced brain infarcts, the corresponding cerebral artery(ies) is(are) occluded (rarely stenosed) by embolisms of various origins or by in situ atherothrombosis. By contrast, in low-flow infarctions the local brain artery(ies) supplying the infarcted area is(are) not diseased. Critically reduced cerebral blood flow and poor oxygen supply are the result of long-distance effects of far-upstream, high-grade vascular lesions of the brain-supplying arteries in the neck, mostly the internal carotid artery, and rarely the common carotid or vertebro-

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basilar arteries. In other words, in low-flow infarctions the underlying vascular lesion is located in the arteries upstream from the circle of Willis whereas the infarcted area is located in the distribution of arteries downstream from it. Only subtotal stenoses or complete occlusions, but not moderate stenoses, can generate a drop in perfusion pressure and ischemia severe enough that low-flow infarctions occur. Historically, the concept of low-flow induced infarctions was based on experimental work done by Schneider in the 1950s (Schneider, 1956), and rapidly picked up by Zülch and his pupils. During this era, fluid dynamic thinking of the cerebral circulation with a plumber’s mentality was fashionable, reflected by terms such as carotid insufficiency (Denny-Brown, 1951) or vertebrobasilar insufficiency (Millikan & Siekert, 1955). In Zülch’s papers, the absolute majority of ischemic brain infarctions were thought to be hemodynamically caused, thus overestimating greatly the low-flow pathogenesis (Zülch, 1961; Zülch & Behrend, 1961). In retrospect, the acceptance of this concept at this time is only understood in view of the upcoming vascular surgery, in particular, the advent of carotid endarterectomy (CEA) (Eastcott et al., 1954; DeBakey et al., 1962). CEA was the first available, active treatment erroneously thought to be beneficial to patients with completed strokes. In rigid tubes, an 80% reduction in cross-sectional area of a water tube (corresponding to an approximately 70% reduction in diameter) causes a critical and progressive drop in perfusion pressure. This is not, however, true for the cerebral circulation, where a hierarchy of compensatory mechanisms counteracts this drop in perfusion pressure, the most important of which is collateral flow via the circle of Willis. For decades, the simplicity of the hemodynamic concept, though false in most stroke patients, in concert with the impressive procedure of CEA and surgical activism, formed a solid citadel against other

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concepts in stroke pathophysiology (Fisher, 1954, 1959, 1962, 1965), and made carotid endarterectomy one of the most frequently abused surgical procedures in the Western world (Pokras & Dyken, 1988). In an overestimation and overuse of the hemodynamic concept in the pathogenesis of brain infarctions, Zülch also described ‘border zone infarctions’ within the basal ganglia, e.g. between the distributions of the anterior choroidal and posterior choroidal arteries, and even in the spinal cord (Zülch, 1961). We have not found any evidence for low-flow-induced ischemic lesion in these locations. Thus, we do not refer to them in more detail. Insights from new diagnostic techniques, including cerebrovascular ultrasound and computed tomography (Ringelstein et al., 1983a,b), as well as striking discrepancies between theoretic expectations and clinical everyday reality, and, last but not least, the negative results of the EC/IC-Bypass Study Group (1985), made clinicians aware of the fact that low-flow infarctions are rare and play a minor role among the broad spectrum of etiologies underlying ischemic stroke.

identified only 0.7 to 2 % low-flow infarctions of the cortical, i.e. ‘superficial’ type among 813 first-ever stroke patients, depending on the definition used (Hupperts et al., 1996). Similar frequencies have recently been reported by Gandolfo et al. (1998) where 7 out of 383 infarcted brains showed deep low-flow infarctions of the confluent type (i.e. 1.5%), and 13 patients had lone, i.e. ‘pure’ deep lowflow infarctions in their CTs, i.e. 3% of the patients investigated, and 2% of the lesions visible on CT (Gandolfo et al., 1998). This number may rise to 10% or more if the cohort investigated has been biased by preselection (Ringelstein et al., 1983a,b; Waterston et al., 1990). From our present experience, we would indeed estimate low-flow induced brain infarctions to account for approximately 5% to 10% of all ischemic infarcts visualized on CT in an etiologically heterogeneous stroke population. In patients with internal carotid artery dissection, however, this proportion will be much higher (see below) (Weiller et al., 1991b; Carpenter et al., 1990).

Pathophysiology Epidemiology Systematic studies on low-flow induced brain infarctions are sparse, and most pathoanatomic work done in the past is anecdotal (Zülch, 1961; Torvik & Skellerud, 1982; Torvik, 1984). More reliable data became available as soon as second- or third-generation CT scanners and MRI were systematically used, allowing investigation of stroke patients with such infarcts in series and prospectively. Ringelstein and coworkers (1983a,b) investigated 107 stroke patients with internal carotid artery (ICA) occlusion(s) by means of history-taking, clinical examination, ultrasonography or angiography, and computed tomography. Patients classified as having low-flow induced infarctions on their CT images accounted for 41% of the entire cohort. This series, however, was not consecutively recruited, which resulted in an artificial overload of lowflow infarctions in the cohort. From the large series published by Bogousslavsky and Regli (1986b), we excluded patients with ‘watershed infarctions’ in whom the diagnosis of an ICA occlusion had already been made long before a stroke had occurred (for rationale see below, ‘Spontaneous course of cerebral low-flow states’). After that, eight low-flow infarctions remained in 154 patients (5.2%), three of them with a purely subcortical lesion. Among 300 consecutively admitted stroke patients, Bladin and Chambers (1993) found 18 patients with subcortical low-flow infarctions, i.e. 6%, and Hupperts et al. (1996)

The pathogenetically crucial parameter is the arterial perfusion pressure. Under certain anatomic conditions, however, it will progressively drop downstream to an arterial stenosis beyond 80% reduction in its cross-sectional area. As a consequence, downstream blood flow will decrease and arteries may even collapse, as can be seen in arteriograms of ICA pseudoocclusion (i.e. near-occlusion) (Ringelstein et al., 1983a,b), or at the retina ipsilateral to subtotal ICA stenoses and occlusions where arterioles may be filled during systole but collapse during diastole (Young & Uppen, 1981; Ringelstein et al., 1988). In the absolute majority of patients, however, the circle of Willis and other collateral pathways fully compensate this drop in perfusion pressure. If this latter parameter could directly be measured in humans within the major cerebral arteries, it would be easy to pinpoint the relatively rare individuals in whom compensatory mechanisms are not capable of balancing downstream loss in perfusion pressure. Unfortunately, this is not the case, and the clinician is confined to indirect parameters of perfusion pressure within a given vascular distribution (Ringelstein et al., 1988; Caplan & Sergay, 1976; Norrving et al., 1982;Widder et al., 1986; Powers et al., 1987). Laboratory parameters that indirectly represent a compromised cerebral perfusion pressure are: (i) a reduced regional cerebral blood flow (rCBF), (ii) a reduced blood flow velocity (BFV) in arteries beyond the circle of Willis, or (iii) a reduced pulsatility index (PI) in these arteries. The pulsatility index refers to the shape of the flow profile,

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particularly to the relationship between systolic peak flow velocity and end-diastolic flow velocity, which becomes abnormally reduced with decreasing perfusion pressure. Most sensitive is (iv) a reduced or lack of increase in BFV or rCBF in the compromised arterial distribution after application of vasodilatory stimuli such as carbon dioxide or acetazolamide. The percent increase of BFV or rCBF after application of a vasodilator stimulus as compared to prestimulus values (␦BFV or ␦CBF, respectively), or derivatives from it, is called the cerebral vasomotor reactivity (Ringelstein et al., 1988) or cerebral perfusion reserve (Widder et al., 1986). The brain is extremely well protected against ischemia. A whole cascade of compensatory mechanisms is operative once blood supply begins to decrease. Most important in the present context is (i) the reduction of the peripheral resistance by dilation of the cerebral arterioles and precapillary sphincters. Further, very effective compensatory mechanisms are implemented in the angioarchitecture of the cerebral vasculature, namely, (ii) the roundabout of the circle of Willis (circulus arteriosus cerebri Willisii) and, (iii) less effective, the ‘transcortical’, that is, leptomeningeal anastomoses, as well as (iv) the ophthalmic artery as an ancillary collateral pathway directly bridging the external carotid distribution with the internal one. (v) Gradually occluding processes beyond the circle of Willis (e.g. slowly progressive, non-embolizing middle cerebral artery (MCA) stenoses due to in situ atherosclerosis) can be compensated for by a moya-moya-like collateral network. (vi) Certain crucial brain areas, such as the parahippocampal gyrus or the calcarine gyrus, are supplied with a double irrigation system from both major blood flow avenues, that is, the anterior and the posterior cerebral circulation. (vii) Also very efficacious is the brain’s capacity to considerably increase the oxygen extraction rate, presumably the ‘very last reserve’ before ischemic damage occurs. Findings by Leblanc et al. (1987) in patients with highgrade ICA stenoses indicated that severe carotid stenosis is associated with a significant reduction of both CBF and hemodynamic reserve capacity in the border zone region between the ICA and MCA distribution, particularly manifested by a diminished CBF-cerebral blood volume (CBV) ratio, as well as an increased oxygen extraction fraction, in this area. In agreement with systematic positron emission tomography (PET) studies by Powers et al. (1987), Leblanc and coworkers (1987) stated that the severity of the carotid lesion per se is a poor indicator of the cerebral hemodynamic status and transhemispheric collateral blood flow via the anterior communicating artery, and its individual distribution has to be taken into consideration. With respect to the site and size of borderzone infarctions, these

authors’ observation, that in ipsilateral severe carotid stenosis the cerebral hemodynamic function may be abnormal in the anterior borderzone even if it is normal in the core MCA territory itself, is of particular interest. Recent 123Iiodoamphetamin-SPECT-studies (Moriwaki et al., 1997) again confirmed this concept in deep low-flow infarctions particularly if restrictive criteria concerning shape and site of the infarctions are applied. However, if asymptomatic or amaurosis fugax patients with severe carotid artery disease are investigated systematically by PET, no evidence for selective border zone hemodynamic impairment will be seen (Carpenter et al., 1990). The recruitment of collateral pathways in ICA occlusions (or very high-grade stenoses) follows a certain hierarchy. The sequence in descending order is anterior communicating artery, posterior communicating artery, and, as the last-ditch stand, the ophthalmic artery or other minor external carotid artery branches (Krayenbühl & Yasargil, 1979), for example, via the arteria carotidotympanica, rami tentorii, truncus meningohypophyses, and so forth (Ringelstein et al., 1994). The recruitment of naturally preformed extracranial artery-to-intracranial artery (ECA–ICA) anastomoses always indicates severe ischemic depletion of the compromised internal carotid distribution (see below). The above physiological protective mechanisms have been mimicked by keen neurovascular surgeons (Yasargil & Yonekawa, 1977) when they installed an artificial collateral pathway in patients with an insufficient circle of Willis or multiple extracranial arterial occlusions, or both. Besides the classic extracranial–intracranial bypass from the superficial temporal artery to a major branch of the middle cerebral artery, extraanatomic bypasses with autologous vein grafts, such as external occipital artery-to-intracranial vertebral artery bypasses, and so-called high-flow EC–IC bypasses (Tulleken et al., 1992) have been proposed to meet individual circumstances. Unfortunately, this approach did not turn out to be superior to conservative medical treatment in a large international prospective trial, the EC/ICBypass Surgery Trial, leaving the scientific community with the unsatisfactory feeling that the negative result of this study could have been the consequence of an inadequate selection of patients for surgery (Sundt, 1987). Mechanisms of low-flow-induced brain infarctions are listed in Table 44.1. Further details of the fluid dynamic aspects of lowflow infarctions are discussed later in ‘Vascular findings’.

Clinical findings In the history of patients with hemodynamically induced strokes, only a few features are characteristic (Table 44.2).

Border zone infarcts

Table 44.1. Pathogenesis of low-flow-induced infarctionsa Carotid borneb Very severe carotid artery lesion (90% ICA stenosis, including pseudo-occlusion or, mostly, complete occlusion) Atherothrombotic Dissection (spontaneous, fibromuscular dysplasia) Moya-moya disease (including pseudo-moya-moya, e.g. tuberculosis) Carotid clamping during surgery Traumatic carotid lesions (including irradiation) Severe systemic arterial hypotension Cardiac arrest, shock Cardiopulmonary bypass surgery Treatment of hypertension (only in combination with severe carotid lesions) Notes: a The ‘microembolic’ orgin of a watershed infarction has also been claimed in the literature, with showers of cholesterol crystals and platelet thrombi being transported into the most distal, tiny branches of the pial arteries and accumulating there to cause ischemic damage. This pathogenetic mechanism has not yet been proved unequivocally and is a rare one, if at all (see text) (Torvik, 1984; Torvik & Skullerud, 1982; Pollanen & Deck, 1989). b Low-flow infarction in carotid disease is only possible if severe insufficiency of the circle of Willis or severe lesion of the contralateral ICA is present.

There are transient ischemic attacks (TIAs), often repetitive and presenting as motor or sensorimotor hemiparesis. Sometimes, there is circumstantial evidence of a perfusion pressure-dependent mechanism of the ischemic event, such as hypostatic stress, referred to as hypostatic TIA or positional cerebral ischemia (Bogousslavsky & Regli, 1986a,b; Ringelstein et al., 1988; Caplan & Sergay, 1976). Slowly progressive visual loss in one eye due to chronic ophthalmopathy (see below), often presenting as ‘red eye’ (rubeosis iridis), is also quite characteristic, as opposed to short-lasting attacks of monocular blindness due to emboli to the retinal arteries from carotid artery or cardiac lesions. Rarely, partial seizures, also referred to as ‘transient upper limb tremor’ or ‘limb shaking’ (Waterston et al., 1990; Baquis et al., 1985; Yanagihara et al., 1985) with or without corresponding EEG-abnormalities may also occur as a consequence of marginal, fluctuating cortical ischemia in the frontal parasagittal borderzone area (compare infarction shown in Fig. 44.1(b), right side) or in the temporo-parieto-occipital triangle (see Fig. 44.1(b), left side). A transient hemichorea has also been described particularly in the deep subcortical type of low-flow infarction

Table 44.2. Clinical findings in patients with low-flowinduced infarctionsa Precentral lesions either cortical-subcortical or exclusively subcortical Crural sensorimotor hemiparesis Brachial monoparesis, mostly motor Proportional motor hemiparesis; face mostly spared, depending on involvement of corona radiata Transcortical motor aphasia (also preceded by mutism) Other, poorly defined types of aphasia Somnolence Focal myoclonic jerks (with or without epileptic seizures) In bilateral lesions (extremely rare) Akinetic mutism Apathia Paraparesis mimicking spinal lesion (pseudospinal stroke) Quadriplegia or triplegia mimicking medullary lesion (pseudobrain stem stroke) Bladder disturbances Focal myoclonic jerks (with or without epileptic seizures) Postcentral lesions either cortical–subcorticalb or exclusively subcortical Cortical hemihypesthesia Sensorimotor hemiparesis, depending on site of involvement of corona radiata; particularly stereoagnosia (‘useless hand’) Wernicke type of aphasia Other poorly defined types of aphasia Hemispatial neglect (visual, tactile) Anosognosia Transcortical sensory aphasia (extremely rare) Hemianopia, predominantly concerning lower quadrant Focal myoclonic jerks (‘limb shaking’; with or without epileptic seizures) Notes: a According to our own observations (Ringelstein et al., 1983a,b; Weiller et al., 1991a,b) and those of Bogousslavsky and Regli (1986b, 1992) and Fisher and McQuillen (1981). b This type of low-flow infarct is very difficult to define and not clearly distinguishable from thromboembolic infarctions in the lateral part of the posterior cerebral artery territory or in the posterior part of the middle cerebral artery territory.

(Waterston et al., 1990; Bogousslavsky & Regli, 1992). As opposed to patients with embolically caused cerebral infarctions, those with low-flow infarctions rarely present with a completed stroke as their index ischemic event, but frequently have a history of preceding TIAs and fluctuating symptoms with minor deficits (Ringelstein et al., 1983a,b) (Table 44.2). We also found a higher rate of preceding TIAs

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(a )

(b)

Fig. 44.1. Schematic drawings of typical low-flow-induced infarctions on CT. (a) Subcortical low-flow infarctions (so-called terminal supply area infarctions) are strictly located subcortically in the white matter and rostral to the basal ganglia. Note the strongly varying size and site. (b) Predilection sites of border zone infarctions (so-called watershed infarcts). While the anterior type can easily be distinguished from territorial infarctions by its sagittal paramedian extension parallel to the midline, the posterior type located in the parieto-temporo-occipital triangle is equivocal.

or minor strokes in low-flow infarction than in ‘pial artery territory infarctions’, with the latter finally leading to more severe deficits. All these peculiarities of the history are not spontaneously reported by the patients, but must be addressed in detail during history-taking. An unsolved question is the role of attacks of systemic hypotension for the pathogenesis of low-flow infarctions. Many authors mention this factor either referring to their patients’ histories or to the previous literature. Although simplicistic, the underlying idea is intriguing, thus tempting many writers to quote systemic hypotension as a serious risk factor. Only few investigators address this topic critically either by contradicting the presumed association of abrupt systemic hypotension and low-flow infarction (Ringelstein et al., 1994), or by sceptically specifying the triggering event as ‘postural syncope unassociated with systemic postural hypotension’ (Waterston et al., 1990). A regular causative role of systemic hypotension (e.g. during heart attacks), for the precipitation of border zone infarc-

tions has never been proven and seems very impropable with respect to the high frequency of low-output heart attacks on the one hand and the rareness of low-flowinduced strokes on the other one. Not infrequently, a complete ICA occlusion corresponding to the symptomatic side has already been diagnosed non-invasively. In conjunction with the above preceding, fluctuating or repetitive, cerebral, or ophthalmic symptoms the clinically important question frequently arises as to whether the patient suffers from a hemodynamically critical ICA occlusion, or a still embolizing ICA pseudoocclusion (Bogousslavsky & Regli, 1986a, Ringelstein et al., 1983a,b). In the latter case (pseudo-occlusion) the patient would doubtless be a candidate for carotid endarterectomy whereas in the former (definite occlusion) he or she would not. Once the symptomatology has progressed to a completed stroke, practically every hemispheric stroke symptom is possible though certain features are characteristic again. Hemiparesis is often incomplete and unproportional, particularly sparing the face (Bogousslavsky & Regli, 1992; Fisher-McQuillen, 1981). Flaccid hemiplegia is only seen in a few cases within the very first days after the ictus (see infarct in Fig. 44.2 affecting the corona radiata). Mild strokes with only minimal neurologic sequelae are a frequent finding and are often misinterpreted as TIA despite a small, fuzzy-edged, visible infarction on CT (Fig. 44.3). From our experience, forced eye deviation is transient and infrequent in hemodynamically caused strokes, as opposed to infarctions of the territorial type. The neuropsychological deficits seen in low-flow infarctions are not characteristic, except for transcortical motor aphasia, an otherwise rare subtype of aphasia that is strikingly frequent in low-flow infarctions, presumably due to undercutting of Broca’s area in the frontal centrum semiovale (see below). Depending on the extension of the subcortical lesion (i.e., the degree of damage of the arcuate fascicle and the corona radiata), however, the patients may suffer from neglect, ideomotor apraxia, acalculia, and even global aphasia (Waterston et al., 1990; Bogousslavsky & Regli, 1992). Again, even initially severe neuropsychological deficits have a relatively benign prognosis in terms of rehabilitation. Ischemic ophthalmopathy is a specific, concomitant, rarely ‘lone’ disorder of uncompensated, critically reduced perfusion pressure due to internal carotid artery occlusive disease (Carter, 1985; Copetto et al., 1985); it is also termed ischemic oculopathy (Young & Uppen, 1981), a chronic progressive disease involving nearly all compartments of the eye. Quite characteristic is the history of gradual, progressive loss of visual acuity, occasionally with bouts of obscuration, leading to slowly progressive, irreversible

Border zone infarcts

Fig. 44.2. Subcortical low-flow infarction on magnetic resonance imaging (MRI). In rare cases, the infarct may have a considerable extension in the centrum semiovale, often showing a chain-like arrangement along the cella media of the lateral ventricle (the image is from the patient described in the section ‘Therapeutic aspects’).

damage of the retinal neuronal layers. Further typical findings are neovascularization of the retina, corpus vitrium and iris (rubeosis iridis), secondary glaucoma, and cataract (Fig. 44.4). During fundoscopy, the ischemic damage of the retina is often misinterpreted as diabetic retinopathy, the more so since diabetes also induces neovascularization. Once opacification of the cornea, lens, or corpus vitrium has occurred, the correct diagnosis can easily be missed. Without simultaneous aggressive treatment by neurovascular surgeons and ophthalmologists, ischemic ophthalmopathy will lead to irreversible blindness. By contrast, timely treatment will promptly improve visual acuity and can even restore vision of a recently blind eye. The course of the ischemic eye disease is not well investigated, presumably due to the rarity of such patients, but from our experience the spontaneous prognosis is poor. As mentioned above, simple partial, sensorimotor seizures with or without Todd’s paresis may occur as a consequence of chronic, fluctuating cortical ischemia, also referred to as ‘limb shaking’ in the literature (Baquis et al.,

1985; Yanagihara et al., 1985). The most common epileptiform pattern seen on electroencephalography (EEG) is a dysrhythmic focus at the typical sites of cortical borderzone infarctions, or, even more characteristic, so-called periodic lateralized epileptiform discharges (PLEDs) (Chatrian et al., 1964; Markand and Daly, 1971; Westmoreland et al., 1986). The discharges are periodic or pseudoperiodic and are often accompanied by motor effects. They tend to subside over periods of days or weeks, but may become chronic. The electrical and corresponding clinical phenomena of borderzone ischemia preferably were attributed to ischemic lesions in the ‘temporo-parieto-occipital triangle’ (Gastaut & Naquet, 1996; Gastaut et al., 1971; Karbowski, 1975), but may also occur in frontolateral ischemic foci. In borderzone infarctions, the discharges occur in the acute phase at the affected site and are clinically paralleled by contralateral or bilateral myoclonus of the paretic limb(s) or continuous contralateral focal motor seizures (epilepsia partialis continua, Kozhevnikov’s or Kojewnikow’s epilepsy), simple partial seizures, Jacksonian seizures, or even secondary grand mal seizures, with eventual Todd’s paresis or postictal deterioration of other focal deficits. Bilateral, symmetric, periodic epileptiform discharges are not characteristic of focal ischemic brain infarction unless it is very large and space occupying, or multifocal or if global ischemia is present. PLEDs are unspecific, although they reflect a localized, excitatory state in the penumbral margins of an ischemic lesion. The zone of marginal but not complete ischemia is particularly large in low-flow infarctions (Weiller et al., 1991) (compare Fig. 44.9), thus facilitating the occurrence of focal seizures. This view would also meet a previous explanation of the transient and alternating focal periodic pattern of the discharges, namely that its ‘periodicity’ represents the time constant of recovery of an electrochemical process at the cellular level’ under ischemic conditions (Cobb, 1979). Natural ECA–ICA anastomoses, once activated, can easily be identified by ultrasonography, but may already be detected during careful physical examination as unphysiologic ‘facial pulses’. These pulses are detected unilaterally or bilaterally by palpating the skin in the periorbital region, particularly along the eyebrow and in the angle between nose and eye. The competence of these collaterals for a sufficient blood supply of the entire hemisphere is questionable. Compression of single feeders of these channels (e.g. the facial artery, or superficial temporal artery) does not, however, lead to transient ischemic attacks. Presumably, a whole network of minor collateral pathways fed by ECA branches is operative in the depth of the facial skull, and facial pulses only represent the ‘tip of an iceberg’, albeit a diagnostically intriguing one.

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(a )

(b )

Fig. 44.3. Very small subcortical low-flow infarction on CT (a) and MRI (b). Note the fuzzy-edged appearance on CT (arrow) and the bright appearance on MRI.

Spontaneous course of cerebral low-flow states A detailed prospective analysis of the clinical prognosis of low-flow infarctions in terms of recurrence rate and disability has not been published, presumably because there is no internationally accepted definition of how to diagnose a low-flow infarction on CT or MRI, and the number of patients with low-flow-induced infarctions is much smaller than that of thromboembolically induced ones. Wedge-shaped infarctions located at the frontolateral or parieto-occipital boundary of the MCI territory are equivocal, and in most publications they are interpreted or misinterpreted as watershed infarctions, thus contaminating the truly ‘hemodynamic’ cohorts investigated with patients suffering from thromboembolic strokes. Nevertheless, on the basis of publications with well-documented lesions that are highly likely to be low-flow induced, some prognostic trends can be pointed out. Because of the initially frequently fluctuating symptoms with a ‘remitting–relapsing’ pattern, the early recurrence rate appears high and has been 12% within one week in one of our cohorts (Weiller et al., 1991). Several weeks later, on release from the hospital, 41% (7 of 17) of the patients had no neurologic deficit, and another patient had improved considerably. In the Lausanne cohort, six of nine patients with comparable low-flow infarcts had no or only

mild disability (Bogousslavsky & Regli, 1992). The relatively better prognosis of hemodynamically induced strokes, as compared to thromboembolic ones, has already been emphasized (Ringelstein et al., 1983a,b). For more than 17 years, intracranial low-flow states due to carotid artery occlusive disease have been investigated by transcranial ultrasonography. One major result has been that an exhausted or severely compromised vasomotor reserve will spontaneously improve over several weeks or months in most cases (Ringelstein & Otis, 1992; Widder et al., 1994) (Fig. 44.5). Follow-up studies by single-photon emission tomography (SPECT) imaging revealed almost complete improvement of vasodilatory capacity one year after the initial assessment in a considerable proportion of patients (Hasegawa et al., 1992). This favourable outcome is, however, less likely in patients with bilateral ICA occlusions (Hasegawa et al., 1992; Kleiser et al., 1992). Obviously, sufficient recruitment of collateral flow to the impaired vascular territory of the brain needs both time and intact alternative arterial pathways that still have the capacity to share their blood with compromised vascular beds (Fig. 44.5). Quite contrary to the relatively low rate of stroke recurrence, the general medical prognosis is not good. Deaths due to cardiovascular complications are frequent and account for an approximately 10% death rate per year (Bogousslavsky & Regli, 1986a,b).

Border zone infarcts

(a )

(b)

Fig. 44.4. Ischemic ophthalmopathy. (a) Outer aspect of the eye with rubeosis iridis, generalized strong neovascularization, and opacification of the cornea and lens. (b) Appearance of the fundus oculi in ischemic ophthalmopathy.

By careful prospective evaluation of a large series of patients with internal carotid artery occlusion(s), Kleiser et al. (1992) demonstrated that the spontaneous clinical course of patients with exhausted vasomotor reserve is much worse than that of those with a normal or only mod-

erately reduced perfusion pressure, despite identical extracranial lesions. This is even true with medical treatment and vascular risk reduction. This unfavourable prognosis refers to patients with both recurring TIAs and completed strokes (Kleiser et al., 1992; Fig. 44.6). During a recent

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(a )

(b)

Fig. 44.5. Spontaneous course of vasomotor reactivity (VMR) in patients with unilateral and bilateral internal carotid artery occlusion over time. (a) Unilateral ICA occlusions (n ⫽ 32). Patients were re-examined after 18 ⫾ 8 months. VMR showed a highly significant improvement from a mean of 49.8 ⫾ 22% to a mean of 61 ⫾ 22%, P ⫽ 0.001. In two cases, deterioration of VMR occurred for unknown reasons. Another two patients with severe VMR impairment did not improve at all. (b) Patients with bilateral ICA occlusion (n ⫽ 22). Patients were re-examined after 22 ⫾ 5 months, VMR showed non-significant changes from a mean of 42.3 ⫾ 22.8% to 46.8 ⫾ 19.4%. Lack of improvement reflects the bilateral exhaustion of collateral pathways.

controversy in the literature about stroke recurrence in ICA occlusions, some authors emphasized a good prognosis (Bornstein & Norris, 1989) while others were struck by an unexpectedly poor outcome. Both observations can be true and the discrepancy would be explained by arbitrary recruitment of cohorts with different hemodynamic compromise since the individual cerebrovascular reserve had not been considered as a factor modifying prognosis.

Vascular findings The diagnosis of a low-flow-induced infarction requires at least two prerequisites: The low-flow state within the vasculature has to be proved by an adequate technique (e.g. transcranial ultrasound, SPECT, PET), and the pattern of infarction during brain imaging on CT or MRI should be characteristic of low-flow-induced lesions. Typical angiographic findings of a hemodynamically compromised arterial distribution of the brain have been pointed out by neuroradiologists. Characteristic are (i) very severe extracranial occlusive disease (Fig. 44.7), (ii) delayed flow of contrast medium downstream to the lesions with faint but prolonged opacification of the vascular tree if at all, (iii)

incompleteness of the circle of Willis (Fig.44.8), and (iv) recruitment of leptomeningeal anastomoses to the MCA territory, mostly from the anterior (ACA) or posterior cerebral arteries (PCA), or both. Vice versa, retrograde flow is also possible to the distribution of a proximally occluded ACA or PCA with collateral support from the MCA. An important diagnostic step forward was the use of rCBF techniques, like the 123I-iodoamphetamine- or the hexamethyl prophylenenamine oxime (HMPAO)-SPECT and stable xenon-computed tomography (Xe-CT). Due to their relative noninvasiveness, rCBF measurements can be applied repetitively, that is, before and after stimulation of the cerebral vasodilators by carbon dioxide or acetazolamide. Individuals with an exhausted cerebrovascular reserve can unequivocally be identified (Moriwaki et al., 1997). Investigators could also prove that EC–IC bypass surgery can completely compensate for carotid-borne hemodynamic compromise. Brain imaging techniques, however, are expensive and limited to large centers, and they subject the patient to repetitive ionizing radiation. Another problem is that SPECT may not be informative in patients with symmetrically reduced vasomotor reactivity. It was the advent of transcranial Doppler sonography in conjunction with carbon dioxide-based or acetazolamide

Border zone infarcts

573

80

80 Exhausted (n = 11) %

%

60

60

40

40

Exhausted (n = 11)

Diminished (n = 26) 20

20 Diminished (n = 26)

Sufficient (n = 48)

Sufficient (n = 48) 0 0

6

12

18

24

30

36

Months

0

0

6

12

18

24

30

Months

Fig. 44.6. Outcome of ICA occlusions in patients with different degrees of vasomotor reserve. (Left) All ipsilateral ischemic events, including TIA. (Right) Ipsilateral ischemic strokes. Eighty-five patients are divided into three groups with sufficient (n ⫽ 48), diminished (n ⫽ 26), and exhausted (n ⫽ 11) carbon dioxide reactivity (from Kleiser et al., 1992 with permission).

stimulation of cerebral vasomotors that made large, systematic, and long-lasting prospective studies possible (Ringelstein et al., 1988, 1994; Widder et al., 1986; Ringelstein & Otis, 1992; Kleiser et al., 1991, 1992). Extracranial continuous-wave Doppler sonography and B-mode imaging, particularly colour-coded B-mode scanning of the neck arteries, can unequivocally demonstrate high-grade ICA stenoses or occlusions. High-grade carotid lesions (⬎90% stenosis or occlusion) are a prerequisite for low-flow infarctions or ischemic ophthalmopathy to occur, whereas moderate stenoses cannot lead to these sequelae. In very rare cases, a subtotal stenosis or occlusion of the common carotid artery will also lead to far-downstream, intracranial hemodynamic exhaustion. Hemodynamically critical carotid lesions are nearly always associated with a retrograde flow through the ophthalmic artery and its periorbital branches (particularly the supratrochlear artery). The higher the retrograde flow velocity, the more compromised is the corresponding hemisphere (Tada et al., 1975; Knop et al., 1992). Experienced ultrasound laboratories can reliably pinpoint the above diagnoses. A potential diagnostic pitfall is, however, the differentiation between complete ICA occlusion and pseudo-occlusion

(Ringelstein et al., 1983; Görtler et al., 1994; Ringelstein, 1998). The clinical consequences of a false diagnosis have already been mentioned. While Doppler ultrasound is superior to both short-series conventional arteriography and intravenous digital subtraction arteriography (IV-DSA; (Ringelstein et al., 1983a,b)), and magnetic resonance angiography (MRA) in detecting pseudo-occlusions, intraarterial (IA) DSA is thought to be superior to ultrasound. Colour-coded flow imaging, a new, sophisticated B-mode imaging technique (Görtler et al., 1994), combined with the application of echocontrast agents (Ringelstein, 1998) turned out to be very reliable in detecting pseudo-occlusions non-invasively. In doubtful cases, IA-DSA should be performed as soon as possible to clarify the diagnosis and the therapeutic strategy (Ringelstein et al., 1983a,b). Transcranial Doppler sonography (TCD) will provide the key findings for the diagnosis of a critical low-flow state. These include (i) low flow-velocity and/or reduced pulsatility in the affected basal brain artery, (ii) retrograde high flow-velocity within the ophthalmic artery (the ophthalmic artery can directly be insonated by means of TCD), and (iii) an incomplete circle of Willis with a lacking or extremely hypoplastic anterior communicating artery

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Vasomotor reactivity in ICA stenoses and occlusions n.s. (P = 0.288)

125

n.s. (P = 0.925)

n.s. (P = 0.053)

VMR (%)

100

P = 0.0006 P < 0.0001

75

n = 10 n = 40 n = 36

50

n = 13 n = 23 n = 21

25

n = 32

Normals

60

70

80

90

99

Unilateral ICA occlusion

Degree of stenosis (%) Fig. 44.7. Vasomotor reactivity and severity of ICA stenoses and occlusions. The VMR values of 135 middle cerebral artery territories are shown (mean values ⫾SD). VMR in 60% ICA stenoses corresponds to normal control, that is 86 ⫾ 16%. VMR is lowest in ICA occlusions. As soon as the degree of stenosis reaches 80%, VMR is significantly different from normal (P ⫽ 0.053). Note that even in ICA occlusion, VMR may be normal in individual cases.

(ACoA) or A1 segment of the ACA, mostly in conjunction with an additionally lacking ipsilateral posterior communicating artery (PCoA) or P1 segment of the PCA (see Fig. 44.8). (iv) Additionally, a markedly reduced vasomotor reserve as evaluated by means of carbon dioxide inhalation (with or without a hypocapnic phase) or by IV injection of acetazolamide must also be present. When comparing the effect of capnic stimuli to acetazolamide injection, we found the two techniques equivalent in identifying patients at risk (Ley-Pozo et al., 1990). By contrast, the pulsatility index only discriminates between groups of normal or reduced vasomotor reserve, but is not reliable enough in the individual case (Ley-Pozo et al., 1990). There is a worldwide consensus among all investigators that only a dramatic reduction in vasomotor reactivity can induce clinically apparent low-flow related symptoms and ischemic retinal or brain damage. For instance, with the technique described by our group (Ringelstein et al., 1988), the vasomotor reactivity within the MCA territory in normal control subjects is 86⫾ 16%. Only after the reduction of this mean value by 3 (!) standard deviations, that is, with a vasomotor reactivity below 39%, do ischemic oph-

thalmopathy, hypostatic TIAs, and borderzone infarctions occur (Table 44.3). Nearly identical findings have been published by Kleiser et al. (1991). The circle of Willis plays a key role and determines whether or not a given patient with complete ICA occlusion will suffer low-flow induced stroke (Norrving et al., 1982; Ringelstein et al., 1994; Keunen et al., 1989). Systematic anatomic, as well as angiographic, studies of the circle of Willis revealed that fewer than 8 to 15% of humans lack either of these collateralizing pathways, leading to an ‘isolated’ middle cerebral artery or a combined ‘isolated’ MCA plus ACA-trunc (Decker & Hipp, 1963). With this unfavorable constellation (see Fig. 44.8), the critical reduction of vasomotor reactivity due to extracranial ICA occlusion occurs significantly more frequently, than in individuals with a more complete circle of Willis and will significantly more often lead to low-flow infarction of the brain than with an intact interhemispheric crossflow (Ringelstein et al., 1994). To summarize: With a complete, large-caliber circle of Willis and intact vertebral arteries, a low-flow induced brain infarction (borderzone infarction) is not possible, even in cases with bilateral ICA occlusions.

Imaging of low-flow induced brain infarctions Various brain imaging techniques can demonstrate the low-flow-induced infarction itself (Torvik, 1984; Bogousslavsky & Regli, 1986a,b; Weiller et al., 1991b; Ringelstein et al., 1983a,b) or the more widespread area of hemodynamic compromise ((Hasegawa et al., 1992; Yonas et al., 1987; Knop et al., 1992; Büll et al., 1988 Chollet et al., 1989); Fig. 44.9). T2-weighted magnetic resonance tomography (T2-MRT) is presently the most reliable technique to demonstrate structural ischemic lesions (see Fig. 44.2), whereas CT is less sensitive (see Fig. 44.3). Particularly, the subcortical type of low-flow-induced infarction may be small, with fuzzy edges, and can be overlooked on CT. The same lesion appears much more prominent on T2-MRI (see Fig. 44.3). The specific topographic features of lowflow infarctions of the brain are evidenced in Figs. 44.1 through 44.3 and 44.8 and 44.9. The cortical border zone (or watershed) area between the cerebrovascular territories may vary considerably, not only between individuals but also intraindividually between the left and right hemisphere. These critical areas represent ‘the meeting point of two opposite streams from two adjacent arteries connected by (leptomeningeal) anastomoses’ (Van der Swan & Hillen, 1993). Since the perfusion pressure from both arteries in this boundary is equal,

Border zone infarcts

(b) (a)

(c)

Fig. 44.8. Illustrative case of ‘isolated’ middle cerebral artery and anterior border zone infarction. (a) Unequivocal border zone (watershed) infarction in the boundary zone between the territories of the anterior and middle cerebral artery. Note the sagittal paramedian extension of the infarct (arrow), not compatible with any subterritory of either artery. (b) The circle of Willis is incomplete on the left (i.e. patient’s right side) with a lack of anterior cross-flow (open asterisk), and only minimal posterior blood supply (closed asterisk). Collateral blood flow to the whole hemisphere is nearly completely dependent on the ophthalmic artery backflow (triangle). (c) Severely reduced vasomotor reactivity (VMR ⫽ 28%) measured within the right middle cerebral artery confirming the expected critical reduction in cerebral perfusion pressure. ICA ⫽ internal carotid artery.

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Table 44.3. Clinical findings in ICA unilateral occlusions related to vasomotor reactivity (n⫽40 patients)

VMR (%)

Occluded ICA (no.)

Ischemic ophthalmopathy (no.)

ⱕ 38 39–66 ⱖ 67

12 20 8

3 – –

Hypostatic TIA (no.)

Low-flow infarct on CT (no.)

2 – –

6 – –

Note: VMR = vasomotor reactivity; normal range: 86 ⫾ 16 %. Source: Ringelstein et al. (1988).

the term ‘equal pressure boundary’ was proposed (Van der Swan & Hillen, 1993; Van der Swan et al., 1992). The variability in anatomy does not, however, mean that a watershed-type infarct cannot be diagnosed as such, as long as its location, extension, and size are typical (Hupperts et al., 1996; Ringelstein et al., 1994). In the case demonstrated in Fig. 44.8, the infarct is unequivocally of the borderzone, or watershed, type, that is, an equal pressure boundary infarction, since it cannot be explained by MCA or ACA branch occlusion even with the most unusual variability of the vascular anatomy (compare also, infarct in Fig. 44.1, templates 3 and 4 in Bogousslavsky & Regli, 1986). By contrast, wedge-shaped cortical infarctions in the lateral frontotemporal and parieto-occipital junction are frequently misinterpreted as hemodynamically induced (compare Fig. 44.1, templates a and b, and Fig. 44.2, templates 2–4 in Bogousslavsky & Regli, 1986). Particularly, the parieto-occipital borderzone infarctions at the MCA–PCA junction are difficult, if not impossible, to distinguish from embolically caused territorial infarctions in the most posterior part of the MCA distribution (see Fig. 44.1(b), left side). Since the location of the infarct is equivocal, such patients should be excluded from scientific studies where the low-flow genesis of the infarction is an inclusion criterion. In clinical practice, these patients should be considered as potentially having either type of infarct. Not infrequently, the subcortical extension of low-flow infarction is combined with the cortical type, either the frontolateral or temporo-parieto-occipital borderzone infarction, indicating an extremely severe hemodynamic compromise (see parietooccipital involvement of the cortex by the chain of lesions visible in Fig. 44.2). In atherothrombotic ICA occlusion, infarctions are of the territorial type in 80% to 90% of cases, whereas low-flow infarctions are rare (Bladin & Chambers, 1993; Ringelstein

et al., 1983a,b). If the occlusion is caused by an ICA dissection, however, low-flow infarcts occur in approximately half of the patients (Weiller et al., 1991b). This reflects the rapidity with which the occlusive process occurs in dissections as opposed to atherothrombosis, and the inability of the cerebral vasculature to recruit collateral pathways quickly enough. By contrast, in Moya-moya disease the progression of the vasculitic process is slow enough to allow bizarre collateral networks to form, but the occlusions of the large basal arteries are (i) multiple, (ii) far distal, that is, close to the circle of Willis, and (iii) mostly complete, with the consequence that in the end the maximum recruitment of compensatory mechanisms cannot prevent the occurrence of low-flow infarctions, which nearly exclusively are of the subcortical type, often in a chain-like arrangement (Suzuki & Kodama, 1983; Kuwabara et al., 1990; Weiller et al., 1991b). Another problem is the differentiation of microangiopathic lacunar infarctions localized in the centrum semiovale, which, simultaneously, represents the terminal supply area of the penetrators (Bladin & Chambers, 1993; Waterston et al., 1990; Bogousslavsky & Regli, 1992). This is why the predilection site of the subcortical type of low-flow infarctions overlaps with lacunae. If the infarct exceeds 2 cm in diameter, it is probably hemodynamically caused (Krapf & Widder, 1994; Bogousslavsky & Regli, 1992). Infarctions with a diameter of less than 1.5 cm are equivocal, however, and additional characteristic features of subcortical low-flow infarctions have to be taken into consideration. These lesions very frequently show a chain-like arrangement in the affected hemisphere extending more or less in a sagittal direction along the centrum semiovale (Fig. 44.2). Unilaterality and a string-like arrangement of the small lesions strictly contradict a microangiopathic causality since severe small vessel disease is diffusely distributed with multiple lesions over both hemispheres (see also SPECT below). Büll et al. (1988) and Weiller et al. (1990, 1991b) had the idea of simultaneously imaging low-flow infarction by means of both CT and SPECT. While on the CT images, a low-flow-induced infarction may be small and hardly seen (see Fig. 44.3), SPECT (and comparable techniques, such as PET) immediately evidence the true extent of the lesion and the nature of its underlying pathophysiology by a striking mismatch (see Fig. 44.9). Severe rCBF reduction or, even more sensitive, the decrease in the rCBF/rCBV ratio indicates severe hemodynamic compromise. The region of a severely reduced vasomotor reserve, as a rule, excessively surmounts the small area of complete infarction visible on CT, thus giving a more realistic impression of the severity and extension of the critical drop in perfusion pressure and

Border zone infarcts

Fig. 44.9. Subcortical low-flow infarction on CT and corresponding rCBF defect on HMPAO-SPECT. (a) The low-flow infarct is visible on the left in the corona radiata, sparing cortex and basal ganglia (vertical arrow). Note also the smaller lesion in chain-like arrangement (horizontal arrow). (b) During HMPAO-SPECT imaging, a large and significant reduction in semiquantitative rCBF is visible, covering nearly the entire MCA distribution.

blood supply (Fig. 44.9). By contrast, in territorial infarctions of the cortex, the infarcted area visible on CT nearly exactly corresponds to the region of the reduced rCBF, or rCBF/rCBV ratio, respectively. Knop et al. (1992) combined SPECT imaging with TCD investigations. They found a strikingly close correspondence of side-to-side asymmetry in tracer uptake with markedly reduced flow velocities in the regional pial arteries. The question remains as to why a few patients present with the typical appearance and location of a borderzone infarct but, simultaneously, have an intact vasomotor reactivity. This seemingly contradictory phenomenon can be explained by the frequent spontaneous improvement of an exhausted cerebrovascular reserve within weeks or months (see Fig. 44.5). And vice versa, why do patients exist

with a very low vasomotor reactivity but a territorial distribution of their brain infarct? In these cases, the insufficient circle of Willis cannot compensate adequately for the drop in cerebral perfusion pressure (downstream to high-grade stenoses or complete ICA occlusions), but independently, the carotid lesion had led already to an artery-to-artery embolus occluding the corresponding pial artery. Unfortunately, the terms watershed infarctions and borderzone infarctions have been overused in the recent literature, leading to evident misdiagnosis and confusion. For instance, in a recent paper on three cases by Graeber et al. (1992), none of their patients fulfilled the criteria of lowflow-induced infarction pointed out in this chapter, and we would have diagnosed a territorial type of infarct with an underlying thromboembolic pathogenesis in at least two

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of their three cases. In Wodarz’s paper (1980), the subcortical low-flow infarctions are correctly presented in a schematic drawing (see their Fig. 3 middle template), whereas the cortical type of watershed infarction is not (see their Fig. 3, left template). The lesions shown may represent typical infarctions that result from embolic occlusions of distal anterior or posterior MCA branches. Similarly, seven patients recently described by Angeloni et al. (1990) as having ‘internal borderzone infarction’ due to embolic MCA main stem or MCA branch occlusion provide another striking example of the present lack of precision in the use of the above terminology and of the subsequent misunderstandings about the underlying pathophysiology. The CT of one of their illustrative cases with ‘extensive internal border zone infarction involving the corona radiata’ clearly demonstrates a so-called ‘large striatocapsular infarct’, which is very characteristic of embolic MCA occlusions (Ringelstein et al., 1983a,b, 1989; Weiller et al., 1990; Bladin & Berkovics, 1984). As pointed out already, the subcortical type of low-flow-induced infarction can only be diagnosed if neither the cortex nor the basal ganglia is involved on CT or MRI (see Figs. 44.2 and 44.9).

Therapeutic aspects Theoretically, the installation of an EC–IC bypass, mimicking an oversized ophthalmic artery or communicating segment of the circle of Willis, and compensating for an unfavorable configuration of the latter, should help to overcome the threat of ischemic damage in the hemodynamically compromised MCA distribution. This is in fact the case if the ‘right patient’ is selected at the ‘right time’, and operated on by the ‘right neurovascular surgeon’. Ideal candidates for this procedure, that is, those who will benefit from it with high probability, are difficult to assess because spontaneous improvement of the exhausted vasomotor reserve is the rule. It is particularly crucial to identify the rare exceptions from this rule. In any case, potential candidates for EC–IC bypass surgery would constitute an extreme minority of stroke-prone or stroke patients. Three aspects, however, justify further consideration of EC–IC bypass surgery (or comparable procedures) for treatment of patients with hemodynamically caused minor strokes or ischemic oculopathy in order to prevent permanent deficits. First, the general prognosis of medically treated patients with ICA occlusions paralleled by an exhausted vasomotor reserve is poor (Bladin & Chambers, 1993; Kleiser et al., 1992; Yonas et al., 1993). Secondly, restoration of cerebrovascular reserve after bypass surgery occurs

Table 44.4. Preoperative evaluation of cerebral vasomotor reactivity in patients undergoing major surgery (n⫽71) Type of surgery Cardiopulmonary bypass Bowel resection Aortic aneurysm Others

37 21 7 6

Type of vascular lesion ⬎ 80% ICA stenoses (unilateral) ICA occlusion Bilateral ⬎ 80% ICA lesions Three-vessel disease Four-vessel disease Others

31 8 12 11 4 5

Vasomotor reactivity Normal (ⱖ 66%) Reduced (ⱖ 38%-65%) Exhausteda (⬍ 38%)

25 44 2

Note: a ⱕ38 is 3 standard deviations below normal range (86 ⫾ 16 %).

promptly and is sufficient (Anderson et al., 1994). Thirdly, beneficial effects in individual patients have been documented convincingly (Anderson et al., 1994; Vorstrup et al., 1985). With respect to neurovascular surgery, five additional groups of patients are of particular interest. (i) For many years, we have used the TCD-based evaluation of cerebrovascular reserve in those scheduled for cardiac or other major surgery who simultaneously suffer from carotid artery occlusive disease. The purpose of cerebrovascular reserve testing in this cohort is to select individual patients for preventive carotid endarterectomy who would otherwise be at risk for perioperative hemodynamic stroke. Table 44.4 indicates that this evaluation protects nearly all patients against unjustified carotid surgery, since their vasomotor reactivity is normal or only moderately reduced. However, stroke represents a major iatrogenic complication of cardiopulmonary bypass surgery and occurs in at least 1 to 5% of such procedures. In order to reduce the incidence of stroke associated with cardiosurgical procedures and other major surgery, it is important to determine its true mechanism. Authors of several recent papers have addressed this issue and have come to the conclusion that the majority of strokes associated with open-heart surgery are embolic in nature (Krul et al., 1989; Hise et al., 1991; Rankin et al., 1994), and only a minority

Border zone infarcts

are considered to be due to hypoperfusion causing infarction in the borderzone between major arterial territories (Hise et al., 1991; Rankin et al., 1994). Nevertheless, there still remains an association of patients classified as having borderzone infarctions with extracranial severe carotid occlusive disease or severe hypotension, or both, during cardiopulmonary bypass surgery. Thus, strategies for stroke prevention during cardiopulmonary bypass should continue to focus on both the prevention of cerebral emboli and the maintenance of adequate cerebral perfusion intra- and postoperatively, particularly in the face of already proven extracranial or intracranial cerebrovascular disease. (ii) A major therapeutic issue is the salvage of an ischemically threatened eye in patients with chronic progressive ophthalmopathy. From our experience, the timely intervention with EC–IC bypass surgery (or carotid endarterectomy) paralleled by goniotomy to prevent acute secondary glaucoma, as well as repetitive laser coagulation of the ocular neovascularization, will successfully preserve or even restore visual acuity of the affected eye. The simultaneousness of the neurovascular and the ophthalmologic intervention is the key issue (Carter, 1985; Copetto et al., 1985). In the individual patient, the therapeutic potential of this approach can be tremendous. One of our patients with a glass eye due to a war injury on the right, and progressive ischemic ophthalmopathy on the left due to ICA occlusion, became completely blind within 3 months despite various therapeutic attempts by ophthalmologists. After an EC–IC bypass connecting the superficial temporal artery with the M2 segment of the middle cerebral artery, the siphoning effect of the cerebral circulation on the ophthalmic and central retinal arteries was reduced to the extent that flow velocity in the retrogradely perfused ophthalmic artery decreased. Immediately afterward the patient could already distinguish silhouettes, and his vision improved within a few months to such a degree that he could read newspapers again. (iii) In other cases, untreatable severe arterial hypertension was the complaint that led to a more sophisticated management. As soon as blood pressure approached normal range, these patients suffered from hypostatic TIAs due to ‘positional cerebral ischemia’ (Caplan & Sergay, 1976). Within 15 years, we have seen four of these cases. Our first approach was ‘to wait and see’ for approximately 6 months. This led to a gradual improvement of vasomotor reactivity in only one of the four patients allowing for adequate antihypertensive treatment. This policy was not successful, however, in the three other patients, who finally had to be subjected to EC–IC bypass surgery to make their arterial hypertension treatable. The risk of the surgical pro-

cedure if performed by a skilled neurovascular surgeon is about 10% major complications but this seems to be lower than the sequelae of a long-standing severe hypertension over decades. (iv) Further potential indications for bypass surgery are patients with Moya-moya disease and recurring strokes (including those with cryptogenic pseudo-moya-moya) in whom the underlying inflammatory occlusive process has not yet come to a spontaneous end. These patients are threatened by high-grade carotid syphon or MCA stenoses, which could progress to complete pial artery occlusions (Suzuki & Kodama, 1983). Bypass surgery (Matsushima et al., 1992) or encephaloduroarteriomyosynangiosis (Kinugasa et al., 1993) would protect these patients against hemodynamically caused infarction, but platelet inhibitors would also become necessary in order to prevent thromboembolic complications. (v) In certain neurosurgical emergencies, EC–IC bypass surgery is the only means to prevent ischemic brain infarction. Such a critical situation is not infrequently seen in aneurysm surgery, in which long-lasting or permanent clamping of major brain arteries is unavoidable (Spetzler & Carter, 1985). Very rarely, comparable emergency situations also occur in neurologic patients, in whom EC–IC bypass surgery could prevent major strokes. One such patient was recently seen in our department. In his mid40s, this gentleman suffered two TIAs with right-sided hemiplegia and global aphasia. Ultrasound investigations revealed a subtotal ICA stenosis 3 cm beyond the carotid bifurcation caused by spontaneous ICA dissection. The diagnosis was confirmed arteriographically. Unfortunately, the patient lacked an ACoA and PCoA on the same side. His ophthalmic artery revealed retrograde hyperperfusion, and he complained of fluctuating visual acuity in the right eye. On the next day, the MRI was normal, vasomotor reactivity was completely exhausted, and the patient was presented to a neurosurgeon for EC–IC bypass surgery in fear of progression of the dissection to complete occlusion. The surgeon rejected bypass surgery on an emergency basis, and on the subsequent night the patient suffered a severe hemodynamically induced stroke due to complete ICA occlusion. The resulting infarcts are shown in Fig. 44.2. This case history again emphasizes the key role of the circle of Willis and suggests a definite, though rare, place for EC–IC bypass surgery in the management of stroke-prone patients. In conclusion, the ‘wait-and-see’ policy seems to be justified under careful control in many patients with recent hemodynamically caused ischemic events, except for those with a surgically accessible, high-grade ICA stenosis. The latter should be operated on. Progressive ischemic eye

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disease is a strong indicator for vascular-surgical reconstruction either extracranial or intracranial. Another randomized and prospective EC–IC bypass surgery trial on highly selected patients is necessary to define its therapeutic value. The selection of candidates should not only rely on an exhausted vasomotor reserve, or ischemic neurologic and ophthalmologic findings, together with an extracranial ICA occlusion and rapid retrograde flow through the ophthalmic artery, but should also consider the insufficiency of the circle of Willis on the affected side as an equally important criterion.

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45

Classical lacunar syndromes John M. Bamford St James’s University Hospital, Leeds, UK

Introduction Few aspects of cerebrovascular disease have generated such intense debate as that of lacunar stroke, although in recent years there has been a more reflective appraisal of the validity and utility of the central tenets of the concept. At the outset, in order to avoid the confusion which is rife in the literature, one needs to have a clear understanding of the terminology. The term lacune is best reserved for a pathological lesion observed at autopsy. A complete classification of lacunes will include the residua of small hemorrhages and also dilatation of the perivascular spaces, but the term is usually used to describe an area of infarction within the territory of a single perforating artery (Poirier & Derouesne, 1984). In theory, CT and MRI allow us to image lacunes in vivo, but there have been very few cases in the literature that have demonstrated precise radiological–pathological correlation, and use of the term lacune as a purely radiological phenomenon should be discouraged. I will use the more neutral term small, deep infarct (SDI), with the presumption that the imaged area of infarction is within the territory of a single perforating artery, although on this matter there is clearly considerable inter- and intraindividual variation (Van der Zwan, 1991). A convention has evolved that, for an SDI to equate with a lacune, the maximum diameter of the imaged lesion should be no greater than 1.5 cm, a figure derived from the original pathological studies which, for the most part, were of chronic lesions (Fisher 1965a, 1969). However, of importance in an era of increasingly acute imaging is the fact that the lesions on CT, and more particularly MRI, may be significantly larger than in the chronic phase or at autopsy (Donnan et al., 1982). Conversely, with techniques such as diffusion weighted imaging there is evidence that the area of signal abnormality may increase over a period of up to 3 days (Schwamm et al., 1998).

Patients with lacunes may present with a large number of clinical stroke syndromes (Orgogozo & Bogousslavsky, 1989; Fisher, 1991). It could be argued that any clinical pattern that has been linked convincingly to a pathological lacune (or equivalent imaged SDI) should be referred to as a lacunar syndrome (LACS). Rare associations, perhaps due to idiosyncratic variations in vascular anatomy, can be of immense value to neuroanatomists, but are of little practical use to clinicians. Thus, the prefix classical, which can be defined as ‘original’ or ‘predictive’, is useful. It will be the predictive properties of these LACS on which I shall concentrate, in line with a recently proposed classification of subcortical infarctions suggesting that the term lacunar syndrome ‘should be restricted to a clinical situation where the mechanism of infarction involves transient or permanent occlusion of a single penetrating artery with a high degree of probability’ (Donnan et al., 1993). Finally, it is worth stressing that we are considering the value of LACS from the point of view of the clinician faced with an individual patient who has presented with a particular constellation of symptoms and signs. Clinical paradigms of this type cannot be used as a way of detecting all lacunes since as many as 80% are clinically ‘silent’ (Tuszynski et al. 1989).

The classical lacunar syndromes A handful of syndromes which initially were correlated, more or less convincingly, with relevant lacunes observed at subsequent autopsy have come to be regarded as the classical LACS – pure motor stroke, pure sensory stroke, homolateral ataxia and crural paresis, dysarthria-clumsy hand syndrome, ataxic hemiparesis, and sensorimotor stroke.

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Pure motor stroke (PMS) The association of pure motor deficits and lacunes has been recognized for over a century, particularly in the French literature (Besson et al., 1992; Hauw, 1995), but the synthesis of this clinico-anatomic correlation came much later (Fisher & Curry, 1965). Fisher and Curry defined the syndrome as: a paralysis complete or incomplete of the face, arm and leg on one side not accompanied by sensory signs, visual field defect, dysphasia, or apractagnosia. In the case of brainstem lesions the hemiplegia will be free of vertigo, deafness, tinnitus, diplopia, cerebellar ataxia, and gross nystagmus. . . . This definition applies to the acute phase of the vascular insult and does not include less recent strokes in which other signs were present to begin with, but faded with the passage of time.

That statement put the fundamental neuro-anatomic concept involved in the diagnosis of LACS into clinical terminology. If a patient presents with symptoms and signs that fulfil the foregoing criteria, it is most likely that the symptomatic lesion will be in an area where the motor fibres are close together; otherwise the lesion would have to be so extensive that non-motor symptoms or signs, and in particular those associated with dysfunction of the overlying cortex, would almost certainly be present. From a clinical point of view it is fortuitous that most of the relevant anatomic areas (e.g. basal ganglia, pons) receive their vascular supply via deep perforating ‘end’ arteries, isolated occlusion of which will result in an ischemic lacune. In the original autopsy report of nine cases (Fisher & Curry, 1965), six of the lacunes were in the internal capsule, and the remainder were in the basis pontis. The clinical presentations of capsular PMS and pontine PMS may be identical. Since then, patients have been reported with lacunes in the corona radiata, the cerebral peduncle, and the medullary pyramid (Bamford & Warlow, 1988). The distribution of SDIs in the large series of PMS patients who have been reported seems to have been broadly in keeping with the original pathological observations, given the limitations of CT scanning of the brainstem. In the early 1980s, clinico-radiological correlation of cases with facio-brachial and brachio-crural deficits began to be reported under the rubric of PMS – hence the preference for that term rather than the original pure motor hemiplegia (Rascol et al., 1982; Donnan et al., 1982). Ideally such cases should be identified separately as ‘partial’ rather than classical LACS but unfortunately many studies have simply reported on the two groups combined. There is good evidence that even more restricted deficits (e.g. pure motor monoparesis) are unlikely to be associated with SDIs (Boiten & Lodder, 1991a). Cases have been

reported in which patients have had a PMS syndrome as well as additional features (e.g. neuro-psychological disturbances, eye movement abnormalities). These ‘extended LACS’ have not been studied in the same detail as have the partial syndromes, and therefore it is not possible to comment on the likelihood of an associated SDI. Many are due to lesions in the brainstem where it seems likely that occlusion of the origin of the perforating arteries by atheroma in the parent (basilar) artery is a more common mechanism than in the anterior circulation. Pure motor stroke (PMS) is generally considered to be the commonest LACS in clinical practice – 45% in the Oxfordshire Community Stroke Project (OCSP), 57% in the Stroke Data Bank (SDB) and 45% in the Northern Manhattan Stroke Study (NMSS) (Bamford et al., 1987; Chamorro et al., 1991; Gan et al., 1997).

Pure sensory stroke (PSS) Pure sensory stroke (PSS), the sensory counterpart of PMS, is encountered much less frequently: 6% of all LACS in the OCSP, and 7% in both the SDB and NMSS (Bamford et al., 1987; Chamorro et al., 1991; Gan et al., 1997). Although the presence of objective sensory loss was part of the original definition (Fisher 1965b), Fisher noted later that there would be patients with persistent sensory symptoms in the absence of objective signs (Fisher, 1982). It is noteworthy that a case of a partial PSS was verified pathologically (Fisher, 1978a). Most studies have reported SDIs in the thalamus, in keeping with the original pathological studies, but PSS has been reported with a lesion in the anterior limb of the internal capsule. Although there may have been another unimaged infarct in the thalamus, it was argued that PSS could arise by disruption of the anterior thalamic radiation (Chamorro et al., 1991). Most authors agree that the lesions causing PSS are the smallest of the symptomatic SDIs (Hommel et al., 1990; Chamorro et al., 1991).

Homolateral ataxia and crural paresis (HACP), dysarthria-clumsy hand syndrome (DCHS), and ataxic hemiparesis (AH) There is probably more debate about these syndromes than about any other of the classical LACS. The original cases of HACP were described as having weakness of the lower limb, specially the ankle and toes, a Babinski sign, and ‘striking dysmetria of the arm and leg on the same side’ (Fisher & Cole, 1965). They described in detail the clinical histories of five patients amongst 14 seen over a number of years with the syndrome. Unfortunately only one patient

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subsequently came to autopsy and, although Fisher and Cole argued that a large lacune in the posterior limb of the internal capsule was responsible, by this time the patient had had at least four more strokes and had multiple cortical and subcortical infarcts. The deficit in DCHS was described originally as being ‘chiefly of dysarthria and clumsiness of one hand’, although two of the original three patients had signs suggestive of pyramidal dysfunction in the ipsilateral leg and an ataxic gait (Fisher, 1967). The one patient who came to autopsy had a pontine lacune. A decade later Fisher reported three further patients who had prominent vertical nystagmus, as well as weakness and cerebellar signs under the new term AH and suggested that this term should supplant the term HACP (Fisher, 1978b). The relevant lacunes were all in the basis pontis, and the variable distribution of the weakness was attributed to the involvement of motor fibres where they are relatively dispersed by the pontine nuclei. Fisher stressed that there was a difference between the ‘wavering’ that was seen in slightly weak limbs and the true dysmetria (shown with finger–nose testing) observed in his cases. In practice, the very striking cases of this type seem to be relatively uncommon and some commentators doubt the validity of the syndrome (Landau, 1988). One certainly encounters patients who have similar signs but who are in the recovery phase from what otherwise would be considered PMS – close scrutiny of the three cases of AH in which autopsies were performed revealed that two of the patients had been examined during recovery from what probably had been more profound motor deficits, and in the other case a more profound motor deficit developed very soon after the examination. Another possible explanation for the syndromes is that there is a second, non-imaged lesion. The data from detailed MRI studies argue against this being common: In one study, five of 26 patients (19%) with AH and with an SDI had more than one such lesion, but the figure for patients with PMS in the same study was six of 33 (18%) (Hommel et al.,1990). Moulin et al, (1995) reported that 10.5% of patients with AH had a ‘double lesion’. Additionally, in the SDB (Chamorro et al., 1991), a history of previous, clinically apparent stroke was no more common in the AH / DCHS group than in those with other LACS. Glass et al. (1990) have suggested that, although it might be reasonable to combine the cases of HACP and AH, DCHS remains a distinct syndrome. Others, however, consider that HACP is almost always caused by partial infarcts of the anterior cerebral artery (Bogousslavsky et al., 1992; Moulin et al., 1995).

Sensory variants of AH have been reported, but there is no evidence that the anatomic and clinical issues raised are significantly different from those between PMS and sensorimotor stroke, as discussed later. In the largest study of AH, lesions were reported in the internal capsule (39%), thalamus (13%), corona radiata (13%), lentiform nucleus (8%), cerebellum – SCA territory (4%) and anterior cerebral artery territory (4%) (Moulin et al., 1995) rather than in the basis pontis as described in the original clinico-pathological reports. An MRI study of DCHS reported lesions in the pons (Glass et al., 1990). In the OCSP, 9% of all LACS were AH (defined as AH⫹ HACP⫹DCHS), in the SDB 10% of LACS were AH and 6% DCHS and in the NMSS 18% of LACS were AH (DCHS excluded) (Bamford et al., 1987; Chamorro et al., 1991; Gan et al., 1997).

Sensorimotor stroke (SMS) For many years it was considered that sensorimotor stroke (SMS) could not be caused by a lacune, because of the differing vascular supplies to the thalamus and to the posterior limb of the internal capsule. However, it should be noted that in the original definition of PMS (Fisher & Curry, 1965), sensory symptoms (but not signs) were allowed, and they were present in 9% of cases of PMS in the SDB (Chamorro et al., 1991). A single case of SMS demonstrated at autopsy (Mohr et al., 1977) was reported almost a decade after the reports for the other LACS. There was a lacune in the ventral posterior nucleus of the thalamus but there was also pallor of the adjacent capsule. Although there were marked sensory and motor signs, all of which persisted, the sensory symptoms preceded the motor symptoms. There is also support from autopsy studies for the idea that an infarct primarily within the internal capsule can cause SMS (Groothuis et al., 1977; Tuszynski et al., 1989), although the former case was due to a small hemorrhage. Those authors considered that the sensory deficit was caused by interruption of the thalamo-cortical pathways. In the SDB (Chamorro et al., 1991) 31% of patients had a lesion in the posterior limb of the internal capsule, compared with 22% in the corona radiata, 7% in the genu of the capsule, 6% in the anterior limb of the capsule, and only 9% in the thalamus. However, it has also been pointed out that the close anatomic and vascular relationships between the motor and sensory rolandic cortices actually make the possibility of a pure SMS from cortical infarction due to ischemia anterior to the rolandic fissure extending backward more likely than a cortical PMS (Orgogozo & Bogousslavsky, 1989). It is also clear that large subcortical striato-capsular infarcts can cause a SMS (Blecic et al.,1993). Several studies

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have reported that the SDIs in cases of SMS are larger than those in PMS in an equivalent site, while still being within the territory of a single perforating artery (Allen et al., 1984; Hommel et al., 1990). The known problems with the reliability of the sensory examination probably account for the fact that whilst SMS accounted for 40% of all LACS in the OCSP, it only constituted 20% in both the SDB and NMSS (Bamford et al., 1987; Chamorro et al., 1991; Gan et al., 1997).

presence of hypertension, is much more predictive of an SDI than is a facio-brachial deficit (Melo et al., 1992). In studies in which classic and partial deficits have been combined, the rates of non-lacunar lesions have ranged from zero to 9% (Bamford et al., 1987; Hommel et al., 1990; Arboix & Marti-Vilalta, 1992) and more recently the NMSS has reported a positive predictive value for PMS of 79% (Gan et al., 1997).

PSS

Do LACS predict . . . The pathological type of stroke? On the basis of clinical patterns alone, one cannot distinguish reliably between stroke and non-stroke pathologies, and it has also been shown repeatedly that any of the classical LACS can, infrequently, be caused by a small hemorrhage (Bamford et al., 1987; Bamford & Warlow, 1988). In the pre-CT era, that fact may have been of some clinical utility, and it may still be in countries with limited access to CT, where therapeutic decisions have to be made on the basis of probability rather than absolute evidence. However, most of the clinico-radiological correlation studies have been performed in predominantly Caucasian populations and, ideally, further validation studies should be performed in other ethnic groups, particularly those where there is thought to be a greater prevalence of both intracranial small vessel disease and cerebral haemorrhage.

The site and size of the ischemic lesion? PMS In a Swedish study of 196 patients with pure motor deficits, 123 were found to have classic PMS with involvement of the face, arm, and leg, of whom 120 (97%) had either a relevant SDI or no relevant lesion seen on CT. The remaining three patients each had a small hematoma (Norrving & Staaf, 1991). In a similar study (Melo et al., 1992) of 128 patients with classic PMS, it was reported that among the 121 cases due to ischemia, 74% of patients had an appropriate SDI, 15% had no visible lesion, 6% had a brain-stem infarct, and only 5% had a superficial infarct. The findings from the Swedish study, where 52 of 57 patients (91%) with partial syndromes each had an SDI or no relevant lesion, demonstrate that although the association is still clinically useful, it may be less specific than for the classic syndrome (Norrving & Staaf, 1991). It has been reported that a brachio-crural deficit, particularly in the

In studies that have combined classic PSS and partial PSS, the positive predictive value for an SDI has ranged from 92 to 100% (Bamford et al., 1987; Hommel et al., 1990; Arboix & Marti-Vilalta, 1992; Gan et al., 1997).

AH In the OCSP, no ‘non-lacunar’ lesions were detected in patients with AH and in the NMSS the PPV for AH was 95%.

SMS In large studies in which classic SMS and partial SMS have been combined, the predictive rates for an SDI have ranged from 79 to 95% (Bamford et al., 1987; Huang et al., 1987; Hommel et al., 1990; Landi et al., 1991; Lodder et al., 1991; Arboix & Marti-Vilalta, 1992; Gan et al., 1997). Blecic et al. (1993) agreed that the presence of a deficit involving the face, arm, and leg was highly predictive of an SDI, but noted that a facio-brachial deficit was much less predictive than a brachio-crural deficit. They also reported that the likelihood of an SDI increased with the number of sensory modalities involved.

All classical and partial LACS In community-based studies when CT was regarded as the gold standard overall sensitivity, specificity, PPV and NPV was generally reported to be greater than 90% (Bamford et al., 1987; Ricci et al., 1991). However, these studies considered CT scans with no visible lesion to be ‘appropriate’ and therefore it was no great surprise when MRI studies began to report higher rates of ‘non-lacunar’ infarcts. In a detailed study of 91 classical and partial LACS (PMS – 59, SMS – 16, PSS – 10, AH – 6) which included both CT and MRI ⫹/⫺ contrast enhancement, Samuelsson et al. (1994) reported that 8 of the 78 (10–95% CI 3.5–17.0%) of the patients who had a visible infarct at any time had evidence of cortical involvement on the gadolinium-enhanced MRI.

The underlying vascular pathophysiology? This question remains unanswered because of the paucity of cases in which the underlying vascular pathology has

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been detailed. However, it is clear that the presence of a LACS is not synonymous with the presence of hypertensive arteriolopathy (Van Gijn & Kraaijeveld, 1982; Lodder et al., 1990; Chamorro et al., 1991), although it has been suggested that the predictive value of the syndrome, particularly if it is a partial syndrome, is increased when hypertension is present (Melo et al., 1992). Indirect evidence suggests that LACS develop in an atherogenic milieu similar to that of large-vessel infarcts, but potential cardiac sources of embolism (in particular, atrial fibrillation) and significant ipsilateral carotid stenosis are less prevalent (Kappelle et al., 1988; Lodder et al., 1990; Boiten & Lodder, 1991a, 1995). Thus, a diagnosis of a LACS should not preclude further investigation, but the possibility that any proximal vascular lesions may be coincidental must be borne in mind (something that is not always reflected in etiological classification systems) – further information on this point may become available from detailed analysis of the carotid endarterectomy trial databases. Equally, the absence of significant cardiac or carotid lesions should not be particularly surprising. In the recent NMSS, using standard diagnostic criteria to allocate mechanism of infarction, the presentation with a classical LACS and an SDI on imaging had a PPV of 75% for a ‘lacunar mechanism of infarction’ (Gan et al., 1997).

Other clinical aspects Although embolism is thought to be an uncommon cause of lacunar infarcts, transient ischemic attacks (TIAs) do occur in about 20%, presumably at a time of incipient occlusion. This would explain the crescendo of attacks, in terms of both frequency and duration, that can be encountered immediately before the completion of the deficit. This has been termed the capsular warning syndrome (Donnan & Bladin, 1987). It has been suggested that one can recognize TIAs that have the clinical characteristics of a LACS, particularly if they are occurring in the dominant hemisphere (Hankey & Warlow, 1991). These may be due to capsular ischemia more often than pontine ischemia. Seizures are uncommon after true lacunar infarcts – Giroud and Dumas (1995) reported that, in patients who had a lenticulo-striate infarct on CT and then had seizures within 15 days of onset, 84% were subsequently shown to have an ipsilateral cortical ischemic lesion on MRI and all patients showed reduced activity in the ipsilateral frontal region on SPECT. Because the diagnosis of a LACS hinges on the clinical examination, great care must be taken. There are wellknown limitations to the sensory examination that can

somewhat blur the boundary between PMS and SMS, which probably accounts for the rather large differences in the quoted frequencies. Two other areas have been shown to cause difficulties: assessment of whether a patient is dysphasic or severely dysarthric; and determination of whether or not there are signs of non-dominant hemisphere higher cortical dysfunction (Lodder et al. 1994; Toni et al. 1994). In the end, this will come down to a question of individual clinical acumen, and it is by no means clear that involvement of speech and language therapists or neuropsychologists actually helps this process. It is vital that, as a method of personal education, one review all clinical diagnoses systematically, both before and after the results of other investigations are known, since it has been shown that the specificity of the clinical diagnosis of LACS improves quite significantly when the diagnosis is made by clinicians with an interest in cerebrovascular disease (Lodder et al., 1994)

LACS in the era of acute stroke treatments One suspects that of the criteria set out by Fisher and Curry (1965) for the diagnosis of a LACS, the necessity to base the diagnosis on the maximum deficit from a single infarct is the most frequently forgotten. It was always recognised that occasionally a patient would appear to have a PMS in the emergency room, but then when re-evaluated a few hours later would have clear signs of cortical dysfunction. This was presumed to occur because in the case of ICA or proximal MCA occlusion the highly metabolic areas of the basal ganglia are the first areas to reach clinically apparent levels of cerebral ischemia, particularly if the cortical collateral supply is good. The advent of thrombolysis has now focused attention on the clinical assessment in the hyper-acute stage of stroke. Toni et al. (1994) reported that 21% of patients admitted to a neurology department with either a classical or partial PMS or SMS at a mean of 6.1 hrs (⫹/⫺3.2 hrs) after onset would go on to develop symptoms of cortical dysfunction over the next few days. For cases with PMS they reported a PPV of 58% (95% CI 50–60%) with no significant difference between the classical and partial syndromes. On the other hand, for SMS the overall PPV was 51% (39–63%) but whilst the PPV was 87% for those with partial syndromes it was only 40% for those with the classical syndrome. The report is also of interest because of the patients who presented with non-lacunar syndromes whose strokes were subsequently considered to have been caused by an SDI. Twenty-three of these 47 patients (49%) actually

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showed resolution of their ‘cortical’ symptoms over the few days after the stroke i.e. a later examination would ‘correctly’ have allocated them to the lacunar group. The patients who improved included 15 of 22 with a motor aphasia, two of two with receptive aphasia, five of ten with a global aphasia and one of three with an hemianopia. The TOAST collaborators reported that an initial (acute) clinical impression of stroke subtype agreed with the final determination in only 62% of patients, with no subtype (including lacunar infarcts) being diagnosed more accurately than others (Madden et al., 1995). They concluded that, at the present time, we should not attempt to restrict entry to trials of acute stroke therapy based on presumed stroke subtype.

Conclusions The classical LACS are clinical paradigms that should be learned, used, and personally fine-tuned by each individual clinician. They have been shown to be simple and reasonably valid markers for a numerically significant and patho-physiologically distinct subgroup of patients with cerebral infarction. There is no doubt that the clinical utility of the classical LACS (and possibly their detailed definitions) will have to be kept under review in an era of hyper-acute stroke assessment and treatment, and also rapidly advancing imaging techniques which are finally moving away from imaging ‘holes in the brain’. However, in the ‘real world’ it will take a considerable time before many clinicians caring for patients with stroke will have access to the imaging technology available in the specialist centres and at present only a minority of patients worldwide are being assessed in the hyperacute phase.

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in motor partial seizures and lenticulostriate infarcts. Epilepsia, 36, 465–70. Glass, J.D., Levey, A.I. & Rothstein, J.D. (1990). The dysarthriaclumsy hand syndrome: a distinct clinical entity related to pontine infarction. Annals of Neurology, 27, 487–94. Groothuis, D.R., Duncan, G.W. & Fisher, C.M. (1977). The human thalamo-cortical sensory path in the internal capsule: evidence from a small capsular hemorrhage causing a pure sensory stroke. Annals of Neurology, 2, 328–31. Hankey, G.J. & Warlow, C.P. (1991). Lacunar transient ischaemic attacks: a clinically useful concept? Lancet, 337, 335–8. Hauw, J.J. (1995). The history of lacunes. In Lacunar and Other Subcortical Infarctions, ed. G.A. Donnan, B. Norrving, J.M. Bamford, J. Bogousslavsky, pp. 3–15. Oxford: Oxford University Press. Hommel, M., Besson, G., Le Bas, J.F., Gaio, J.M., Pollak, P., Borgel, F. & Perret, J. (1990). Prospective study of lacunar infarction using magnetic resonance imaging. Stroke, 21, 546–54. Huang, C.Y., Woo, E., Yu, Y.L. & Chan, F.L. (1987). When is sensorimotor stroke a lacunar syndrome? Journal of Neurology, Neurosurgery and Psychiatry, 50, 720–6. Kappelle, L.J., Koudstaal, P.J., Van Gijn, J., Ramos, L.M.P. & Keunen, J.E.E. (1988). Carotid angiography in patients with lacunar infarcts – a prospective study. Stroke, 19, 1093–6. Landau, W.M. (1988). Ataxic hemiparesis: special deluxe stroke or standard brand? Neurology, 38, 1799–801. Landi, G., Anzalone, N., Cella, E., Boccardi, E. & Musicco, M. (1991). Are sensorimotor strokes lacunar strokes? A case-control study of lacunar and non-lacunar strokes. Journal of Neurology, Neurosurgery and Psychiatry, 54, 1063–8. Lodder, J., Bamford, J.M., Sandercock, P.A.G., Jones, L.N. & Warlow, C.P. (1990). Are hypertension or cardiac embolism likely causes of lacunar infarction? Stroke, 21, 375–81. Lodder, J., Boiten, J. & Raak, L.H-V.R. (1991). Sensorimotor syndrome relates to lacunar rather than to non-lacunar cerebral infarction. Journal of Neurology, Neurosurgery and Psychiatry, 54, 1097. Lodder, J., Bamford, J., Kappelle, J. & Boiten, J. (1994). What causes false clinical prediction of small deep infarcts? Stroke, 25, 86–91. Madden, K.P., Karanjia, P.N., Adams, H.P. Jr. & Clarke, W.R. (1995).

Accuracy of initial stroke subtype diagnosis in the TOAST study. Neurology, 45, 1975–9. Melo, T.P., Bogousslavsky, J., Van Melle, G. & Regli, F. (1992). Pure motor stroke: a reappraisal. Neurology, 42, 789–98. Mohr, J.P., Kase, C.S., Meckler, R.J. & Fisher, C.M. (1977). Sensorimotor stroke due to thalamo-capsular ischemia. Archives of Neurology, 34, 734–41. Moulin, T., Bogousslavsky, J., Chopard, J-L. et al. (1995). Vascular ataxic hemiparesis: a re-evaluation. Journal of Neurology, Neurosurgery and Psychiatry, 58, 422–7. Norrving, B. & Staaf, G. (1991). Pure motor stroke from presumed lacunar infarct. Incidence, risk factors and initial course. Cerebrovascular Diseases, 1, 203–9. Orgogozo, J.M. & Bogousslavsky, J. (1989). Lacunar syndromes. In Handbook of Clinical Neurology. Vol. 10: Vascular Diseases, Part II, ed. J.F. Toole, pp. 235–69. Amsterdam: Elsevier. Poirier, J. & Derouesne, C. (1984). Cerebral lacunae. A proposed new classification. Clinical Neuropathology, 3, 266. Rascol, A., Clanet, M., Manelfe, C., Guiraud, B. & Bonafe, A. (1982). Pure motor hemiplegia: CT study of 30 cases. Stroke, 13, 11–17. Ricci, S., Celani, M.G. & Caputo, N. (1991). SEPIVAC: a communitybased study of stroke incidence in Umbria, Italy. Journal of Neurology, Neurosurgery and Psychiatry, 54, 695–8. Samuelsson, M., Lindell, D. & Norrving, B. (1994). Gadoliniumenhanced magnetic resonance imaging in patients with presumed lacunar infarcts. Cerebrovascular Diseases, 4, 12–19. Schwamm, L.H., Koroshetz, W.J., Sorensen, A.G. (1998). Time course of lesion development in patients with acute stroke: serial diffusion- and hemodynamic-weighted magnetic resonance imaging. Stroke, 29, 2268–76. Toni, D., Duca, R. D. & Fiorelli, M. (1994). Pure motor hemiparesis and sensorimotor stroke – accuracy of very early clinical diagnosis of lacunar strokes. Stroke, 25, 92–6. Tuszynski, M.H., Petito, C.K. & Levy, D.E. (1989). Risk factors and clinical manifestations of pathologically verified lacunar infarctions. Stroke, 20, 990–9. Van Der Zwan, A. (1991). The variability of the major vascular territories of the human brain. MD thesis, University of Utrecht. Van Gijn, J. & Kraaijeveld, C.L. (1982). Blood pressure does not predict lacunar infarction. Journal of Neurology, Neurosurgery and Psychiatry, 45, 147–50.

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Putaminal hemorrhages Kazuo Minematsu and Takenori Yamaguchi Department of Medicine, National Cardiovascular Center, Osaka, Japan

Changing clinical features of putaminal hemorrhages Before computed tomography (CT) became a routine examination for stroke patients, primary brain hemorrhage (PBH) was considered to entail extremely high morbidity and mortality. The reported incidences of PBH have varied in a number of studies, but its clinical severity has consistently been decreasing since the advent of CT has allowed earlier detection (Hier et al., 1977; Drury et al. 1984; Kutsuzawa, 1987; Ueda et al., 1988; Broderick et al., 1989). A population study in Rochester, Minnesota documented a dramatic decrease in the 30-day mortality rate among patients with PBH, from approximately 90% in 1945–74 to less than 50% in 1980–4 (Broderick et al., 1989). Kutsuzawa (1987) studied 1247 patients with PBH and found that the 30-day mortality rate declined from 23.9% in 1969–76 to 13.4% in 1982–6. The decrease in mortality from PBH reported in those studies coincided with the introduction of CT scanning, indicating that smaller hemorrhages were more frequently being identified by CT. Drury et al. (1984) estimated that 24% of patients with PBH were misdiagnosed as having brain infarction before the CT era. In addition, a decrease in the incidence of hypertension and improvements in antihypertensive therapy may have contributed to the reduced severity of PBH, because the trend has continued since the CT era began (Ueda et al., 1988; Schütz et al., 1992). The putamen is located deep inside the brain and is surrounded by the internal and external capsules and the corona radiata. It is supplied by the lenticulostriate arteries, whose lateral branches are the most common site of origin for hypertensive hemorrhage – labelled ‘the artery of cerebral hemorrhage’ by Charcot and Bouchard in 1868 (Omae et al., 1982). Many pathological and CT studies have demonstrated that PBH most frequently occurs in the

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putamen, accounting for 15–48% of cases of PBH in the United States and European countries (Garde et al., 1983; Brott et al. 1986; Massaro et al., 1991; Daverat et al., 1991; Lampl et al., 1995), and 35–64% in Japan (Waga & Yamamoto, 1983; Suzuki et al., 1987; Yamaguchi et al., 1987; Omae et al., 1982). Therefore, the clinical picture of putaminal hemorrhage has been recognized as representative for that of PBH. Putaminal hemorrhage has several clinical subtypes determined by the size and pattern of extension of the hematoma. Recent studies suggest that putaminal hemorrhage occasionally presents with milder clinical symptoms and signs that cannot be reliably distinguished from the manifestations of brain infarction (Mizukami et al. 1981; Tapia et al., 1983; Garde et al., 1983; Mori et al. 1985; Arboix & Marti-Vilalta, 1992). In addition, recent MRI studies indicate that putaminal hemorrhage can sometimes occur without causing any symptoms or neurological signs (Nakajima et al., 1991). We analysed the clinical and neuroradiological features of 45 consecutive patients with putaminal hemorrhages (32 men and 13 women, with a mean age of 60 years; 46 hemorrhagic episodes), who were admitted within 7 days of the onset of symptoms over a period of 6 years. The patients were divided into the following five subgroups according to their initial clinical manifestations: (i) fulminant hemorrhage with massive hematoma (n⫽4), (ii) classic putaminal hemorrhage associated with deficits of higher cortical function (n⫽16), (iii) classic putaminal hemorrhage without any disturbance of higher cortical function (n⫽6), (iv) small putaminal hemorrhage presenting with a lacunar syndrome (n⫽18), and (v) silent hemorrhage (n⫽1). One patient could not be classified because of a complex clinical picture due to an old, contralateral hemispheric infarction, and a second putaminal hemorrhage in another patient was also excluded from analysis.

Putaminal hemorrhages

The detailed clinical and neuroradiological features of each subtype are described below. We also discuss on hematoma enlargement and uncommon neurological symptoms and signs following putaminal hemorrhages.

Fulminant putaminal hemorrhages Early mortality and morbidity from putaminal hemorrhages can be predicted by the volume of hematoma on a CT scan and initial neurologic severity. The abrupt development of neurological symptoms typical of putaminal hemorrhage, such as flaccid hemiparesis and hemisensory deficits, is sometimes followed by rapid deterioration to coma within a few minutes or hours. Such patients may be found stuporous or comatose and frequently will vomit immediately after the onset. Patients will present with coma, bilateral extensor plantar reflexes, ipsilateral (possibly bilateral) dilated pupil(s), with or without a light reflex, and Cheyne–Stokes or ataxic respiration, indicating the rapid development of brain herniation. The mortality rate is extremely high (Weisberg, 1979). The fulminant type of putaminal hemorrhage is always accompanied by massive hematoma, ventricular compression, and intraventricular hemorrhage. Enlargement of the hematoma may be documented by serial CT studies. In our series, four patients (8.9%) had a clinical picture compatible with fulminant putaminal hemorrhage when admitted to our hospital within 12 h after the onset. Initial CT scans revealed that each of those patients had a massive hematoma, with a volume of more than 100 cm3, that extended across the thalamus and into the ventricles (Fig. 46.1). All four patients died due to brain herniation within 3 days of admission.

Fig. 46.1. CT scan from a patient with fulminant putaminal hemorrhage. A massive hematoma occupies the central portion of the right cerebral hemisphere and is associated with a shift of midline structures and intraventricular bleeding. This 73-year-old man suffered on abrupt onset of left motor weakness, followed by vomiting and deterioration of consciousness over several hours. He was admitted to our hospital 12 h after the onset, by which time he was in a coma. He died on hospital day 2.

Classic putaminal hemorrhages The typical syndrome of putaminal hemorrhage is considered to feature (i) an abrupt onset of flaccid hemiplegia, (ii) a complete hemisensory deficit, (iii) homonymous hemianopia, (iv) paralysis of conjugate gaze to the side opposite the lesion or conjugate gaze deviation to the side of the lesion, and (v) mild to moderate impairment of consciousness. In addition to these classic syndromes, abnormalities of higher cortical functions, such as aphasia and unilateral spatial neglect (USN), frequently appear in noncomatose patients (Hier et al., 1977). Typically, there is a gradual worsening of both the focal deficit and the level of consciousness during the first minutes or hours, often accompanied by headache and vomiting.

Classic syndromes Six patients in our series who had classic symptoms and signs, but without deficits of higher cortical functions, had small to medium size hematomas ranging from 5 to 40 cm3. Each of them was diagnosed as having right putaminal hemorrhage at the initial neurological examination before CT scanning. Three patients had conjugate gaze deviation to the side of the lesion or homonymous hemianopia, or both, in association with hemiparesis and hemisensory deficits. They were either alert or slightly disoriented at the time of admission. It was believed that the hemiparesis, hemisensory deficits, and conjugate gaze deviation could all be explained by extension of a hematoma into the

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posterior limb of the internal capsule, whereas the homonymous hemianopia probably was attributable to disruption or compression of the optic radiation by the hematoma. One patient, whose hematoma increased in size from 39 to 70 cm3 over the next 3 days, became comatose. In the remaining three patients, the motor and sensory deficits were associated with only mild to moderate disturbance of consciousness for several days after admission, and the hematoma volumes were relatively small (5–18 cm3).

P = 0.004 (Kruskal–Wallis) Volume of hematoma (ml)

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Aphasia No aphasia

Temporary aphasia

Persistent aphasia

Fig. 46.2. Comparison of hematoma volumes for patients with no aphasia, transient aphasia, and persistent aphasia. The differences in volumes were statistically significant (P ⫽ 0.0004, Kruskal–Wallis), indicating that hematoma volume is a significant factor influencing the development of aphasic syndromes and the clinical course. (Adapted from Sugimoto et al., 1989.)

(a )

(b)

Fig. 46.3. Sites of left putaminal hemorrhage in non-aphasic patients and patients with persistent aphasia seen on CT. (a) The hematoma site in non-aphasic patients. The arrows indicate the periventricular white-matter deep to Broca’s area, the temporal isthmus, and the deep periventricular white-matter and corona radiata. (b) Hematoma site in patients with persistent aphasia. Note that the hematoma extends across the three important white-matter regions shown by arrows in part (a). (Adapted from Sugimoto et al., 1989.)

Aphasia due to left putaminal hemorrhage is relatively nonspecific (Hier et al., 1977), possibly reflecting variability in the direction of hematoma extension and selective involvement of the surrounding fibre tracts (Alexander & LoVerme, 1980; Naeser et al., 1982). The effects of putaminal hemorrhage on cortical functions have not been completely determined. A positron-emission tomography (PET) study performed in seven patients with left putaminal or thalamic hemorrhages (Metter et al., 1986) indicated that persistent aphasia was associated with severe left-toright asymmetry (left ⬍ right) of glucose metabolism in the posterior middle temporal region. In one of our previous studies, the pattern of development of aphasia and recovery from aphasia in 27 consecutive patients with left putaminal hemorrhage was strongly correlated with the volume of the hematoma and the extent of white-matter involvement (Sugimoto et al. 1989). When the patients were divided into three groups, nonaphasics, transient aphasics who recovered fully within the first 3 months, and persistent aphasics, the hematoma volumes seen on the initial CT scans were significantly different for the three groups (Fig. 46.2). In each of the patients with persistent aphasia, the hematoma extended into the temporal isthmus and periventricular whitematter, whereas it did not do so in the non-aphasic patients (Fig. 46.3). That observation supports the suggestion by Naeser et al. (1982) that the striatal structures themselves are not important, but that damage to specific white-matter regions surrounding them is likely to be critical for the development of aphasic syndromes. In our series, 12 patients with left putaminal hemorrhages had aphasic symptoms, which varied from global to amnestic. Three patients presenting with amnestic aphasia at the time of admission had relatively small hematomas (approximately 10 cm3 in volume), and their aphasias resolved fully within 1 month. The other nine patients were evaluated in detail 1 to 2 months after the onset, and their aphasia subtypes were classified as follows: moderate Broca aphasia in one patient, mild to moderate Wernicke

Putaminal hemorrhages

aphasia in two patients, global aphasia in one patient, and mild to moderate unclassified aphasia in five patients. Since arcuate fasciculus fibres are commonly interrupted by putaminal hemorrhage, conduction aphasia is predicted. However, none of the patients had conduction aphasia in our sites. Patients with hematomas extending anteriorly had Broca-type aphasia, whereas hematomas extending posteriorly into the temporal isthmus tended to cause global or Wernicke aphasia. Thus, the direction of hematoma extension appears to be related to the type of aphasia that develops. Those results were fairly consistent with a recent study by D’Esposito & Alexander (1995). They demonstrated that the acute language profile of patients with left putaminal hemorrhage had weak anatomic correlations, but the late language profiles were associated with specific lesion sites. In their late assessment 8 to 10 weeks postonset, six patients with anomic aphasia had lesions that were always within the capsulostriatal and paraventricular region (Fig. 46.4). A conduction aphasia patient had a lesion that extended laterally into the external capsule and insula, and just into the temporal white-matter. Three patients with Wernicke aphasia had lesions that extended posteriorly into the temporal white-matter area, whereas three patients with Broca aphasia had lesions that extended anteriorly to involve much of deep frontal white-matter. One patient with global aphasia had a lesion that extended both anteriorly and posteriorly.

Non-dominant-hemisphere syndromes In a study by Hier et al. (1977), 9 of 11 noncomatose patients with right putaminal hemorrhages (82%) showed disturbances of higher cortical function, such as apractognosia, USN, and anosognosia. In a series reported by Kawahara et al. (1984), 29 of 50 patients with right putaminal hemorrhages (58%) had USN, which persisted for more than 2 months in 18 patients (36%). Motor impersistence, nonaphasic misnaming, and other non-dominant-hemisphere syndromes can be caused by right putaminal hemorrhages. Non-dominant-hemisphere syndromes including USN, hemiasomatognosia and anosognosia for hemiplegia, were observed in only four of the 21 patients (19%) with right putaminal hemorrhage in our series. The hematomas were of moderate volume (17–85 cm3) in those patients and consistently extended into the posterior limb of the internal capsule and the temporal isthmus (Fig. 46.5 left). All but one patient had relatively good recovery, with only mild USN persisting a couple of months after the onset (Fig. 46.5 right). However, one patient with a large hematoma involving the temporal and parietal subcortices (68 cm3 in volume) had pronounced anosognosia even 2 months after

Fig. 46.4. Left putaminal hemorrhage accompanied by dominanthemisphere syndromes. CT scan obtained on hospital day 1 from a 55-year-old man who had profound motor and sensory deficits, conjugate gaze deviation and severe aphasia. Hematoma was moderate in volume (18 cm3), but was restricted within the capsulostriatal and paraventricular region. His acute language profile 2 weeks postonset was moderate-to-severe transcortical sensory aphasia, which improved rapidly and changed to mild amnestic aphasia 6 weeks postonset.

the onset. The frequency of non-dominant hemisphere syndromes was lower than that of aphasia. Non-dominant hemisphere syndromes due to right putaminal hemorrhage are more likely to be missed at routine neurologic examinations, as compared with aphasia.

Small putaminal hemorrhages Recent clinical studies have shown that small putaminal hemorrhages often produce only contralateral hemiparesis andhemisensorydeficits,withoutabnormalitiesofextraocular movements or consciousness (Hier et al., 1977). Some

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Fig. 46.5. Right putaminal hemorrhage accompanied by non-dominant hemisphere syndromes. (Left) CT scan obtained on hospital day 1 in a 72-year-old woman who had profound motor and sensory deficits, conjugate gaze deviation, USN, and anosognosia for hemiplegia. A moderate-sized hematoma extended posteriorly across the temporal isthmus and the posterior limb of the internal capsule. (Right) Examiner’s drawing of a house and trees (top) and the patient’s drawing (bottom), indicating that the patient had USN. This test was performed 1 month after the onset of symptoms.

patients with small putaminal hemorrhages have been reported to present with pure motor hemiparesis (PMH) and dysarthria-clumsy-hand syndrome, which are usually considered to be specific for lacunar infarction (Minematsu et al., 1981; Tapia et al., 1983; Misra & Kalita, 1994). In a study by Mori et al. (1985), 19 of 174 patients with PBH (10.9%), including six with putaminal hemorrhages, had lacunar syndromes. The deficits were compatible with PMH in two patients, whereas three patients had dysarthria-clumsy-hand syndrome, and one patient had sensorimotor stroke. All patients recovered almost fully within 1 week. The hematomas were very small, with volumes ranging from 1.0 to 5.7 cm3 (mean 2.9 cm3), and were not accompanied by ventricular compression or intraventricular hemorrhage. In a report by Arboix and Marti-Vilata (1992), 30 of 286 consecutive patients with

lacunar syndromes (10.5%) were diagnosed as having PBH, which was most frequently located in the putamen (n⫽ 13). The patients with putaminal hemorrhages presented with PMH in 10 cases and sensorimotor stroke in three cases. Many patients with a small internal-capsule hematoma (capsular hemorrhage) verified by CT have also been reported to have presented with lacunar syndromes (Weisberg & Wall, 1984; Mori et al., 1985; Arboix & MartiVilalta, 1992). Some of them might have been diagnosed as having either putaminal or thalamic hemorrhages by the higher-resolution CT and MRI equipment that is currently available. A recent study suggested that anterio-posterior extension of small or moderate size putaminal hemorrhage can spare the medially located sensory fibres in the internal capsule, and produce a motor deficit alone (Misra & Kalita, 1994).

Putaminal hemorrhages

courses were generally excellent, with no significant or only slight residual disability. Six patients (33%) had no neurological deficits 1 month after the onset. Excellent neurological and functional recovery was reported when the hematoma volume was less than 15 cm3 and there were no hyperdense areas at the level of the body of the lateral ventricles on CT scans (Mizukami et al., 1981; Steiner et al., 1984). Those findings are in accordance with our results.

Enlargement of hematoma

Fig. 46.6. CT scan obtained on hospital day 1 in a 62-year-old man who had mild PMH. This demonstrates clearly that the hematoma is localized mainly within the putamen but involves the posterior limb of the internal capsule.

In our series, 17 patients presented with lacunar syndromes, including PMH in seven patients (Fig. 46.6), sensorimotor stroke in nine patients, and pure sensory stroke (PSS) in one patient. The other patient had isolated dysarthria. One patient complained of headache after the onset, but none of them had vomiting and their deficits were usually stable. The hematoma volume in that group was 7.4 ± 8.1 cm3 (range: 0.5–28 cm3), being significantly smaller than for any of the other clinical subtypes. The hematoma remained localized within the putamen in ten patients, extended across the anterior limb of the internal capsule in one, and involved the posterior limb in the remaining seven. None of those patients had intraventriclar hemorrhage. The patient who presented with PSS had a small hematoma involving the lowest portion of the posterior limb of the internal capsule (Fig. 46.7), in which the thalamocortical sensory pathways are localized. The clinical

Although onset of neurological deficits is usually sudden in putaminal hemorrhage, some patients may have delayed neurological deterioration. In early studies on PBH, clinical deterioration after admission was frequently attributed to the effect of brain edema. Recent studies, however, demonstrated with serial CT or MRI examinations that enlargement of hematoma size due to active bleeding is a major cause of clinical deterioration (Broderick et al., 1990; Weisberg et al., 1990; Bae et al., 1992; Wijdicks & Fulgham, 1995; Brott et al., 1997). In our recent studies on 204 patients with PBH, including 70 patients with putaminal hemorrhage, expansion of hematoma on CT scan was not uncommon in the hyperacute stage (Kazui et al., 1996). Of 74 patients who underwent the initial CT scan within 3 h from onset of PBH, 27 patients (36%) showed enlargement of the hematoma. Clinical deterioration was observed in 50 patients; 27 of 41 patients (66%) with hematoma enlargement and 23 of 163 patients (14%) with unchanged hematoma size. The odds ratio was 11.7 with 95% confidence intervals of 5.0 to 27.8. Thus, enlargement of PBH is a major cause of clinical deterioration. A patient examined ⬎6 h after ictus who has a hematoma volume ⬍25 cm3 is unlikely to experience further hematoma growth (Kazui et al., 1997).

Uncommon symptoms and signs Convulsive seizures following PBH are not frequently encountered except for subcortical hemorrhages and massive hematomas with ventricular extension. In a study by Sung et al. (1989), the incidence of seizure was only 2% in patients with putaminal hemorrhage, being much lower as compared with that in patients with subcortical hemorrhage (32%). Extrapyramidal-tract signs such as hemichorea and hemichorea–hemiballism have been documented in patients with putaminal hemorrhages (Jones et al., 1985; Altafullah et al., 1990). Unilateral asterixis was also

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(a )

(b )

Fig. 46.7. CT scan (a) and proton-weighted MR image (b) obtained in a 62-year-old man who had PSS that persisted throughout his hospitalization. The hematoma is seen to originate from the posterior part of the putamen and extend across the lowest portion of the posterior limb of the internal capsule.

documented in a patient with a small putaminal hemorrhage (Trejo et al., 1986). ‘Cortical deafness’ can occur following bilateral putaminal hemorrhages, which destroy bilaterally the acoustic radiations between the medial geniculate bodies and the auditory cortices (Nakayama et al., 1986).

Of the 41 survivors in our series, 21 patients were examined by MRI. In 2 of them (9.5%), old, asymptomatic brain hemorrhage was demonstrated in the contralateral putamen. A fresh but silent putaminal hemorrhage was incidentally documented by follow-up CT examination in a patient with a history of cerebellar hemorrhage (Fig. 46.8).

Silent putaminal hemorrhages

Conclusion

MRI can accurately detect even old, asymptomatic brain hemorrhages (Gomori et al., 1985). Nakajima et al. (1991) reported that asymptomatic brain hemorrhage was detected by MRI in their 17 patients and was most frequently observed in the putamen (n⫽10). Asymptomatic hemorrhage has been estimated to be present in 1.5% of all stroke patients and 9.5% of patients with PBH.

As suggested by previous studies and by the findings in our series, the hematoma size and its direction of extension are critically important factors governing the development of clinical symptoms and signs after putaminal hemorrhage (Hier et al., 1977; Mizukami et al., 1981). Except for the extrapyramidal signs seen in only a few patients, the symptoms and signs associated with putaminal hemorrhage are

Putaminal hemorrhages

Fig. 46.8. A fresh but silent putaminal hemorrhage documented incidentally by follow-up CT examination in a 76-year-old man with a history of left cerebellar hemorrhage. Detailed clinical examination failed to detect any deficits caused by the hematoma.

unlikely to have any relation to damage to the putamen itself. Although the true incidence and severity of putaminal hemorrhage in the general population remain unknown, milder clinical manifestations than those previously considered, and even asymptomatic hemorrhage, should be included in the clinical spectrum of putaminal hemorrhages.

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discriminators of lobar and deep hemorrhages: the Stroke Data Bank. Neurology, 41, 1881–5. Metter, E.J., Jackson, C., Kempler, D. et al. (1986). Left hemisphere intracerebral hemorrhage studied by (F-18)-fluorodeoxyglucose PET. Neurology, 36, 1155–62. Minematsu, K., Tagawa, K. & Yamaguchi, T. (1981). A case of putaminal hemorrhage presenting as dysarthria-clumsy hand syndrome (in Japanese). Neurological Medicine (Tokyo), 14, 291–2. Misra, U.K. & Kalita, J. (1994). Putaminal hemorrhage leading to pure motor hemiplegia. Acta Neurologica Scandinavica, 91, 283–6. Mizukami, M., Nishijima, M. & Kin, H. (1981). Computed tomographic findings of good prognosis for hemiplegia in hypertensive putaminal hemorrhage. Stroke, 12, 648–52. Mori, E., Tabuchi, M. & Yamadori, A. (1985) Lacunar syndrome due to intracerebral hemorrhage. Stroke, 16, 454–9. Naeser, M.A., Alexander, M.P., Helm-Estabrooks, N., Levine, H., Laughlin, S.A. & Geshwind, N. (1982). Aphasia with predominantly subcortical lesion sites. Description of three capsular/putaminal aphasia syndromes. Archives of Neurology, 39, 2–14. Nakayama, T., Nobuoka, H., Wada, S. & Matsukado, Y. (1986). Cortical deafness following bilateral hypertensive putaminal hemorrhage (in Japanese, with English astract). Brain and Nerve (Tokyo), 38, 565–70. Nakajima, Y., Ohsuga, H., Yamamoto, M. & Shinohara, Y. (1991). Asymptomatic cerebral hemorrhage detected by MRI (in Japanese with English abstract). Clinical Neurology (Tokyo), 31, 270–4. Omae, T., Ueda, K., Ogata, J. & Yamaguchi, T. (1982). Parenchymatous hemorrhage: etiology, pathology and clinical aspects. In Handbook of Clinical Neurology, Vol. 10 Vascular Diseases, Part II, ed. J.F. Toole, pp. 287–31. Amsterdam: Elsevier. Schütz, H., Dommer, T., Boedeke, R-H., Damian, M., Krack, P. & Dorndorf, W. (1992). Changing pattern of brain hemorrhage during 12 years of computed axial tomography. Stroke, 23, 653–6. Steiner, I., Gomori, J.M. & Melamed, E. (1984). The prognostic

value of the CT scan in conservatively treated patients with intracerebral hematoma. Stroke, 15, 279–82. Sugimoto, K., Minematsu, K. & Yamaguchi, T. (1989). Aphasia and size of hematoma in patients with left putaminal hemorrhage (in Japanese with English abstract). Clinical Neurology (Tokyo), 29, 574–8. Sung, C-Y. & Chu, N-S. (1989). Epileptic seizure in intracerebral hemorrhage. Journal of Neurology, Neurosurgery and Psychiatry, 52, 1273–6. Suzuki, K., Kutsuzawa, T., Takita, K. et al. (1987). Clinicoepidemiologic study of stroke in Akita, Japan. Stroke, 18, 402–6. Tapia, J.F., Kase, C.S., Sawyer, R.H. & Mohr, J.P. (1983). Hypertensive putaminal hemorrhage presenting as pure motor hemiparesis. Stroke, 14, 505–6. Trejo, J.M., Gimenez-Roldan, S. & Esteban, A. (1986). Focal asterixis caused by a small putaminal hemorrhage. Movement Disorders, 1, 271–4. Ueda, K., Hasuo, Y., Kiyohara, Y. et al. (1988). Intracerebral hemorrhage in a Japanese community, Hisayama: incidence, changing pattern during long-term follow-up, and related factors. Stroke, 19, 48–52. Waga, S. & Yamamoto, Y. (1983). Hypertensive putaminal hemorrhage: treatment and results. Is surgical treatment superior to a conservative one? Stroke, 14, 480–5. Weisberg, L.A. (1979). Computerized tomography in intracranial hemorrhage. Archives of Neurology, 36, 422–6. Weisberg, L.A. & Wall, M. (1984). Small capsular hemorrhages. Clinical-computed tomographic correlations. Archives of Neurology, 41, 1255–7. Weisberg, L.A., Stazio, A., Elliott, D. & Shamsnia, M. (1990). Putaminal hemorrhage: clinical-computed tomographic correlations. Neuroradiology, 32, 200–6. Wijdicks, E.F.M. & Fulgham, J.R. (1995). Acute fatal deterioration in putaminal hemorrhage. Stroke, 26, 1953–5. Yamaguchi, T., Miyashita, T., Minematsu, K., Yamaguchi, S. & Moriyasu, H. (1987). Incidence of thalamic infarction and hemorrhage, and their distribution in the thalamus (in Japanese with English abstract). Japanese Journal of Stroke, 9, 513–18.

47

Lobar hemorrhages Carlos S. Kase Department of Neurology, Boston University School of Medicine, Boston, MA, USA

Introduction Lobar intracerebral hemorrhages (ICHs) involve the whitematter of the cerebral lobes, and originate at the corticosubcortical grey–white-matter junctions. During the acute phase, the hemorrhages displace adjacent structures, and the subsequent gradual removal of the necrotic tissue leaves either ‘slits’ with orange-stained margins, or cavities that may be indistinguishable from old infarctions on computerized tomography (CT) (Fig. 47.1). Lobar hemorrhages are distinct from other forms of ICH in their clinical presentation, mechanisms, prognosis and management.

Frequency Lobar ICHs account for between 23 and 46% of the cases of ICH in clinical series (Table 47.1). In some series (Schütz, 1988; Norrving, 1998) they are reported with the highest frequency (34 and 36%, respectively), surpassing the putaminal location (23 and 32%, respectively). Among patients younger than 45 years of age, Toffol et al. (1987) found that the lobar location had an even higher frequency of 55% (40 of 72 patients).

Mechanisms Hypertension Lobar ICHs have been reported as being less often of hypertensive mechanism than the other varieties of ICH (Ropper & Davis, 1980; Kase et al., 1982). The frequency of hypertension as the cause of lobar ICHs is estimated to be between 20 and 47.5%, in comparison with figures of 57 to

97% for the other locations of ICH. The explanations for these differences include the fact that the arterial lesions responsible for ICH in hypertensives, lipohyalinosis and/or microaneurysms, favour the basal ganglia and thalamus, brainstem, and cerebellum, with relative sparing of the cortico-subcortical area. In addition, ICHs from mechanisms that are not primarily hypertensive, such as cerebral amyloid angiopathy, vascular malformations, sympathomimetic drugs, and bleeding disorders, all tend to produce predominantly subcortical lobar hemorrhages, less often affecting the basal ganglia, thalamus, and posterior fossa structures. However, Broderick et al. (1993) reported a similar frequency of hypertensive mechanism (67%) in lobar hemorrhages as in those occurring elsewhere in the brain (73% for deep hemispheric, 73% for cerebellar, and 78% for pontine hemorrhages). Furthermore, the significance of hypertension as a cause of lobar ICH did not decline with advancing age, their data suggesting that despite the rise in the frequency of ICH due to conditions that typically affect the elderly (age ⱖ75 years), such as cerebral amyloid angiopathy, the impact of hypertension remains strong in this age group as well.

Non-hypertensive mechanisms The ‘non-hypertensive’ causes of ICH are listed in Table 47.2. Cerebral amyloid angiopathy involves the small and medium-size arteries and veins of the cerebral cortex and adjacent leptomeninges (Vinters, 1987). Rupture of the amyloid-laden vessels leads to superficially located lobar hemorrhages, which often have local extension into the subarachnoid space, confering them a variegated character. The angiopathy is strongly age related, and its frequency in routine autopsy series increases steadily from age 60 up, reaching 37% at age 80 and 58% at age 90

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(a )

(b ) Fig. 47.1. (a) Noncontrast CT scan of acute left parieto-occipital hemorrhage with irregular, variegated character in a 38-year-old woman with labile hypertension. (b) CT scan performed 2 yr later, showing large residual cavity with CSF density, indistinguishable from old infarction.

(Tomonaga, 1981). Cerebral amyloid angiopathy is thus responsible for hemorrhage in the elderly and in predominantly lobar locations, as a result of its superficial, cortical–meningeal distribution. Additional features include a recurrent character and, occasionally, the occurrence of several simultaneous lobar ICHs. Multiple hemorrhages in cerebral amyloid angiopathy can at times occur in a subclinical manner, and an acute, clinically apparent lobar ICH can coexist with imaging evidence of multiple smaller superficial hemorrhages. This occurrence is characteristic of cerebral amyloid angiopathy, and the MRI demonstration of small petechial size hemorrhages in gradient-echo sequences (Fig. 47.2) has been suggested as strongly indicative of the diagnosis of cerebral amyloid angiopathy (Greenberg et al., 1996). These observations, in addition, raise the concern that some of these small hemorrhages may be responsible for the transient neurologic symptoms that occur in patients with cerebral amyloid angiopathy (Greenberg et al., 1993), and which are generally labelled as transient ischemic attacks, often leading to consideration of anticoagulant or antiplatelet treatment (Greenberg et al., 1996). This is a particularly worrisome scenario, as cere-

bral amyloid angiopathy is considered a potential substrate underlying hemorrhages that occur in elderly patients treated with anticoagulant or fibrinolytic agents (Wijdicks & Jack, 1993). Small, ‘occult’ (i.e. not visible angiographically) vascular malformations tend to favour superficial hemispheric locations, and often result in lobar hematomas upon rupture. In young patients (15–45 years old), Toffol et al. (1987) found ruptured arteriovenous malformations (AVMs) as the main mechanism of ICH, the majority of which were lobar. Similarly, in a group of 29 patients with lobar ICH and non-diagnostic angiography, Wakai et al. (1992) found nine patients with vascular malformations (six AVMs, three cavernous angiomas) and 11 with microaneurysms, totaling 20 of 29 patients, or 69%, with vascular lesions. There were six other patients with cerebral amyloid angiopathy, and two with brain tumours; the remaining patient had no diagnosis made after histologic examination of the surgical specimen. Recently, Hino et al. (1998) documented AVMs in 30/137 (22%) patients with lobar ICH, this mechanism predominating in young patients without history of hypertension. Four of the 30 AVMs were

Lobar hemorrhages

Table 47.1. Distribution of ICH by site Series

Type of ICH Putaminal Lobar Thalamic Cerebellar Pontine Other

Kase et al., 1982 Number of cases (%)

Bogousslavsky et al., 1988 Number of cases (%)

Norrving, 1998a Number of cases (%)

31 (33) 22 (23) 19 (20) 7 (8) 6 (7) 8 (9)

46 (42) 43 (40) 4 (4) 9 (8) 7 (6)b —

580 (32) 645 (36) 326 (18) 62 (3) 112 (6) 85 (5)

Notes: Aggregate data from a review of 1810 cases from the literature. b Cases labelled as ‘brainstem’ hemorrhages. a

Table 47.2. Non-hypertensive mechanisms of ICH Vascular malformations Aneurysms (saccular, mycotic) Anticoagulant treatment Arteriovenous malformations Fibrinolyticangiomas treatment Cavernous Cerebral amyloid angiopathy Intracranial tumours Granulomatous of(malignant, the nervousbenign) system and other Primary brainangiitis tumours vasculitides Brain metastases Sympathomimetic agents Pituitary adenomas Phenylpropanolamine Bleeding disorders Cocaine Coagulopathies

Bleeding disorders (cont.) Anticoagulant treatment Fibrinolytic treatment Cerebral amyloid angiopathy Granulomatous angiitis of the nervous system and other vasculitides Sympathomimetic agents Amphetamines Phenylpropanolamine Cocaine

documented only after a repeat angiogram, following a non-diagnostic study during the acute phase of the hemorrhage. This observation stresses the value of delayed angiography in the documentation of vascular malformations in patients with lobar ICH. In addition, magnetic resonance imaging (MRI) makes possible the diagnosis of small vascular malformations, either AVMs or cavernous angiomas (Fig. 47.3). Cavernous angiomas can now be diagnosed with increasing accuracy and, although less prone to develop hemorrhage than AVMs, their bleeding potential is considerable: Simard et al. (1986) documented bleeding in 40 of 138 patients (29%) from the literature. The majority of the hemispheric ICHs due to cavernous angiomas were lobar. These hemorrhages are usually round and confined within the capsule of the cavernoma. Cerebral tumours are occasionally found as the underlying cause of lobar ICHs (Ropper & Davis, 1980; Kase et al., 1982). They are almost always malignant, more often metastatic than primary, and their lobar location follows the

predilection of hematogenously spread deposits for the gray/white junction of the cerebral hemispheres. The primary tumours most likely to lead to hemorrhagic metastases are bronchogenic carcinoma, renal-cell carcinoma, choriocarcinoma, and melanoma (Kase, 1986). The presence of an underlying tumour has to be considered in patients presenting with ICH, usually of lobar location, that is associated with a disproportionate amount of surrounding edema and mass effect, as well as postcontrast enhancement of nodules adjacent to the acute ICH (Fig. 47.4). The use of anticoagulant and fibrinolytic agents is a wellrecognized cause of ICH, which frequently occurs in a lobar location, especially after use of the latter drugs. Warfarin increases the risk of ICH by eight to 11-fold in comparison with patients not receiving the drug. Their main risk factor is an excessive prolongation of the international normalized ratio (INR) (Hylek & Singer, 1994), with a sharp increase in their frequency with INR > 5.0 (The European Atrial Fibrillation Trial Study Group, 1995). The

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(b )

Fig. 47.2. (a) and (b). MRI (echo-gradient sequence, TR ⫽ 700 ms, TE ⫽ 25 ms) with multiple old small cortical petechial hemorrhages (arrows), shown as low-signal hemosiderin deposits, in patient with probable cerebral amyloid angiopathy.

ICHs are generally large and of poor prognosis, with a mortality in the 55 to 70% range (Hart et al., 1995). The location of the hemorrhages is thought to be no different from that of patients not receiving anticoagulants (Franke et al., 1990; Hart et al., 1995). The use of the fibrinolytic agents streptokinase and tissue plasminogen activator (tPA) for treatment of acute myocardial infarction has been associated with the complication of ICH in 0.5 to 0.65% of patients (Kase et al., 1992; Longstreth et al., 1993; Gebel et al., 1998). The majority of the ICHs are lobar (Fig. 47.5), and a role for cerebral amyloid angiopathy in their causation has been suggested (Wijdicks & Jack, 1993). ICH is more common after use of fibrinolytic agents for the treatment of acute ischemic stroke. The use of various agents, by either intravenous or intraarterial routes, is associated with a frequency of ICH between 6.4 and 15.4% (Table 47.3). The majority of these hemorrhages occur at the site of the preceding infarction, and their identified risk factors include a severe neurological deficit (measured as an NIH Stroke Scale score ⬎20), CT signs of early infarction (hypo-

density and mass effect) at baseline (The NINDS t-PA Stroke Study Group, 1997), and deviations of protocol/guidelines for use of tPA, especially the premature use of antithrombotic agents after fibrinolytic treatment (Tanne et al., 1999). Sympathomimetic drugs, including amphetamines, phenylpropanolamine, and cocaine, have been implicated in numerous instances of ICH in patients without previous history of hypertension. These hemorrhages generally occur within periods of minutes or hours after drug use, and acute hypertension has been present in approximately 50% of the patients. Most hemorrhages are lobar (Kase et al., 1987; Levine et al., 1990). These agents, particularly the amphetamines and phenylpropanolamine, are associated with a vasculopathy on cerebral angiography in the form of alternating areas of focal constriction and dilatation (‘beading’), thought to sometimes represent vasculitis, although such diagnosis has rarely been confirmed histologically (Tapia & Golden, 1993). Vasculitis is an uncommon cause of ICH, the main effect

Lobar hemorrhages

Fig. 47.3. MRI (T2-weighted, TR ⫽ 3243 ms, TE ⫽ 80 ms) showing cavernous angioma in medial frontal cortex (arrow), with mixed signal centrally and surrounding hemosiderin hypointense halo. From Kase & Caplan (1994). With permission.

of the angiopathy being cerebral infarction. On rare occasions, ‘granulomatous angiitis of the nervous system’ has been responsible for ICH, which has been predominantly lobar (Clifford-Jones et al., 1985). Despite the existence of these various mechanisms of lobar ICH, between 20% and 60% of the patients have hemorrhages that remain of unknown cause even after extensive investigation, including repeat angiography (Table 47.4).

Clinical features These will be analysed first as the general clinical features of lobar ICH, regardless of its location, and secondly as the specific neurologic manifestations in the various anatomic sites of lobar ICH.

General clinical features Lobar ICH is characteristically of sudden onset and it occurs during activity, like ICH at other sites. The most

common symptom is headache which is reported by 60–70% of the patients (Ropper & Davis, 1980; Kase et al., 1982; Weisberg, 1985; Massaro et al., 1991; Flemming et al., 1999). Vomiting occurs in 26 to 45% of patients, and is usually present in the first hours of illness. Seizures have been reported more frequently in lobar ICH than in other types of brain hemorrhage, with a frequency of 16.3 (Massaro et al., 1991) to 36% (Sung & Chu, 1989), although a low figure of 6% was recently reported by Flemming et al. (1999). The seizures characteristically occur at the onset of the ICH (Berger et al., 1988), they are more often focal than generalized, and in some series (Sung & Chu, 1989) onehalf of the patients presented in status epilepticus. The occurrence of seizures in lobar ICH relates to the extension of the hematoma into the cerebral cortex, having been reported in 26% of patients with cortical involvement, in comparison with only 3% of patients without cortical extension of the hemorrhage (Berger et al., 1988). The occurrence of coma at presentation is less common in patients with lobar ICH than with hemorrhage at other sites. Its relatively low frequency of 5 to 19% at onset reflects the peripheral location of the lobar hematomas, that produce less displacement of midline structures than deep hemispheric hematomas.

Clinical features by anatomic site Lobar ICH can occur in any of the cerebral lobes, generally favouring the parietal and occipital areas of the brain (Ropper & Davis, 1980; Kase et al., 1982; Schütz, 1988; Iwasaki & Kinoshita, 1989), although some series have reported a predominance of frontal (Weisberg, 1985; Loes et al., 1987) or temporal (Flemming et al., 1999) lobar locations.

Frontal hematomas Frontal hemorrhages (Fig. 47.6) present clinically with prominent limb paresis and bifrontal headache, which predominates on the side of the hemorrhage (Ropper & Davis, 1980). The pattern of motor weakness favours the contralateral arm, at times in the form of isolated monoplegia. Leg and face weakness tend to be slight, and conjugate gaze deviation toward the side of the hematoma is uncommon. The clinicoradiologic correlations of the various locations of hematomas within the frontal lobe have been analyzed by Weisberg (1985) and by Weisberg and Stazio (1988a). In patients with hemorrhages located superiorly, above the frontal horns of the lateral ventricle, frontal headache and contralateral leg weakness predominated. In contrast, patients with inferior frontal hemorrhages,

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(b )

Fig. 47.4. Frontal intracerebral hemorrhage in biopsy-proven metastasis from melanoma. (a) CT with acute hemorrhage in left frontal pole, with surrounding hypodense edema. (b) MRI (T1-weighted, TR ⫽ 608 ms, TE ⫽ 14 ms) after gadolinium infusion, showing enhancing tumour superiorly, a heavily enhancing tumour nodule centrally, and hemorrhage inferiorly.

located below the frontal horn of the lateral ventricle, had more severe clinical findings, with impaired consciousness, hemiparesis, hemisensory loss, and horizontal gaze palsy towards the side of the hemiparesis. On rare occasions, frontal hematomas in anterior locations have presented without hemiparesis or aphasia, but rather with mental state abnormalities, in the form of abulia (Kase & Caplan, 1994). The general features of patients with frontal hemorrhages reported by Weisberg and Stazio (1988a) included a high frequency of headache (80%), vomiting (80%), and seizures (32%), with an abnormal level of consciousness in 52%, and 40% with gaze preference. The cause of the hemorrhage was thought to be hypertension in only 20%, while ruptured aneurysms or AVMs accounted for 32%, brain tumours, anticoagulant treatment, and coagulopathy for 4% each, leaving 36% of the patients with an unknown cause for the hemorrhage.

Temporal hematomas Temporal hematomas present with specific syndromes in relation to their laterality and location within that lobe.

Headache is a common symptom at onset, and is usually centered in front of the ear or around the eye (Ropper & Davis, 1980). Dominant hemisphere hematomas (Fig. 47.7) produce a fluent aphasia with poor comprehension, and associated paraphasias and anomia (Ropper & Davis, 1980; Weisberg, 1985). A right-sided visual field defect, either a hemianopia or an inferior quadrantanopia, generally accompany posterior temporal hematomas, which are infrequently associated with hemiparesis and hemisensory loss. In a series of 30 patients with temporal lobe hematomas, Weisberg et al. (1990b) reported seizures at presentation in 23%. Patients with posterior temporal hematomas had retroauricular headache at onset, and those with left-sided lesions had in addition Wernicke aphasia and right homonymous hemianopia. In instances of right-sided lesions, the patients were described as having ‘confusion without focal neurological signs’. Many such patients have an agitated delirium characterized by hyperactivity and pressured speech which goes from one topic to another. On occasion, an early and rapid improvement of Wernicke aphasia occurs in patients with dominant temporal lobe

Lobar hemorrhages

Table 47.3. Symptomatic ICH in trials of thrombolysis in acute ischemic stroke Intracerebral hemorrhage

(b)

(a )

(c )

(g)

(f )

(h)

Thrombolytic

Placebo

ECASS Ia NINDSb ECASS IIc PROACT Id PROACT IIe

N/A 6.4% 8.8% 15.4% 10.2%

N/A 0.6% 3.4% 7.1% 1.9%

Notes: N/A ⫽ not available. a Hacke et al. (1995). b The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995). c Hacke et al. (1998). d Del Zoppo et al. (1998). e Furlan et al. (1999).

(d )

(e )

Study

to correlate with the presence of AVMs or aneurysms as the cause of ICH (Weisberg et al., 1990b). Temporal hematomas with extension to adjacent lobes produce less welldefined clinical syndromes. Those that extend medially into the basal ganglia area are accompanied by hemiplegia, hemisensory abnormalities, aphasia, hemianopia, and horizontal gaze palsy, mimicking the clinical profile of large putaminal hemorrhages. Right temporal hematomas with extension into the parietal lobe are characterized by prominent left-sided hemi-inattention.

(i)

Fig. 47.5. Sites of intracranial hemorrhages in nine patients treated with tPA for acute myocardial infarction. (a) Lefttemporal lobe hematoma (left panel), and chronic and acute subdural hematoma (arrow) (right panel). (b) Right parasagittal frontoparietal lobe ICH. (c) Bilateral multiple occipital lobe hematomas. (d) Left frontal and occipital hematomas (arrows). (e) Right cerebellar ICH (arrow) (right panel), with extension to the vermis and fourth ventricle (left panel). ( f ) Left posterior temporal lobe ICH. (g) Left frontoparietal lobe ICH with ventricular extension. (h) Small right posterior parietal parasagittal hematoma. (i) Left temporoparietal lobe hemorrhage. (From Kase et al., 1992, with permission.)

hematomas (Kase et al., 1982). This event may relate to the cessation of focal temporal lobe seizure discharges, although this mechanism of early improvement has been rarely documented (Kase & Caplan, 1994). In temporal hematomas of inferior-basal location, the association with blood in the basal cisterns or cortical sulci on CT was found

Parietal hematomas Parietal hematomas (Fig. 47.8) frequently present with prominent unilateral headache localized around the temple region (Ropper & Davis, 1980). Hemisensory syndromes are often severe, generally involving the limbs and trunk, and they are commonly associated with hemiparesis (Ropper & Davis, 1980; Kase et al., 1982; Weisberg, 1985). Seizures at onset were reported in 28% of the patients in the series of Weisberg and Stazio (1989). These authors analysed the clinical features of 25 patients with parietal hemorrhages. In patients with anterior-lateral hemorrhages, motor and sensory deficits predominated, in addition to homonymous hemianopia in one-half of them. Aphasia or hemi-inattention occurred depending on the laterality of the ICH. Patients with anterior-medial hematomas presented with a similar clinical syndrome, except for more commonly altered consciousness in those with medially-located hematomas, reflecting their frequent extension into the thalamus, with distortion of midline

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Table 47.4. Causes of lobar ICH in series from the literature

Cause

Kase et al., 1982 (N⫽22) N (%)

Schütz, 1988 (N⫽98) N (%)

Weisberg et al., 1990a (N⫽25) N (%)

Hino et al., 1998 (N⫽137) N (%)

Hypertension Bleeding disorders Neoplasms Vascular malformations, aneurysms Other Unknown

10 (45) 1 (5) 3 (14) 2 (9) — 6 (27)

36 (37) 14 (14) 4 (4) 24 (24.5) — 20 (20.5)

5 (20) 2 (8) 1 (4) 8 (32) — 9 (36)

36 (27) 8 (6) 4 (3) 38 (28) 5 (4) 46 (32)

Fig. 47.6. MRI (spin-echo sequence, TR ⫽ 2500 ms, TE ⫽ 19 msec) of left subacute frontal lobe hemorrhage, with moderate midline shift.

structures. In instances of posterior hematomas, seizures were common at onset, and the clinical syndromes included constructional apraxia, dressing apraxia, and hemi-inattention.

Occipital hematomas Occipital hemorrhages (Fig. 47.9) often cause severe headache in or around the ipsilateral eye, associated with acute awareness of a visual disturbance, that on examination cor-

Fig. 47.7. Non-contrast CT of acute left temporal lobe hematoma. Also shown is the residual cavity of an old, large right putaminocapsular infarction.

responds to a contralateral homonymous hemianopia (Ropper & Davis, 1980). Motor weakness is not a feature of occipital ICH, but contralateral sensory extinction to double simultaneous stimulation, dysgraphia and dyslexia, and the syndrome of ‘alexia without agraphia’ have been reported (Ropper & Davis, 1980; Weisberg & Wall, 1987). In the series of Weisberg & Stazio (1988b) patients with occipital hemorrhages in a medial location presented with headache and ‘visual blurring’, and examination showed a

Lobar hemorrhages

Fig. 47.8. Noncontrast CT of acute left parietal lobe hemorrhage, with slight surrounding edema and effacement of the body of the lateral ventricle.

homonymous hemianopia in all, but without weakness, memory deficits, or decreased mental alertness. Patients with lateral occipital hematomas reported headache at onset, but had no neurologic abnormalities on examination, including visual field defects, sensory-motor deficits, or behavioral abnormalities. In patients with occipital hematomas that extend to adjacent lobes, thus usually reaching a larger size than hematomas confined to the occipital lobe, the neurologic deficits are more dramatic, including mental status abnormalities, agitation, contralateral inattention, and homonymous hemianopia.

Outcome and prognosis Lobar hemorrhage has been thought to have a better prognosis than the deep hemispheric (putaminal, thalamic) and posterior fossa hemorrhages (Ropper & Davis, 1980; Kase et al., 1982; Helweg-Larsen et al., 1984). The mortality rates reported have been between the extremes of 11.5 (Ropper & Davis, 1980) and 32% (Kase et al., 1982), in comparison with 42% for basal ganglionic and thalamic ICH, and 43% for posterior fossa hemorrhages (Steiner et al.,

1984). However, in larger series of patients comparisons of mortality between lobar and deep hemispheric ICH have shown no significant differences (Massaro et al., 1991). These authors reported a 30-day fatality rate of 27.7% for patients with lobar hemorrhage, and 31.8% for those with deep hemorrhages. These differences in mortality among series of lobar and deep ICH may reflect variations in hematoma size and mass effect more than their superficial vs. deep location. Hematoma size and decreased level of consciousness are the most important determinants of survival in ICH (Helweg-Larsen et al., 1984; Tuhrim et al., 1988); intraventricular extension of the hemorrhage, which generally correlates with hematoma size, represents an additional poor prognostic factor, regardless of the location of the parenchymal component of the hemorrhage (Young et al., 1990). The factors predicting deterioration in patients with lobar ICH were recently studied by Flemming et al. (1999). These authors found neurologic deterioration after onset in 16/61 (26%) patients, and the level of consciousness at presentation (measured by a Glasgow Coma Scale score of ⬍14) was the only clinical factor that correlated with this clinical course. CT features of hemorrhage volume ⬎60 cm3, shift of the septum pellucidum, effacement of the contralateral ambient cistern, and dilatation of the contralateral temporal horn all correlated with neurologic deterioration. The instances of early neurologic deterioration (within 12 hours of onset) generally corresponded to enlargement of the hematoma, while those that occurred in a more delayed fashion (beyond 12 hours from onset) were most commonly due to the effects of increasing perihematoma edema. In conclusion, it is uncertain whether the mortality is lower in lobar ICH than in deep hemispheric hemorrhages. The differences in mortality rates reported in some series may reflect other features that are important for survival, including hematoma size, displacement of midline structures, and ventricular extension, rather than the mere superficial vs. deep location of the hematoma. The functional outcome in lobar ICH is thought to be better than that of the deep varieties of ICH (HelwegLarsen et al., 1984; Steiner et al., 1984). However, it is unclear whether this observation is real or is the result of patient selection bias. In some series reporting low mortality rates in lobar ICH (Ropper & Davis, 1980), a very low frequency of coma at onset (0.4%) may indicate that patients with large hematomas may have been excluded from referral, on account of severe neurologic signs at onset, early mortality, or poor surgical risk. In other series (Portenoy et al., 1987; Massaro et al., 1991) no differences in functional outcome between lobar and deep hemorrhages have been found. However, in the series of patients with deep and

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(a )

(b )

Fig. 47.9. (a) Non-contrast CT of acute left occipital lobe hemorrhage. (b) MRI (spin-echo sequence, TR ⫽ 3000 ms, TE ⫽ 45 ms), coronal view, of same patient as in part (a), showing acute low-signal occipital hematoma surrounded by halo of hyperintense edema.

lobar hemorrhages reported by Portenoy et al. (1987), subdivision of the hematomas into four size quartiles showed that those patients with the largest hematomas fared poorly and those with the smallest hematomas did well, irrespective of hematoma location. For patients in the middle two quartiles of hematoma size, a good outcome occurred in patients with lobar hematomas (46%) more often than in those with deep hematomas (21%).

Management The choice of medical or surgical treatment in lobar ICH remains a controversial issue. Based on their findings of low mortality and good functional prognosis in non-operated patients, Ropper & Davis (1980) and Iwasaki & Kinoshita (1989) concluded that surgical treatment is not indicated in lobar hemorrhages. However, other series have suggested an improved outcome in subgroups of patients with lobar

ICH treated surgically (Kase et al., 1982; Volpin et al., 1984; Weisberg, 1985; Wakai et al., 1992). Kase et al. (1982) reported that patients with small hematomas (⬍20 cm3) did well without surgical treatment, whereas those with large hematomas (⬎40 cm3) did poorly, regardless of the form of therapy employed. In the intermediate group of hematoma volumes between 20 and 40 cm3, outcome was better after surgical drainage of the hematoma. Similarly, Volpin et al. (1984) reported that patients with hematoma volumes below 26 cm3 did well without requiring surgical therapy, while all those with hematomas larger than 85 cm3 died, irrespective of the form of therapy used. In the intermediate group with hematoma volumes between 26 and 85 cm3, the surgical group fared better than the non-surgical group. Finally, the data from Gårde et al. (1983) also suggested that surgical treatment is of no value in the small (5–10 cm3) or in the very large (70–80 cm3) hematomas, but in those of intermediate size (30–80 cm3) surgery improved survival rates in those who were not comatose preopera-

Lobar hemorrhages

tively. Since a hematoma volume of ⬎60 cm3, along with features of mass effect, has recently been identified as a CT predictor of eventual clinical deterioration (Flemming et al., 1999), it is appropriate to follow these patients closely, and consider them for surgical evacuation in the event of developing signs of neurologic deterioration. In view of these data, a non-surgical approach is the treatment of choice for clinically stable patients with small (up to 20–30 cm3 volume) lobar hematomas, and only supportive measures are appropriate for those in the poor prognostic category of large (> 80 cm3) hematomas, especially if they are comatose and have marked mass effect and midline shift on CT. Patients with intermediate size hematomas (30–80 cm3), who are obtunded or lethargic, with midline shift on CT and neurologic deterioration, probably benefit from surgical evacuation of the hematoma (Broderick et al., 1999). An additional advantage of surgical therapy in this setting is the possible resection of lesions with potential for recurrent bleeding, such as AVMs or cavernous angiomas. The value of medical and surgical therapy for lobar ICH will be ultimately determined by clinical trials involving randomization of comparable groups of patients (by clinical severity and hematoma volume at baseline) to one or the other type of treatment (Hankey & Hon, 1997). The feasibility of such randomized clinical trials was recently documented by Morgenstern et al. (1998), who randomized 34 patients with lobar or deep hemispheric hemorrhage into a standardized protocol of medical management or surgical evacuation of the hematoma within 12 hours of onset of symptoms of ICH. Although the surgical group had a lower mortality rate (6%) than the medical group (24%) at 1 month, there were no significant differences in mortality at 6 months. This small experience proved that a randomized clinical trial to test the value of surgery in well defined subgroups of patients with acute ICH is feasible. The efforts at mounting such trial should continue in order to finally clarify the value and potential indications of surgical treatment of ICH.

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rhage in the elderly: the undiminishing importance of hypertension. Stroke, 24, 49–51. Broderick, J.P., Adams, H.P., Barsan, W. et al. (1999). Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke, 30, 905–15. Del Zoppo, G.J., Higashida, R.T., Furlan, A.J., et al. (1998). PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke, 29, 4–11. Flemming, K.D., Wijdicks, E.F.M., St Louis, E.K. & Li, H. (1999). Predicting deterioration in patients with lobar haemorrhages. Journal of Neurology, Neurosurgery and Psychiatry, 66, 600–5. Franke, C.L., de Jonge, J., van Swieten, J.C., Op de Coul, A.A.W. & van Gijn, J. (1990). Intracerebral hematomas during anticoagulant treatment. Stroke, 21, 726–30. Furlan, A., Higashida, R., Wechsler, L., et al. (1999). Intra-arterial prourokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial. Journal of the American Medical Association, 282, 2003–11. Gårde, A., Böhmer, G., Seldén, B. & Neiman, J. (1983). 100 cases of spontaneous intracerebral haematoma: diagnosis, treatment and prognosis. European Neurology, 22, 161–72. Gebel, J.M., Sila, C.A., Sloan, M.A. et al. (1998). Thrombolysisrelated intracranial hemorrhage: a radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation. Stroke, 29, 563–9. Greenberg, S.M., Vonsattel, J.P., Stakes, J.W., Gruber, M. & Finklestein, S.P. (1993). The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage. Neurology, 43, 2073–9. Greenberg, S.M., Finklestein, S.P. & Schaefer, P.W. (1996). Petechial hemorrhages accompanying lobar hemorrhage: detection by gradient-echo MRI. Neurology, 46, 1751–4. Hacke, W., Kaste, M., Fieschi, C., et al. (1995). Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). Journal of the American Medical Association, 274, 1017–25. Hacke, W., Kaste, M., Fieschi, C. et al. (1998). Randomized doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Lancet, 352, 1245–51. Hankey, G.J. & Hon, C. (1997). Surgery for primary intracerebral hemorrhage: is it safe and effective?: a systematic review of case series and randomized trials. Stroke, 28, 2126–32. Hart, R.G., Boop, B.S. & Anderson, D.C. (1995). Oral anticoagulants and intracranial hemorrhage. Stroke, 26, 1471–7. Helweg-Larsen, S., Sommer, W., Strange, P., Lester, J. & Boysen, G. (1984). Prognosis for patients treated conservatively for spontaneous intracerebral hematomas. Stroke, 15, 1045–8. Hino, A., Fujimoto, M., Yamaki, T., Iwamoto, Y. & Katsumori, T. (1998). Value of repeat angiography in patients with spontaneous subcortical hemorrhage. Stroke, 29, 2517–21.

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Hylek, E.M. & Singer, D.E. (1994). Risk factors for intracranial hemorrhage in outpatients taking warfarin. Annals of Internal Medicine, 120, 897–902. Iwasaki, Y. & Kinoshita, M. (1989). Subcortical lobar hematomas: clinico-computed tomographic correlations. Computerized Medical Imaging and Graphics, 13, 195–8. Kase, C.S. (1986). Intracerebral hemorrhage: non-hypertensive causes. Stroke, 17, 590– 5. Kase, C.S. & Caplan, L.R. (1994). Intracerebral Hemorrhage. Stoneham, MA: Butterworth Heinemann. Kase, C.S., Williams, J.P., Wyatt, D.A. & Mohr, J.P. (1982). Lobar intracerebral hematomas: clinical and CT analysis of 22 cases. Neurology, 32, 1146–50. Kase, C.S., Foster, T.E., Reed, J.E., Spatz, E.L. & Girgis, G.N. (1987). Intracerebral hemorrhage and phenylpropanolamine use. Neurology, 37, 399–404. Kase, C.S., Pessin, M.S., Zivin, J.A. et al. (1992). Intracranial hemorrhage after coronary thrombolysis with tissue plasminogen activator. American Journal of Medicine, 92, 384–90. Levine, S.R., Brust, J.C.M., Futrell, N. et al. (1990). Cerebrovascular complications of the use of the ‘crack’ form of alkaloidal cocaine. New England Journal of Medicine, 323, 699–704. Loes, D.J., Smoker, W.R.K., Biller, J. & Cornell, S.H. (1987). Nontraumatic lobar intracerebral hemorrhage: CT/angiographic correlation. American Journal of Neuroradiology, 8, 1027–30. Longstreth, W.T., Litwin, P.E., Weaver, W.D. & the MITI Project Group (1993). Myocardial infarction, thrombolytic therapy, and stroke: a community-based study. Stroke, 24, 587–90. Massaro, A.R., Sacco, R.L., Mohr, J.P. et al. (1991). Clinical discriminators of lobar and deep hemorrhages: the Stroke Data Bank. Neurology, 41, 1881–5. Morgenstern, L.B., Frankowski, R.F., Shedden, P., Pasteur, W & Grotta, J.C. (1998). Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology, 51, 1359–63. Norrving, B. (1998). Cerebral hemorrhage. In Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management, ed. M.D. Ginsberg & J. Bogousslavsky, chapter 105, pp. 1447–73. Malden, MA: Blackwell Science. Portenoy, R.K., Lipton, R.B., Berger, A.R., Lesser, M.L. & Lantos, G. (1987). Intracerebral haemorrhage: a model for the prediction of outcome. Journal of Neurology, Neurosurgery and Psychiatry, 50, 976–9. Ropper, A.H. & Davis, K.R. (1980). Lobar cerebral hemorrhages: acute clinical syndromes in 26 cases. Annals of Neurology, 8, 141–7. Schütz, H. (1988). Spontane intrazerebrale Hämatome: Pathophysiologie, Klinik und Therapie. Heidelberg: Springer-Verlag. Simard, J.M., Garcia-Bengochea, F., Ballinger, W.E., Mickle, J.P. & Quisling, R.G. (1986). Cavernous angioma: a review of 126 collected and 12 new clinical cases. Neurosurgery, 18, 162–72. Steiner, I., Gomori, J.M. & Melamed, E. (1984). The prognostic value of the CT scan in conservatively treated patients with intracerebral hematoma. Stroke, 15, 279–82.

Sung, C-Y. & Chu, N-S. (1989). Epileptic seizures in intracerebral haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry, 52, 1273–6. Tanne, D., Bates, V.E., Verro, P. et al. (1999). Initial clinical experience with IV tissue plasminogen activator for acute ischemic stroke: a multicenter survey. Neurology, 53, 424–7. Tapia, J.F. & Golden, J.A. (1993). Case records of the Massachusetts General Hospital (Case 27–1993). New England Journal of Medicine, 329, 117–24. The European Atrial Fibrillation Trial Study Group (1995). Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. New England Journal of Medicine, 333, 5–10. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995). Tissue plasminogen activator for actue ischemic stroke. New England Journal of Medicine, 333, 1581–7. Toffol, G.J., Biller, J. & Adams, H.P. (1987) Nontraumatic intracerebral hemorrhage in young adults. Archives of Neurology, 44, 483–5. Tomonaga, M. (1981). Cerebral amyloid angiopathy in the elderly. Journal of the American Geriatrics Society, 29, 151–7. Tuhrim, S., Dambrosia, J.M., Price, T.R. et al. (1988). Prediction of intracerebral hemorrhage survival. Annals of Neurology, 24, 258–63. Vinters, H.V. (1987). Cerebral amyloid angiopathy: a critical review. Stroke, 18, 311–24. Volpin, L., Cervellini, P., Colombo, F., Zanusso, M. & Benedetti, A. (1984). Spontaneous intracerebral hematomas: a new proposal about the usefulness and limits of surgical treatment. Neurosurgery, 15, 663–6. Wakai, S., Kumakura, N. & Nagai, M. (1992). Lobar intracerebral hemorrhage: a clinical, radiographic, and pathological study of 29 consecutive operated cases with negative angiography. Journal of Neurosurgery, 76, 231–8. Weisberg, L.A. (1985). Subcortical lobar intracerebral haemorrhage: clinical-computed tomographic correlations. Journal of Neurology, Neurosurgery and Psychiatry, 48, 1078–84. Weisberg, L.A. & Stazio, A. (1988a). Nontraumatic frontal lobe hemorrhages: clinical-computed tomographic correlations. Neuroradiology, 30, 500–5. Weisberg, L.A. & Stazio, A. (1988b). Occipital lobe hemorrhages: clinical-computed tomographic correlations. Computerized Medical Imaging and Graphics, 12, 353–8. Weisberg, L.A. & Stazio, A. (1989). Nontraumatic parietal subcortical hemorrhage: clinical-computed tomographic correlations. Computerized Medical Imaging and Graphics, 13, 355–61. Weisberg, L.A., Stazio, A., Shamsnia, M. & Elliott, D. (1990a). Nontraumatic parenchymal brain hemorrhages. Medicine, 69, 277–95. Weisberg, L.A., Stazio, A., Shamsnia, M. & Elliott, D. (1990b). Nontraumatic temporal subcortical hemorrhage: clinical computed tomographic analysis. Neuroradiology, 32, 137–41. Weisberg, L.A. & Wall, M. (1987). Alexia without agraphia: clinical-

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computed tomographic correlations. Neuroradiology, 29, 283–6. Wijdicks, E.F.M. & Jack, C.R. (1993). Intracerebral hemorrhage after fibrinolytic therapy for acute myocardial infarction. Stroke, 24, 554–7.

Young, W.B., Lee, K.P., Pessin, M.S., Kwan, E.S., Rand, W.M. & Caplan, L.R. (1990). Prognostic significance of ventricular blood in supratentorial hemorrhage: a volumetric study. Neurology, 40, 616–19.

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48

Intraventricular hemorrhages Peter C. Gates Department of Neuroscience, Greelong Hospital, Victoria, Australia

Introduction Intraventricular hemorrhage (IVH) can occur following rupture of parenchymal hemorrhage into the ventricular system (secondary IVH) or can result from disease processes either within the ventricular system or just beneath the ventricular wall (primary IVH). This chapter will concentrate on primary IVH and briefly discuss secondary IVH. IVH during the neonatal period and IVH in the presence of generalized subarachnoid hemorrhage are not discussed. In 1881, following a review of 94 cases, Sanders (1881) coined the term primary intraventricular hemorrhage. He described the clinical syndrome as occurring in the very young and the very old. It was of rapid onset, with profound coma from the outset, with convulsions (though paralysis frequently was absent), rapidly leading to death. He further added that ‘most authors agree with the statement that extravasation of the blood into the ventricles is uniformly and rapidly fatal’. Such pessimistic views continued for half a century (Gordon, 1916). It is not surprising that such a view was common, because those earlier observations had been based on postmortem studies. Subsequent to the introduction of computed tomography (CT), non-fatal IVH has been recognized (Butler et al., 1972; De Weerd, 1979; Gates et al., 1986).

Neuroanatomic considerations In the circulation in the subependymal or periventricular region, there is a distinct periventricular centrifugal supply of blood, with the direction of flow being from the ventricular surface toward the parenchyma for a distance of up to 1.5 cm. The periventricular arteries originate beneath the

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ependyma as terminal branches of the anterior and posterior choroidal arteries and of some of the striatal rami of the middle cerebral artery. There are no anastomoses between these vessels and the deep-penetrating centripetal arteries (Van den Burgh, 1969). On the basis of earlier work, Butler et al. (1972) offered a more rigorous definition of primary IVH. They suggested that primary IVH arose from rupture of vessels within the choroid plexus or the periventricular region up to 1.5 cm distance from the ependymal wall.

Clinical features of IVH The symptoms that can be directly attributed to blood within the ventricular system can best be understood by studying cases of primary IVH. Minor IVH is indistinguishable from subarachnoid hemorrhage, with the sudden onset of severe headache, nausea, vomiting, and neck stiffness, with minimal or no focal neurological deficit. With more extensive hemorrhage, consciousness progressively declines, and focal or generalized seizures may occur. In massive IVH, signs of brainstem compression occur (Gates et al., 1986; Jayakumar et al., 1989). Rarely, a localized intraventricular hematoma simulating a tumour can occur (Fig. 48.1), believed to form as a result of bleeding into the ventricle under low pressure (Avol & Vogel, 1955; McDonald, 1962). Rupture of a subependymal hematoma not detected by CT has been reported as a cause of primary IVH (Gates et al., 1986). Repeated hemorrhages were described prior to the CT era (Scully, 1937). Primary IVH is rare, and the identified causes are listed in Table 48.1. Secondary IVH can also occur in patients with large parenchymal hemorrhage of any cause. In those cases, the

Intraventricular hemorrhages

Fig. 48.1. This 52-year-old woman presented with a 6-month history of progressive weakness in her legs, difficulty in walking, and slowing of her thought processes. Memory and sphincter functions were not disturbed. The CT scan revealed a localized mass in the left lateral ventricle near the foramen of Munro, resulting in hydrocephalus. It was initially thought to be a tumour, but at surgery only hematoma was found. The findings at follow-up CT were normal.

clinical features are dominated by the parenchymal component: focal neurological deficits, focal or generalized seizures, and variable decreases in consciousness, in addition to severe headache, nausea, and vomiting (Little et al., 1977). (See Chapter 47 for more detailed discussion of intracerebral hemorrhage.) The increased densities on CT scans that reveal the presence of IVH will disappear in 12 days (Little et al., 1977). Cerebral angiography is indicated when CT suggests an underlying arteriovenous malformation (AVM) or aneurysm. Isolated IVH can be seen in patients with aneurysmal subarachnoid hemorrhage if there has been a delay between onset of symptoms and CT scanning. Spetzger et al., 1995 have described a case of fourth ventricular hemorrhage due to a metastatic hypernephroma, that was not detected on initial CT or angiography, nor on an MRI scan 6 weeks after the hemorrhage. Approximately 6 months

later, however, the patient presented with pressure symptoms related to a fourth ventricular tumour detected on MRI scan. Chang et al., (1998) in a retrospective review of 24 patients advocated cerebral angiography in all patients less than 45 years of age on the basis of finding five AVMs and two aneurysms in 18 angiograms.

Prognosis and treatment The prognoses for patients with IVH are variable (Table 48.2). Primary IVH entails a better outcome (Van den Burgh, 1969; De Weerd, 1979; Gates et al., 1986) than secondary IVH (Little et al., 1977; Cahill & Ducker, 1982) where the outcome depends on the nature and severity of the underlying intracerebral hemorrhage. Several prognostic factors have been described, such as

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Table 48.1. Causes of primary IVH (confirmed by autopsy, surgery, or angioplasty) Cause

Reference

Choroid plexus malformation Choroid plexus hemangioma Normal choroid plexus Intraventricular AVM Intraventricular aneurysm Intraventricular varix Intraventricular cavernous hemangioma AVM of caudate nucleus Moya-moya syndrome Subependymal hemorrhagic lacunar infarction Saccular aneurysm ACA, ICA, MCA, PICA, basilar artery PICA saccular aneurysm (fourth-ventricle hematoma) Miliary aneurysm Cerebral vein thrombosis Intraventricular hypernephroma metastasis Intraventricular meningioma Choroid plexus papilloma Intraventricular neurocytoma Ependymoma (fourth ventricle) Chromophobe adenoma (apoplexy) Benign third ventricular astrocytoma Suprasellar granular cell tumour Intraventricular dermoid Thrombolytic treatment Leukemia Scurvy Purpura Meningitis Intraventricular parasitic granuloma Cocaine abuse Churg-Strauss Ommaya reservoir Traumatic tear of the tela choroidea

Scully (1937) Doe et al. (1955) Gordon (1916) Faeth (1954) Schuermann et al. (1968) Roda et al. (1988) Jain (1966) Carton and Hickey (1955) Kodoma et al. (1976) Gates et al. (1986) (Moore, Jackson, Hanot, Van der Byl)a Walton (1956) Crompton (1965) (Charcot)a (Barot)a Spetzger et al. (1995) Smith et al. (1975) Ernsting (1955) Smoker et al. (1991) Poon and Solis (1985) Patel and Shields (1979) Lena et al. (1991) Graziani et al. (1995) (Verrattus)a Uglietta et al. (1991) McCallum et al. (1978), (Blache)a (Machlachlan)a (Hallowes)a (Goelis)a Wong and Ho (1994) Levine et al. (1990) Chang et al. (1998) Lishner et al. (1990) Berry and Rice (1994)

Notes: Abbreviations: ACA: anterior cerebral artery, MCA: middle cerebral artery, ICA: internal carotid artery, PICA: posterior inferior cerebellar artery, AVM: arterio-venous malformation. a Authors of case reports reviewed by Sanders (1881).

the extent of the intraventricular blood, the severity of the deficit as graded by the Glasgow coma scale (GCS), the age of the patient, and the delay before treatment (Chan & Chan, 1988). In general, older patients with more extensive IVH and lower scores on the GCS fare worse. Not all authors (De Weerd, 1979) agree that the extent of intraventricular blood (i.e. whether confined to one or both lateral ventricles or involving the lateral third and fourth ventricles) correlates with prognosis. They argue that it is not merely the

distribution of the IVH, but rather the volume of blood within the ventricular system, its mass effect, and the expansion of the ventricular system that influence outcome. Treatment will depend on the severity of the IVH. In mild cases, no specific treatment is necessary following determination of the underlying cause. In severe IVH, surgical evacuation, ventricular drainage, and more recently, thrombolytic treatment have all been advocated (Butler et

Intraventricular hemorrhages

Table 48.2. Morbidity and mortality in report series of IVH

Reference

Number of patients

Primary or secondary

Mortality

Severe morbidity

Mild deficit or good outcome

Little et al. (1977) De Weerd (1979) Cahill and Ducker (1982) Gates et al. (1986) Verma et al. (1987) Chan and Chan (1988) Hayashi et al. (1988) Jayakumar et al. (1989) Angelopoulos et al. (1995)

54 40 38 5 21 22 101 15 14

P, S ?S S P P, S S S P P

83% 53% 68% 20% 47% 23% 38% 47% 36%

6% 17% 11% — 10% 36% 31% — —

6% 30% 21% 80% 43% 41% 31% 53% 64%

al. 1972; Chan & Chan, 1988; Todo et al., 1991) based on the poor prognosis from historical controls. Chan and Chan (1988) claimed improvement in outcome following ventricular drainage using a one-way-valve-regulated system (which, in their view, prevented infection) and applying some drainage to prevent blockage. Surgical treatment of the underlying cause (e.g. AVM) may be necessary even when the severity of the IVH does not warrant surgical evacuation (Butler et al., 1972). Coplin et al., (1998) retrospectively reviewed their experience of 40 patients, 18 treated with ventriculostomy alone, whilst 22 received adjunctive urokinase therapy. The initial Glasgow coma score was similar in both groups, but the volume of parenchymal hemorrhage was greater in the group treated with urokinase. Mortality was less in the urokinase treated group (31.8 vs. 66.7%; P ⫽0.003), but there was only a trend towards a better outcome (22.2 vs. 36.4%; P⫽0.03). This lack of proof of a better outcome may relate to the small number of patients treated. Thrombolytic treatment directly into the ventricle will result in more rapid resolution of the intraventricular clot (Todo et al., 1991). Urokinase (Todo et al., 1991) and tissue plasminogen activator (rtPA) (Findlay et al., 1991) have been used primarily in patients with aneurysmal IVH after clipping of the aneurysm. Todo et al. (1991) instilled 10 000–12 000 units of urokinase at a time, followed by 1 h of drain clamping. That was performed once or twice per day, and was continued until opening and clearance of both the third and fourth ventricles was confirmed; in general, that took 3–4 days. Rainove and Burkert (1995) treated 16 patients with predominantly intraventricular but also parenchymal hemorrhage. They used 10 000 units of urokinase dissolved in 5 ml of sterile saline every 12 hours. This was administered by a ventriculostomy. Twelve patients had an excellent

outcome, three good and one poor. There were no reported complications. Findlay et al. (1991) first reported their experience with rtPA in a case report and then subsequently reported (Findlay et al., 1993) ten patients treated with intraventricular rt-PA. They treated ten patients with intraventricular hemorrhage and a decreased level of consciousness, eight were due to a ruptured aneurysm, one an AVM and one following posterior fossa surgery for a tumour. The rt-PA was commenced postoperatively, four received only one injection, five received two and one a third injection on consecutive days. Four mg of rt-PA was delivered slowly to a ventricular drain that was clamped for an hour and then allowed to drain freely. The majority of the intraventricular clot cleared within 4.6 ⫹/⫺1.8 days. They were able to document a significant reduction of intracranial pressure and a significant increase in CSF drainage. There were no complications. Communicating hydrocephalus is a common sequel to IVH. Treatment in the short term will include ventricular drainage; in the long term, ventriculoperitoneal shunting may be necessary. Aoki (1991), however, suggested that trauma to the brain and use of a general anesthetic can be avoided by performing a lumboperitoneal shunt, with spinal anesthesia, in this setting. In summary, primary IVH is a rare entity that can be associated with a large number of causes. The clinical picture depends on the severity of the hemorrhage, and management consists in determining the underlying cause. No definite statements can be made about surgical vs. medical treatment because of the lack of controlled data. In minor IVH, no specific treatment is required. There is little doubt that intraventricular thrombolytic therapy leads to a more rapid resolution of intraventricular clot and therefore reduces intracranial pressure. Compared

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to historical controls, outcome would seem to be improved, but the absence of randomised studies means it is impossible to unequivocally recommend thrombolytic therapy. Moreover, recently deterioration due to recurrent hemorrhage has been described in two patients 20 minutes and 4 hours after instillation of intraventricular tPA (Schwarz et al., 1998). This is the first report of a deleterious effect of intraventricular thrombolytic therapy. At this point in time, thrombolytic therapy cannot be recommended until the results of a randomized trial are available. (N.J. Naff is currently undertaking a multicenter trial of intraventricular thrombolytic therapy in patients with intraventricular hematoma secondary to subarachnoid or intracerebral hemorrhage. Source: http://cpmcnet.columbia.edu/dept/ neuro-icu/clinic.html.)

xReferencesx Angelopoulos, M., Gupta, S.R. et al. (1995). Primary intraventricular hemorrhage in adults: clinical features, risk factors, and outcome. Surgical Neurology, 44(5), 433–6; discussion 437. Aoki, N. (1991). Treatment for intraventricular hemorrhage. Journal of Neurosurgery, 75, 494–5. Avol, M. & Vogel, P.J. (1955). Circumscribed intraventricular hematoma simulating an encapsulated neoplasm. Bulletin the Los Angeles Neurological Society, 20, 25–9. Berry, K. & Rice, J. (1994). Traumatic tear of tela choroidea resulting in fatal intraventricular hemorrhage. American Journal of Forensic Medical Pathology, 15(2), 132–7. Butler, A.B., Partain, R.A. et al. (1972). Primary intraventricular hemorrhage. Neurology, 22, 675–87. Cahill, D.W. & Ducker, T.B. (1982). Spontaneous intracerebral hemorrhage. Clinical Neurosurgery, 29, 722–9. Carton, C.A. & Hickey, W.C. (1955). Arteriovenous malformation of the head of the caudate nucleus: report of a case with total removal. Journal of Neurosurgery, 12, 414–18. Chan, K.H. and Chan, M.K.S. (1988). Intraventricular haematoma: management of comatose patients with valve regulated external ventricular drainage. British Journal of Neurosurgery, 2(4), 465–9. Chang, D.S., Lin, C.L. et al. (1998). Primary intraventricular hemorrhage in adult – an analysis of 24 cases. Kao Hsiung I Hsueh Ko Hsueh Tsa Chih, 14(10), 633–8. Coplin, W.M., Vinas, F.C. et al. (1998). A cohort study of the safety and feasibility of intraventricular urokinase for nonaneurysmal spontaneous intraventricular hemorrhage. Stroke, 29(8), 1573–9. Crompton, M.R. (1965). Subtentorial changes following rupture of cerebral aneurysms. Brain, 88, 75–84. Darby, D.G., Donnan, G.A. et al. (1988). Primary intraventricular hemorrhage: clinical and neuropsychological findings in a prospective stroke series. Neurology, 38, 68–75.

De Weerd, A.W. (1979). The prognosis of intraventricular hemorrhage. Journal of Neurology, 222, 45–54. Doe, F.D., Shuangoshoti, S. et al. (1955). Cryptic haemangioma of the choroid plexus. A cause of intraventricular haemorrhage. Neurology, 22, 134–6. Ernsting, J. (1955). Choroid plexus papilloma causing spontaneous subarachnoid haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry, 18, 134–6. Faeth, W.H. (1954). Intraventricular arteriovenous vascular malformation: bleeding point demonstrated by angiography. Bulletin of the Los Angeles Neurological Society, 24, 49–53. Findlay, J.M., Weir, B.K.A. et al. (1991). Lysis of intraventricular hematoma with tissue plasminogen activator. Journal of Neurosurgery, 74, 803–7. Findlay, J.M., Grace, M.G. et al. (1993). Treatment of intraventricular hemorrhage with tissue plasminogen activator. Neurosurgery, 32(6), 941–7. Gates, P.C., Barnett, H.J.M. et al. (1986). Primary intraventricular hemorrhage in adults. Stroke, 17, 872–7. Gordon, A. (1916). Ventricular hemorrhage. A symptom group. Archives of Internal Medicine, 17, 343–53. Graziani, N., Dufour, H. et al. (1995). Suprasellar granular-cell tumour, presenting with intraventricular haemorrhage. British Journal of Neurosurgery, 9(1), 97–102. Hayashi, M., Hayashi, H.Y. et al. (1988). Management of intraventricular haemorrhage in patients with haemorrhagic cerebrovascular diseases. British Journal of Neurosurgery, 2(1), 23–32. Jain, K.K. (1966). Intraventricular cavernous hemangioma of the lateral ventricle: case report. Journal of Neuosurgery, 24, 762–4. Jayakumar, P.N., Taly, A.B. et al. (1989). Prognosis in solitary intraventricular haemorrhage. Acta Neurologica Scandinavica, 80, 1–5. Kodoma, N., Mineura, K. et al. (1976). Ventricular hemorrhage due to chronic cerebral ischemia. Brain and Nerve (Tokyo), 28, 823–31. Lena, G., Genitori, L. et al. (1991). [Meningeal hemorrhage disclosing a brain tumor in a child]. Annales Pediatrique (Paris), 38(3), 193–5. Levine, S.R., Brust, J.C.M. et al. (1990). Cerebrovascular complications of the use of the ‘crack’ form of alkaloidal cocaine. New England Journal of Medicine, 323, 699–704. Lishner, M., Perrin, R.G. et al. (1990). Complications associated with Ommaya reservoirs in patients with cancer. Archives of Internal Medicine, 150, 173–6. Little, J.R., Blomquist, G.A.J. et al. (1977). Intraventricular hemorrhage in adults. Surgical Neurology, 8(3), 143–9. McCallum, J.E., Lodoke, D. et al. (1978). CT scan in intraventricular hemorrhage correlation of clinical findings with computerized tomographic scans of the brain. Neurosurgery, 3, 22–5. McDonald, J.V. (1962). Midline hematomas simulating tumors of the third ventricle. Neurology, 12, 805–9. Patel, D.V. & Shields, M.C. (1979). Intraventricular hemorrhage in pituitary apoplexy. Journal of Computer Assisted Tomography, 6, 829–31. Poon, T.P. & Solis, O.G. (1985). Sudden death due to massive intra-

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ventricular hemorrhage into an unsuspected ependymoma. Surgical Neurology, 24, 63–6. Rainove, N.G. & Burkert, W.L. (1995). Urokinase infusion for severe intraventricular haemorrhage. Acta Neurochirurgica, 134(1–2), 55–9. Roda, J.M., Bencosme, J. et al. (1988). Intraventricular varix causing hemorrhage. Journal of Neurosurgery, 68, 472–3. Sanders, E. (1881). A study of primary, immediate, or direct hemorrhage into the ventricles of the brain. American Journal of Medical Science, 82, 85–128. Schuermann, K., Brock, M. et al. (1968). Circumscribed hematoma of the lateral ventricle following rupture of an intraventricular saccular aneurysm. Journal of Neurosurgery, 29, 195–8. Schwarz, S., Schwab, S. et al. (1998). Secondary hemorrhage after intraventricular fibrinolysis: a cautionary note: a report of two cases. Neurosurgery, 42(3), 659–62; discussion 662–3. Scully, F.J. (1937). Internal hydrocephalus following repeated intraventricular hemorrhages. Annals of Internal Medicine, 11, 684–6. Smith, V.R., Stein, P.S. et al. (1975). Subarachnoid hemorrhage due to lateral ventricular meningiomas. Surgical Neurology, 4(2), 241–3. Smoker, W.R.K., Townsend, J.J. et al. (1991). Neurocytoma accom-

panied by intraventricular hemorrhage: case report and literature review. American Journal of Neuroradiology, 12, 765–70. Spetzger, U., Mull, M. et al. (1995). Subarachnoid and intraventricular hemorrhage caused by hypernephroma metastasis, accompanied by innocent bilateral posterior communicating artery aneurysms. Surgical Neurology, 44(3), 275–8. Todo, T., Usui, M. et al. (1991). Treatment of severe intraventricular hemorrhage by intraventricular infusion of urokinase. Journal of Neurosurgery, 74(1), 1–6. Uglietta, J.P., O’Connor, C.M. et al. (1991). CT patterns of intracranial hemorrhage complicating thrombolytic therapy for acute myocardial infarction. Radiology, 181, 555–9. Van den Burgh, R. (1969). The Periventricular Intracerebral Blood Supply. Springfield: Charles C. Thomas. Verma, A., Maheshwari, M.C. et al. (1987). Spontaneous intraventricular haemorrhage. Journal of Neurology, 234(4), 233–6. Walton, J.N. (1956). Subarachnoid Haemorrhage, London: Churchill Livingstone. Wong, C.W. & Ho, Y.S. (1994). Intraventricular hemorrhage and hydrocephalus caused by intraventricular parasitic granuloma suggesting cerebral sparganosis. Acta Neurochirurgica, 129, 205–8.

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Subarachnoid hemorrhage syndromes Jan van Gijn and Gabriel J.E. Rinkel University Department of Neurology, University Medical Centre, Utrecht, The Netherlands

Causes of subarachnoid hemorrhage It is not the purpose of this chapter to go into great depth about the variety of disease conditions that may cause subarachnoid hemorrhage, but we should like to point out that 15% of spontaneous hemorrhages in the subarachnoid space are not caused by aneurysms (Table 49.1), and that certain elements of the history or the physical examination may sometimes point to one of these specific causes.

History Sudden headache The key feature in diagnosing subarachnoid hemorrhage (SAH) is the history of sudden, severe and unusual headache. Classically it comes on in seconds (‘a flash’, ‘just like that’, ‘a bolt from a blue sky’, ‘as if I was hit on the head’), or in a few minutes at most. A potential pitfall is that patients may sometimes use the word ‘sudden’ to describe an episode of headache that came on in half an hour or longer, depending on the interval after which the history is given. And, even if the headache really comes on within seconds or minutes, such a history is not specific for ruptured aneurysms or even for SAH in general. Sudden onset headache may also occur with other intracranial hemorrhages, with non-hemorrhagic brain disease, and especially with innocuous forms of ‘thunderclap headache’: variants of vascular headache, migrainous or not, or of muscle contraction headache. Sexual activity may precipitate not only SAH, but also either type of the relatively harmless headaches (Lance, 1976; Pascual et al., 1996). In general practice, exceptional forms of common headaches outnumber common forms of a rare disease, in this case a ruptured aneurysm. That statement sounds para-

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doxical, but there are many other examples of this so-called risk paradox (Rose, 1992): although high maternal age is a strong risk factor for Down’s syndrome, most children with that chromosomal abnormality are born from mothers under 30. Similarly, most patients with ischemic stroke have no or only mild hypertension, etc. The incidence of aneurysmal hemorrhage is about 6 per 100 000 population per year (Linn et al., 1996); therefore a family physician with a practice of 2000 persons will, on average, see one such patient every year. Patients with headache may present not only to general practitioners but also to an accident and emergency department; they constitute around 1% of all attendances (Fodden et al., 1989). The proportion with serious neurological conditions ranges from 16% for all patients with any headache (Fodden et al., 1989), to 75% for those with episodes of sudden headache specifically referred to a neurologist (van der Wee et al., 1995; Linn et al., 1994). Table 49.2 lists the frequencies of the different disease categories in the setting of primary care as well as in that of a neurology service in a university hospital. The exact speed of onset of headache, seconds or minutes, in patients without any other deficits, is of little help for the hospital physician in distinguishing aneurysmal hemorrhage from innocuous headaches, or from nonaneurysmal perimesencephalic hemorrhage, a disorder with an unknown cause but an invariably good outcome (van Gijn et al., 1985b; Rinkel et al., 1991). The predictive value of the speed of onset (seconds vs. 1–5 minutes) can be calculated from two data sets. First, ruptured aneurysms are nine times as common as non-aneurysmal perimesencephalic hemorrhages (Rinkel et al., 1993), and in hospital series these two forms of subarachnoid hemorrhage together are twice as common as innocuous headaches (van der Wee et al., 1995). Second, headache develops almost instantaneously in 50% of patients with aneurysmal SAH, 35% of patients with non-aneurysmal

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Table 49.1. Causes of subarachnoid hemorrhage Ruptured aneurysm Non-aneurysmal perimesencephalic hemorrhage (of venous origin?) Rarities Arterial dissection (transmural) Cerebral arteriovenous malformation Dural arteriovenous fistula Pituitary apoplexy Mycotic aneurysm Cardiac myxoma Sickle cell disease Tumours Spinal arteriovenous malformation or aneurysm Trauma (without contusion) Cocaine abuse

‘Warning leaks’ 85% 10% 5%

perimesencephalic hemorrhage, and 68% of patients with ‘benign thunderclap headaches; for an onset within 1 to 5 minutes these proportions are 19, 35, and 19%, respectively (Linn et al., 1998). If, for the sake of simplicity, we briefly ignore patients with sudden headache from other serious (non-hemorrhagic) brain disease, such as cerebral venous thrombosis (De Bruijn et al., 1996), calculations on the back of an envelope lead to the disappointing conclusion that an onset within seconds correctly predicts aneurysmal hemorrhage in only 55%, and that headache onset in 5–10 minutes correctly predicts innocuous headache in only 30%. In brief, there are no single or combined features of the headache that distinguish reliably and at an early stage between SAH and innocuous types of sudden headache (Linn et al., 1998). The discomfort and cost of referring the majority of patients for a brief consultation in hospital (which should include CT scanning and a delayed lumbar puncture if this is negative (van der Wee et al., 1995)) is probably outweighed by avoidance of the potential disaster that a ruptured aneurysm is missed and the patient is readmitted with rebleeding or another secondary complication. Pain at onset in the lower part of the neck (upper neck pain is common also with ruptured intracranial aneurysms), or a sudden and stabbing pain between the shoulder blades (coup de poignard or dagger thrust), with or without radiation to the arms, suggests a spinal arteriovenous malformation or fistula (Kinouchi et al., 1998) as the source of SAH. Even if there is severe headache initially, this may evolve into backache or radicular pain, especially if the patient keeps out of bed.

‘Sentinel headaches’, previous episodes of sudden headache, are generally believed to be common in patients with aneurysmal subarachnoid hemorrhage and are attributed to a ‘warning leak’. On specific questioning 20–40% of patients recall a previous episode of headache that was unusually severe and lasted several hours (Verweij et al., 1988; Tolias & Choksey, 1996). Many neurosurgeons and neurologists are therefore convinced that important advances in the overall management of ruptured aneurysms can be expected from early recognition of minute episodes of subarachnoid hemorrhage, followed by emergency clipping of the aneurysm. A major difficulty with the notion of these ‘warning leaks’ is that almost all studies have been hospital based, most have been retrospective, and that even prospectively conducted studies are probably biased by hindsight (recall bias). In a prospective study of 148 patients with sudden, severe headache identified in general practice, 37 had subarachnoid hemorrhage; other serious neurological conditions were diagnosed in 18. In the remaining 93 patients, no neurological cause of headache was found; 1 year of follow-up failed to uncover subsequent episodes of SAH or sudden death. Only two of the 37 patients with SAH had had previous episodes of sudden headache on systematic questioning by the general practitioner at the time of presentation for the headache (Linn et al., 1994). Also, the amount and distribution of extravasated blood on brain CT as well as the overall outcome was similar to that in a previous hospital series of patients with subarachnoid hemorrhage. In other words, first-ever episodes of subarachnoid hemorrhage detected in general practice are not ‘small leaks’, but represent the same spectrum of severity as that seen in hospital. A second way to confirm or falsify the existence of ‘warning leaks’ is to study the clinical and radiological features in a prospective series of patients admitted to hospital with aneurysmal subarachnoid hemorrhage and subsequently to compare the subgroup of patients with a history of preceding episodes of sudden headache with the others. The distribution of clinical and radiological features was exactly the same in the two groups, and distinctly less severe than in those with a documented rebleed in hospital (Linn et al., 2000). In brief, the notion of frequent ‘warning leaks’ is not supported by epidemiological, clinical and radiological evidence. This does not mean that an episode of subarachnoid hemorrhage cannot be missed by primary care physicians, but avoidance of these errors is unlikely to result in substantial improvement of the overall outcome (J.W. Hop, unpublished observations).

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Table 49.2. Causes of sudden headache, according to frequency

General practice

Hospital series (neurology referrals)

Intracranial hemorrhage (aneurysmal, non-aneurysmal perimesencephalic, primary intraventricular, intracerebral, cerebellar, subdural)

25%a

50%

Other serious brain disorders (intracranial venous thrombosis, arterial dissection, colloid cyst)

12%

25%

Functional syndromes (idiopathic thunderclap headache, benign exertional headache, venous strain, related to sexual activity, icepick headache)

63%

25%

Note: a 12% if headache is the only symptom. Sources: Linn et al. (1994); van der Wee et al. (1995)

A truly biphasic headache may occur in patients with SAH from transmural dissection of a vertebral artery: a severe occipital headache radiating from the back of the neck, followed after an interval of hours or days by a sudden exacerbation of a headache of a more diffuse type. The initial episode probably represents the process of dissection and not (yet) meningeal irritation; such occipital headaches are common also in patients with ischemic deficits or lower cranial nerve palsies as a result of vertebral artery dissection without rupture of the outer wall, and headache may even be the only manifestation (Mokri et al., 1988; Yamaura et al., 1990). On the other hand, biphasic headache is not a necessary feature of SAH from dissection of a vertebral artery; the hemorrhage may well occur right at the onset (Aoki & Sakai, 1990).

Antecedent events A history of even quite minor neck trauma or of sudden, unusual head movements before the onset of headache may provide a clue to the diagnosis of vertebral artery dissection as a cause of SAH. Head trauma and primary SAH may be confused. Trauma should always be suspected in patients found unconscious in the street, even if there is marked neck stiffness and no superficial wound. Conversely, a traffic accident may sometimes be the result

rather than the cause of SAH, and invaluable information may be obtained from the police or ambulance workers; in a patient known to have swerved from one side of the road to the other before crashing into someone else, the a priori probabilities are quite different from those in someone reported to have ignored a red traffic light. The ultimate conundrum is a direct blow on the head, that causes an aneurysm to rupture (Sahjpaul et al., 1998). Cocaine ingestion as a risk factor may not immediately be known in the case of an unconscious patient. Cocaine (or ephedrine) should be considered in young adults with SAH, particularly if the social background is unstable, although in some regions of the world the use of cocaine affects all social strata. Even if the family turns up in large numbers, one may find that not every relative is aware of illicit drugs being used or willing to volunteer this information even if they are. In cocaine-associated SAH there is usually an underlying aneurysm (Levine et al., 1991; Nolte et al., 1996). It is unknown whether cocaine induces not only the rupture but also the development of aneurysms.

Loss of consciousness Loss of consciousness at onset had occurred in approximately 50% of almost 500 patients with proven or pre-

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sumed aneurysmal hemorrhage who were well enough to be entered into a clinical trial of medical treatment within 3 days (Vermeulen et al., 1984). The overall proportion must be even higher, as in population-based studies 10–12% of patients died at home or during transportation (Linn et al., 1994; Schievink et al., 1995), and in a large, unselected series of patients who reached hospital alive the case fatality within the first 24 hours was more than 20% (Hijdra & van Gijn, 1982). Some patients complain of headache before they lose consciousness, and all patients have severe headache if they regain consciousness. Some patients may enter a confusional, agitated state (delirium), with or without preceding coma. Bizarre actions may include grimacing, spitting, making sucking or kissing sounds, spluttering, singing, whistling, yelling and screaming (Fisher, 1975). More than once, such behaviour has been misinterpreted as psychological in origin. Nonaneurysmal (perimesencephalic) SAH is typically associated with normal cognitive function; loss of consciousness or altered behaviour practically rules out this diagnosis, but amnesia may occur, mostly in association with an enlarged ventricular system (Hop et al., 1998). Head trauma should always be considered in patients who are found unconscious (see above). In patients with an impaired level of consciousness on admission, it is important to ascertain whether this condition existed from the onset, in which case it should be interpreted as the result of a global perfusion failure by the high CSF pressure at the time of rupture, or sometimes of an intraparenchymal haematoma, or whether the level of consciousness decreased only in subsequent hours. In the latter case a treatable complication should be suspected, such as acute hydrocephalus (van Gijn et al., 1985a), or edema formation around an intraparenchymal hematoma.

Epileptic seizures Epileptic seizures at the onset of aneurysmal SAH occur in approximately 6–16% of patients (Sarner & Rose, 1967; Hart et al., 1981; Pinto et al., 1996). Patients with a large amount of cisternal blood on brain CT are relatively often affected (Hart et al., 1981). The majority of patients with de novo epilepsy above age 25 will have underlying conditions other than subarachnoid hemorrhage, but the diagnosis should be suspected if the postictal headache is unusually severe. Seizures have not been documented in patients with perimesencephalic SAH, presumably of venous origin, but they may well complicate hemorrhages from arterial sources other than aneurysms, such as dissection of the vertebral artery or an AVM.

Past medical history In patients with a distant history of head injury, and particularly with a skull fracture, a dural AVM should be suspected, since healing of the fracture may be accompanied by the development of such a malformation (Chaudhary et al., 1982). Mycotic aneurysms may give rise to SAH even in patients not known to suffer from a disorder of the heart valves, but such a presentation of infective endocarditis is exceptional (Vincent et al., 1980; Salgado et al., 1987). For practical purposes this possibility can be safely dismissed in a previously healthy patient in whom the hemorrhage is located at the base of the brain. A diagnosis of a ruptured mycotic aneurysm may well be entertained, however, with a history of malaise and a hemorrhage located at the convexity of the brain. Usually it will not be hard for the physician to get acquainted with the existence of sickle cell disease, a history of cardiac myxoma, or the influence of other coagulation disorders. The use of anticoagulants probably does not contribute to the risk of rupture, but it is important to know that in such patients the prognosis is worse than average (Rinkel et al., 1997), and that therefore normal coagulation should be urgently restored by intravenous administration of clotting factors. Pituitary apoplexy may be difficult to diagnose if an adenoma was not known to exist and particularly if a decrease in the level of consciousness precludes a proper assessment of visual and oculomotor deficits. Usually, the underlying adenoma has insidiously manifested itself before the dramatic occurrence of the hemorrhage, such as by a dull retro-orbital pain, fatigue, a gradual decrease of visual acuity or a constriction of the temporal fields, but often these symptoms lead to the diagnosis only in retrospect and not before. There are many contributing conditions and factors that may precipitate hemorrhagic infarction of a pituitary tumour, such as pregnancy, raised intracranial pressure, anticoagulant treatment, cerebral angiography or the administration of gonadotrophinreleasing hormone (Reid et al., 1985; Masson et al., 1993). On CT scanning, the hemorrhage remains usually confined within the tumour capsule; rarely it extends throughout the basal cisterns as with ruptured aneurysms.

Family history A family history of SAH can be a useful clue in patients with sudden headache. Some families exist in which numerous relatives are struck down by ruptured aneurysms (Bromberg et al., 1995a). Even in cases of so-called sporadic SAH the risk in first-degree relatives is increased (Bromberg et al., 1995b). Families in which aneurysm

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rupture has occurred in two or more first-degree relatives may have an underlying or associated disorder, such as Marfan’s syndrome, Ehlers–Danlos syndrome type IV, pseudoxanthoma elasticum, hereditary hemorrhagic telangiectasia, polycystic kidney disease, polycystic liver disease or coarctation of the aorta, but in most cases of familial aneurysms there is no such overt disorder of connective tissue.

Examination Neck stiffness This is a common sign in SAH of any cause, but it takes hours to develop and therefore it cannot be used to exclude the diagnosis if a patient is seen soon after the suddenonset headache. Neck stiffness is also absent in deep coma. If present, the sign does not distinguish between different causes of SAH, and not even between hemorrhagic disorders and meningitis.

Pyrexia During the first 2–3 days after SAH, of aneurysmal or other origin, the body temperature rarely exceeds 38.5 oC, but thereafter it may rise to over 39 oC (Rousseaux et al., 1980). This raises the possibility of an intercurrent infection, but an important and common feature in any patient with SAH is an aseptic meningeal inflammatory response, with fever but with a pulse rate that remains disproportionately low.

the decrease in cerebral perfusion resulting from increased CSF pressure and later vasospasm. In brief, antihypertensive drugs are not indicated if the patient was previously normotensive, unless the raised blood pressure itself causes complications, such as heart failure or renal failure.

Subhyaloid hemorrhages The sudden increase in CSF pressure that occurs with rupture of an aneurysm is transmitted to the CSF spaces surrounding the optic nerves and blocks the venous outflow from the retina, which in turn may lead to rupture of retinal veins (Manschot, 1954). Such intraocular hemorrhages occur in approximately 17% of patients who survive the acute phase (Pfausler et al., 1996; Frizzell et al., 1997); in half of them the blood remains confined to the space between the retina and the vitreous body, in the other half it ruptures into the vitreous body (Terson’s syndrome). The vitreous hemorrhages give rise to disabling scotomas; vitrectomy is an effective treatment, given the patient has sufficiently recovered from the intracranial hemorrhage and its treatment (Kuhn et al., 1998). Sometimes the preretinal hemorrhages are the only sign of SAH (Kiriakopoulos et al., 1998).

Visual field defects Anterior communicating artery aneurysms may, in exceptional cases, compress an optic nerve and cause monocular blindness after rupture (Chan et al., 1997), or they may even penetrate one side of the optic chiasm, with or without involvement of the optic tract (Horiuchi et al., 1997).

Hypertension Hypertension is a well-established risk factor for subarachnoid hemorrhage (Teunissen et al., 1996), and 20–25% of patients have a history of hypertension (Artiola i Fortuny et al., 1980; Vermeulen et al., 1984). On admission, about 50% of patients with aneurysmal SAH have a markedly raised blood pressure. In many patients this raised blood pressure is a reactive phenomenon, and not a marker of long-standing hypertension; often the blood pressure returns to normal within a few days. It makes intuitive sense that hypertension increases the risk of rebleeding, and indeed there is some evidence that this is so (Torner et al., 1981), although in that study the diagnosis of rebleeding was not systematically supported by CT scanning. On the other hand, antihypertensive therapy substantially increases the risk of delayed cerebral ischemia (Wijdicks et al., 1990). The blood pressure changes probably serve to counteract

Third nerve palsy Complete or partial IIIrd nerve palsy degree is a wellrecognized sign after rupture of aneurysms of the internal carotid artery at the origin of the posterior communicating artery (Hyland & Barnett, 1954). It can also occur with aneurysms of the basilar bifurcation or even of the superior cerebellar artery, but these are relatively infrequent sites (Vincent & Zimmerman, 1980). There may be an interval of several days between the hemorrhage and the oculomotor palsy, presumably by expansion of the wall of the aneurysm without rupture. Third nerve palsy also occurs with unruptured aneurysms that compress or even fenestrate the nerve (Griffiths et al., 1994; Horiuchi et al., 1997). Reactive pleiocytosis may occur, which erroneously suggests a primary inflammatory process (Keane, 1996). The pupil is most often dilated and unreactive, but in some

Subarachnoid hemorrhage syndromes

patients the pupil is spared (Nadeau & Trobe, 1983; Kissel et al., 1983).

Parinaud’s syndrome The presence of small, unreactive pupils with impairment of downward gaze usually signifies hydrocephalus, and rarely a direct impact of the hemorrhage on the midbrain. In a prospective study of 34 patients with acute hydrocephalus after SAH, 30 had an impaired level of consciousness, nine of these 30 had small, non-reactive pupils, and four of these nine also showed persistent downward deviation of the eyes, with otherwise intact brainstem reflexes (van Gijn et al., 1985b). The eye signs reflect dilatation of the proximal part of the aqueduct, which causes dysfunction of the pretectal area (Swash, 1974). All nine patients with nonreactive pupils had a relative ventricular size of more than 1.20 and were in coma, i.e. they did not open their eyes, did not obey commands and did not utter words.

Sixth nerve palsies Sixth nerve palsies, often bilateral in the acute stage, usually result from the sustained rise of cerebrospinal fluid (CSF) pressure, at the time of rupture or later, but occasionally aneurysms of the posterior circulation cause direct compression (Fisher, 1975).

Lower cranial nerve palsies Transmural dissection of the vertebral artery may lead not only to SAH, but also to compression of the IXth or Xth nerve (Senter & Sarwar, 1982), and to ischemia in the territory of the posterior inferior cerebellar artery (Caplan et al., 1988). Lower cranial nerve palsies (IXth–XIIth nerve) may also accompany dissection of the carotid artery in the neck, but this is an extremely uncommon cause of SAH (Sturzenegger & Huber, 1993). If the source of the hemorrhage is a giant aneurysm, it may have caused symptoms such as multiple cranial nerve palsies before rupture (Drake, 1979).

Hemiparesis Hemiparesis at onset occurs in approximately 15% of patients with a ruptured aneurysm, usually with aneurysms of the middle cerebral artery (Sarner & Rose, 1967). As with other motor symptoms that follow below, the deficit may be only short lived (for a period of a few minutes); as these deficits may provide a clue to the cause

of SAH or the site of the aneurysm, they should not be disregarded. Because aneurysms vastly outnumber all other potential causes of SAH, the presence or absence of hemiparesis does not contribute much to the diagnosis of rarer causes, in which hemiparesis may be relatively common, for example, with mycotic aneurysms.

Cerebellar signs Deficits indicating lesions of the cerebellum or brainstem, such as dysmetria, scanning speech, rotatory nystagmus or Horner’s syndrome, strongly suggest vertebral artery dissection (Caplan et al., 1988).

Paraparesis Paraparesis may complicate rupture of an aneurysm of the anterior communicating artery complex, as a manifestation of a bifrontal hematoma, if present initially, or of delayed ischemia in the territory of both anterior cerebral arteries, if developing after an interval of several days (Greene et al., 1995).

Monoparesis Weakness of a single leg in the setting of subarachnoid hemorrhage is most often caused by a ruptured aneurysm of the anterior communicating artery, but occasionally and quite unexpectedly the aneurysm is at the posterior inferior cerebellar artery (Ferrante et al., 1992). In that case the deficit is explained by the close proximity of the aneurysm to the corticospinal tract, to the contralateral leg.

xReferencesx Aoki, N. & Sakai, T. (1990). Rebleeding from intracranial dissecting aneurysm in the vertebral artery. Stroke, 21, 1628–31. Artiola i Fortuny, L., Adams, C.B. & Briggs, M. (1980). Surgical mortality in an aneurysm population: effects of age, blood pressure and preoperative neurological state. Journal of Neurology, Neurosurgery and Psychiatry, 43, 879–82. Bromberg, J.E.C., Rinkel, G.J.E., Algra, A. et al. (1995a). Familial subarachnoid hemorrhage: Distinctive features and patterns of inheritance. Annals of Neurology, 38, 929–34. Bromberg, J.E.C., Rinkel, G.J.E., Algra, A. et al. (1995b). Subarachnoid hemorrhage in first and second degree relatives of patients with subarachnoid hemorrhage. British Medical Journal, 311, 288–9.

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Kinouchi, H., Mizoi, K., Takahashi, A., Nagamine, Y., Koshu, K. & Yoshimoto, T. (1998). Dural arteriovenous shunts at the craniocervical junction. Journal of Neurosurgery, 89, 755–61. Kiriakopoulos, E.T., Gorn, R.A. & Barton, J.J. (1998) Small retinal hemorrhages as the only sign of an intracranial aneurysm. American Journal of Ophthalmology, 125, 401–3. Kissel, J.T., Burde, R.M., Klingele, T.G. & Zeiger, H.E. (1983). Pupilsparing oculomotor palsies with internal carotid-posterior communicating artery aneurysms. Annals of Neurology, 13, 149–54. Kuhn, F., Morris, R., Witherspoon, C.D. & Mester, V. (1998). Terson syndrome – results of vitrectomy and the significance of vitreous hemorrhage in patients with subarachnoid hemorrhage. Ophthalmology, 105, 472–477. Lance, J.W. (1976). Headaches related to sexual activity. Journal of Neurology, Neurosurgery and Psychiatry, 39, 1226–30. Levine, S.R., Brust, J.C., Futrell, N. et al. (1991). A comparative study of the cerebrovascular complications of cocaine: alkaloidal versus hydrochloride – a review. Neurology, 41, 1173–7. Linn, F.H.H., Wijdicks, E.F.M., van der Graaf, Y., Weerdesteyn-van Vliet, F.A., Bartelds, A.I. & van Gijn, J. (1994). Prospective study of sentinel headache in aneurysmal subarachnoid hemorrhage. Lancet, 344, 590–3. Linn, F.H.H., Rinkel, G.J.E., Algra, A. & van Gijn, J. (1996). Incidence of subarachnoid hemorrhage – role of region, year, and rate of computed tomography: a meta-analysis. Stroke, 27, 625–9. Linn, F.H.H., Rinkel, G.J.E., Algra, A. & van Gijn, J. (1998). Headache characteristics in subarachnoid hemorrhage and benign thunderclap headache. Journal of Neurology, Neurosurgery and Psychiatry, 65, 791–3. Linn, F.H.H., Rinkel, G.J.E., Algra, A. & van Gijn, J. (2000). The notion of ‘warning leaks’ in subarachnoid haemorrhage: are such patients in fact admitted with a rebleed? Journal of Neurology, Neurosurgery and Psychiatry, 68, 425–9. Manschot, W.A. (1954) Subarachnoid hemorrhage: intraocular symptoms and their pathogenesis. American Journal of Ophthalmology, 38, 501–5. Masson, E.A., Atkin, S.L., Diver, M. & White, M.C. (1993). Pituitary apoplexy and sudden blindness following the administration of gonadotrophin releasing hormone. Clinical Endocrinology Oxford, 38, 109–10. Mokri, B., Houser, O.W., Sandok, B.A. & Piepgras, D.G. (1988). Spontaneous dissections of the vertebral arteries. Neurology, 38, 880–5. Nadeau, S.E. & Trobe, J.D. (1983). Pupil sparing in oculomotor palsy. A brief review. Annals of Neurology, 13, 143–8. Nolte, K.B., Brass, L.M. & Fletterick, C.F. (1996). Intracranial hemorrhage associated with cocaine abuse: a prospective autopsy study. Neurology, 46, 1291–6. Pascual, J., Iglesias, F., Oterino, A.,Vazquez-Barquero, A. & Berciano, J. (1996). Cough, exertional, and sexual headaches: an analysis of 72 benign and symptomatic cases. Neurology, 46, 1520–4. Pfausler, B., Belcl, R., Metzler, R., Mohsenipour, I. & Schmutzhard, E. (1996). Terson’s syndrome in spontaneous subarachnoid hemorrhage: a prospective study in 60 consecutive patients. Journal of Neurosurgery, 85, 392–4.

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Brain venous thrombosis syndromes Caroline Arquizan, Jean-François Meder and Jean-Louis Mas Neurology Services, Sainte Anne Hospital, Paris, France

The syndrome of intracranial vein and sinus thrombosis or cerebral venous thrombosis (CVT) has been recognized since the early part of the nineteenth century, when Ribes (1825) described the clinical and autopsy findings in a 45year-old man with disseminated malignancy and thrombosis of the superior sagittal sinus (SSS), left lateral sinus (LS), and a cortical vein. For a long time, CVT was considered a rare disease associated with a poor prognosis, and because confirmation was by autopsy initially, only severe manifestations were recognized (Ehlers & Courville, 1936; Symonds, 1937; Garcin & Pestel, 1949; Barnett & Hyland, 1953; Kalbag & Woolf, 1967; Krayenbuhl, 1967). Since the 1970s, the advent of sensitive neuroimaging techniques has clearly added to our understanding, earlier diagnosis and management of this condition, with effective treatments for both thrombosis and its underlying causes (Ameri & Bousser, 1992).

Venous anatomy The intracranial venous system is considerably more variable than the arterial anatomy (Figs. 50.1 and 50.2). Blood from the brain is drained by cerebral veins which empty into dural sinuses, themselves drained mostly by internal jugular veins.

Veins Cortical cerebral veins These veins receive blood from the superficial medullary veins that begin about 2 cm beneath the cortex. They drain the cortex and the adjacent white-matter. The cortical cerebral veins can be subdivided into three groups, based on the venous sinus into which they empty (Lasjaunias & Berenstein, 1990): (i) a dorsomedial system draining the

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high convexity and midline cortical veins, mainly into the SSS or the inferior sagittal sinus; (ii) a posteroinferior (ventrolateral) group draining temporo-occipital cortical veins into the LS; and (iii) an anterior system draining the anterior temporal lobe, parasylvian cortex, and anterior inferior frontal lobes into the cavernous sinus or the pterygoid venous plexus via the sylvian vein, which runs in the lateral portion of the sylvian fissure. The venous drainage is variable and reciprocal. Any of the three major components may be normally missing or hypoplastic, in which case the other components will be enlarged.

Deep cerebral veins The deep venous system shows much less variation than the cortical veins. It drains deep white-matter, the periventricular regions, and structures of the diencephalon. Small medullary veins in the deep white-matter drain perpendicularly towards subependymal veins in the walls of the lateral ventricles. The most important subependymal veins, the septal and thalamostriate veins, drain into the internal cerebral veins. The latter course posteriorly in the roof of the third ventricle, beneath the corpus callosum and around the splenium, to join their counterpart and to form the vein of Galen. Early in its course, the vein of Galen is joined by the paired basal veins of Rosenthal; it drains into the straight sinus. The basal veins of Rosenthal receive not only the drainage of the deep basal nuclei but also the superficial drainage of the insular and anterior cerebral venous territories, as well as the medial temporal and occipital venous territories (Simonds & Truwit, 1994).

Posterior fossa veins The venous drainage of the posterior fossa is extremely variable, but three main drainage pathways can be distinguished (Simonds & Truwit, 1994). The galenic system receives a superior group of veins draining the dorsal cere-

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Fig. 50.1. Venous phase of a right carotid artery angiogram in lateral projection. 1, superior sagittal sinus; 2, cortical veins (mediodorsal group); 3, inferior sagittal sinus; 4, internal cerebral vein; 5, great vein of Galen; 6, straight sinus; 7, torcular Herophili; 8, temporal vein (posteroinferior group); 9, lateral sinus.

bellum, vermis, and upper portion of the brainstem. The petrosal system drains the anterolateral and inferior portions of the posterior fossa structures. Finally, the straight and tentorial sinuses collect blood from the medial superior and inferior cerebellar hemispheres and the inferior vermian vein. Posteroinferior cerebellar hemispheric veins may drain into the transverse sinus.

Dural sinuses The venous sinuses are situated between the leaves of the falx and tentorium and are triangular in cross-section. They collect blood from the brain, meninges, and calvarium and deliver it to the internal jugular veins at the skull base. They also communicate with extracranial veins in the scalp by way of emissary veins. The calvarian and emissary veins provide pathways for the spread of extradural infections and may explain some cases of dural thrombosis fol-

lowing cutaneous contusions. The superior sagital sinus (SSS) and other sinuses play a major role in cerebrospinal fluid (CSF) circulation because they contain most of the arachnoid villi and granulations in which CSF absorption takes place. There is a direct dependency of CSF pressure upon the intracanial venous pressure, which explains the frequent increase in intracranial pressure in CVT. The superior sagital sinus (SSS) starts at the foramen caecum, just anterior to the crista galli. It courses along the curve of the inner table of the skull to reach the torcular Herophili (confluence of sinuses) at the internal occipital protuberance. The SSS increases progressively in caliber as it passes from the frontal to the occipital region. The SSS classically converges with the straight sinus at the torcular Herophili, and their combined flow drains into the transverse sinuses. The anterior SSS is often normally absent and replaced by two superior cerebral veins that join behind the coronal suture. The SSS drains the major part of

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Fig. 50.2. Venous phase of a right carotid angiogram in frontal view. 1, superior sagittal sinus; 2, left transverse sinus; 3, left sigmoid sinus; 4, right internal jugular vein; 5, cortical veins. Note the absence of opacification of the right transverse sinus (atresia) contrasting with the opacification of the right sigmoid sinus (arrows).

the cortex through frontal, parietal, and occipital superior cerebral veins. The inferior sagittal sinus follows a similar curve within the free margin of the falx cerebri and receives blood from the medial cerebral hemispheres and corpus callosum. It may communicate with the SSS by way of veins contained within the falx. The straight sinus lies in the junction of the falx cerebri and tentorium cerebelli. It drains inferiorly from the confluence of the vein of Galen and the inferior sagittal sinus to the internal occipital protuberance. Drainage may occur into the torcular Herophili, but more typically the straight sinus drains preferentially into one transverse sinus, usually the left (Cure et al., 1994; Cure & Van Tassel, 1994). The lateral sinuses (LSs) extend from the torcular Herophili to the jugular foramen and consist of two portions : the transverse portion which lies in the peripheral margin of the tentorium cerebelli and the sigmoid portion,

which begins where the transverse sinus leaves the tentorial margin. It courses inferiorly and medially toward the internal jugular vein. The transverse sinuses are often of unequal size (Cure et al., 1994, Cure & Van Tassel, 1994; Hacker, 1974; Zouaoui, 1988), the sinus with the more direct connection to the SSS being the larger. The right transverse sinus is more often a direct continuation of the SSS, whereas the left transverse sinus frequently receives most of its blood supply from the straight sinus. In approximately 20% of cases, there is total or partial agenesis of portions of the transverse sinus. The left transverse sinus is more frequently affected than the right. Atresia of the sigmoid sinus is rare. In case of transverse sinus atresia, the sigmoid sinus may fill through the vein of Labbé. The cavernous sinuses are situated laterally and superiorly to the sphenoid bone, lying on either side of the sella turcica. Cranial nerves III, IV, V1, and V2 travel in the lateral wall of the cavernous sinus. The internal carotid artery,

Brain venous thrombosis syndromes

sympathetic plexus, and cranial nerve V1 are within the cavernous sinus lumen. The cavernous sinus’s venous inflow includes the orbital venous drainage (ophthalmic veins), anterior middle cranial fossa drainage, and sphenoparietal sinus (the medial extension of the superficial sylvian vein). Blood drains posterolaterally along petrosal sinuses to the lateral sinus and the jugular vein. The two cavernous sinuses are connected by the intercavernous sinuses, which pass anteriorly and posteriorly to the sella turcica and pituitary gland, explaining why cavernous sinus thrombosis is often bilateral.

Venous anastomoses The cerebral veins and venous sinuses have no valves, permitting reversal of the direction of blood flow depending on pressure gradient. Anastomotic channels connect various groups of cortical veins, allowing the development of a collateral circulation when the sinus in which they drain is occluded. The vein of Trolard on the lateral surface of the hemisphere provides a connection between the SSS and the superficial sylvian vein. A similar inferior anastomotic vein (vein of Labbé) connects the superficial sylvian vein to the transverse sinus. Other ‘bipolar veins’ connect the superfical sylvian vein to the sinuses, particularly in the sylvian and rolandic regions (Petit Dutaillis et al., 1950; Meder et al., 1994). At the pole of the temporal lobe the basal vein of Rosenthal allows a communication between cortical veins and the galenic system. Additional collateral channels may develop in the cerebral parenchyma to connect the superficial and the deep venous systems (transcerebral veins). The dural sinuses also communicate with the meningeal, diploic, and scalp veins through the emissary veins. A rich plexus of venous channels exists in the dura adjacent of the sinus, representing a potential source of venous collateral circulation, and explaining the delta sign that may be seen on computed tomography (CT) scanning with SSS thrombosis (Virapongse et al., 1987).

Pathophysiology Although numerous conditions can cause or predispose to CVT, the causal factors by which they induce thrombosis may be grouped, with some overlap, into the triad of blood disorders leading to a prothrombotic state, venous stasis, and direct involvement of the venous wall (Enevoldson & Ross Russel, 1990). Venous obstruction causes a rise of venous and tissue pressure in its drainage territory leading to venous distention and edema. Many of the consequences of CVT are

related to brain swelling and increased intracranial pressure due to cerebral venous engorgement and decreased CSF absorption secondary to venous hypertension. Blood flow to the region with impaired venous drainage may be reduced, but if alternative venous pathways are available, ischemia may be insufficient to cause tissue damage. Occlusion of one of the larger venous sinuses is not likely to cause localized tissue damage unless thrombosis extends retrogradely to block cortical veins. When the thrombosis has extended into both a sinus and a portion of its tributaries or to the galenic venous system, there will be serious interference with venous drainage of brain tissue. The affected cortex and underlying white-matter may become congested, swollen, and hemorrhagic, leading to venous infarction. Hemorrhages, mainly in the whitematter, range from petechial to large and may be associated with some subarachnoid hemorrhage. In clinical practice, however, the frequent resolution of focal lesions, both clinically and radiologically, suggests that the pathologic process may be largely one of temporary ischemia and edema rather than true infarction. The natural history of the thrombotic process is poorly known. The occluded sinus may recanalize, may remain occluded and stimulate alternate pathways of drainage or cause persistently increased intracranial pressure, or may develop into a dural arteriovenous malformation. In the few reports of autopsy studies many months after CVT (Kalbag, 1984; Graeb & Dolman, 1986), the sinus was described as occupied by more or less dense fibrous connective tissue and thin-walled vascular channels of various sizes. Persistent occlusion and partial or complete recanalization have been documented both by angiography and magnetic resonance imaging (MRI) (Mas et al., 1992), but the relative frequency, timing, and determinant factors of each type of evolution remain poorly known.

Epidemiology CVT is considered as a rare disease, although the exact frequency of CVT in the general population is poorly known. Epidemiologic studies have been difficult to perform because CVT presents with a wide spectrum of clinical manifestations; it certainly goes unrecognized in many patients, and a definite diagnosis requires MRI, angiography, or autopsy. All that can be said is that CVT is far less common than arterial disease. Most reported incidences are based on autopsy studies, and range from 0.1% of 12 500 consecutive autopsies (Ehlers & Courville, 1936) to 9% of all deaths due to cerebrovascular disease (Towbin, 1973). Kalbag (1984) indicated that CVT was the principal cause of

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death in only 21.7 persons per year in the United Kingdom from 1952 to 1961. There is no doubt, however, that the clinical incidence of CVT is much higher than thought from autopsy studies, as suggested by the large number of reports on CVT published over the last 10 years (Ameri & Bousser, 1992; Mas et al., 1992; Bousser et al., 1985; Thron et al., 1986; Milandre et al., 1988; Einhäulp et al., 1991; Kaplan et al., 1991; Rondepierre et al., 1995; Daif et al., 1995). An extensive literature search revealed 306 articles on CVT published between 1983 and 1990 (MacLean, 1991). Estimates of CVT associated with pregnancy or puerperium range from 2 to 60 per 100 000 deliveries in western Europe and North America and from 200 to 500 per 100 000 in India. In many reports, however, the diagnosis of CVT was assumed rather than proved, and most studies identified CVT at single referral academic institutions, which certainly creates a selection bias. In a series of 110 CVT (Ameri & Bousser, 1992), the female-male sex ratio was 1:3 and the mean age was 38.7 years (⫹/⫺14.8). The age distribution was uniform in men, whereas in women 38 cases (61%) occurred between 20 and 35 years. This probably reflects the frequency of specific causes such as puerperium and oral contraceptive use in young women.

Clinical features CVT may present with a wide spectrum of symptoms and signs, and a high index of suspicion is necessary to make an early diagnosis. CVT should be suspected when a patient develops any combination of symptoms and signs of raised intracranial pressure (headache, vomiting, papilledema, and altered consciousness), focal neurological deficits, and seizures (generalized or focal). Headache is the most frequent complaint (75% of cases) and often the presenting one (Ameri & Bousser, 1992). Headache associated with CVT has no typical clinical characteristic or specific temporal profile (HCCIHS, 1988). Papilledema occurs in about 50% of cases (Ameri & Bousser, 1992). The progressive onset over days or weeks of signs of isolated intracranial hypertension with headache, bilateral papilledema, and less frequently, sixth-nerve palsy, tinnitus and transient visual obscuration is the most homogeneous pattern, accounting for about 40% of cases of CVT (Ameri & Bousser, 1992). Such a presentation is that of the ‘benign intracranial hypertension’ or ‘pseudotumour cerebri’ syndromes. Since CVT can mimic all clinical, CSF and CT scan criteria for benign intracranial hypertension, a search for CVT should be part of the work-up of all

patients with isolated benign intracranial hypertension. In a prospective study of 24 consecutive patients presenting with features of the benign intracranial hypertension syndrome (Tehindrazanarivelo et al., 1992), angiography showed CVT in six (25%). Focal deficits, seizures, and disorders of consciousness (drowsiness, mental changes, confusion, or coma) each occur in about a third of cases (Ameri & Bousser, 1992), compared with 50 to 75% in older series. This changing pattern probably reflects the earlier diagnosis now offered by neuroimaging techniques in patients presenting with headache. Today, the classic and complete syndrome with a prodromal phase of headaches, leading to seizures, bilateral deficits, and coma is rarely encountered. Unusual presentations (MacLean, 1991) include psychiatric disturbances (which in the puerperal cases may be mistaken for puerperal psychosis, just as the convulsions may be thought to be from toxemia in pregnancy), subarachnoid hemorrhage with bloody CSF, cranial nerve disorders, pulsatile tinnitus, transient ischemic attacks (Bousser et al., 1985), and migraine-like visual phenomena (Newman et al., 1989).The features of CVT may be obscured by the underlying disease process, such as meningioma or meningitis. The spectrum of disease may even extend to completely asymptomatic cases (Goldberg et al., 1989). The time over which symptoms and signs develop is also highly variable. In the series of Ameri and Bousser (1992), the mode of onset was acute (less than 48 hours) in 28%, subacute (more than 48 hours but less than 30 days) in 42% and chronic (more than 30 days) in 30% of cases. Depending on the variable grouping of the previously mentioned symptoms and signs and their mode of onset, the clinical presentation may suggest a variety of alternative diagnoses, such as arterial stroke, encephalitis, cerebral abscess, or tumour.

Topographic diagnosis In a series of 110 patients with CVT (Ameri & Bousser, 1992), the SSS (72%) and the LS (70%) were the most commonly affected sinuses, followed by the straight sinuses (15%) and the cavernous sinus (3%). Isolated involvement of the SSS and LS occurred in 13 and 9%, respectively. Thrombosis of the galenic system was observed in 8%. Cerebellar veins were involved in 3%, and isolated involvement of cortical veins occured in 2% of cases. The variations in normal intracranial venous anatomy, together with the frequent association of sinus and cerebral vein thrombosis, explain the difficulty in delineating topographic clinical syndromes, similar to those described in arterial occlusions.

Brain venous thrombosis syndromes

Patients with SSS and LS thrombosis can present with any combination of symptoms and signs of raised intracranial pressure, focal neurological deficits and seizures. Cavernous sinus thrombosis (Southwick et al., 1986; Dinubile, 1988; Levine et al., 1988) should be considered when a patient develops any combination of unilateral chemosis, proptosis, and diplopia associated with variable involvement of cranial nerves II, III, V1, V2 and VI. Headache (retro-orbital pain) and fever may be present. The symptoms and signs are initially confined to one side, but often progress to involve the contralateral eye. Thrombosis can also extend from the cavernous sinus to other dural venous sinuses. Acute and chronic presentations of cavernous sinus thrombosis have been recognized. When the cavernous sinus is slowly obliterated, the orbital manifestation is often unimpressive, and the patient often presents with an isolated abducens nerve palsy. Patients with deep cerebral venous thrombosis are more commonly women (Crawford et al., 1995). They usually present with altered level of consciousness (stupor, obtundation, unarousability or coma) and signs of long tract injury, including Babinski’s sign, paresis, hyperreflexia, and decorticate or decerebrate posturing (Garcin & Pestel, 1949; Crawford et al., 1995; Bots, 1971; Johnsen et al., 1973; Vines & David, 1971; Averback, 1978; Kim & Walczak, 1986; Baumgartner & Landis, 1992). They often die in a few days or recover with severe sequelae such as akinetic mutism, dementia, bilateral athetoid movements, vertical gaze palsy, and dystonia. A few survivors have been reported who recovered well. These patients presented primarily with neuropsychological deficits (in particular, impaired anterograde memory) that, in some, were transiently masked by impaired consciousness. In these cases, the lesions were less extensive and often unilateral. The clinical spectrum of cerebellar venous thrombosis has not been defined (Eng et al., 1990) and may simulate a posterior fossa tumour (Bousser et al., 1985; Rousseaux et al., 1987). The few reported cases of isolated cortical vein thrombosis presented with acute or rapid onset of focal deficits, seizures, or both (Garcin & Pestel, 1949; Dowman, 1926; Jacobs et al., 1996). If headache is frequent, there are no associated signs suggesting intracranial hypertension (Jacobs et al., 1996). The picture typically fluctuates during the first few days or first week (Jacobs et al., 1996).

Woolf, 1967). A retrospective analysis of 25 cases seen over 10 years (Barron et al., 1992) suggests that the disease in neonates is different from that in older children. In children, the disease was not unlike that in adults (although infections were more frequent). In neonates (less than 1 month old), CVT was often associated with acute systemic illness (shock, dehydratation, acidosis), but no causative factor was found in 40%. Eighty percent presented with seizures, and at the first neurological examination 40% were normal, even without signs of intracranial hypertension. Deep veins were involved in 60% of cases. The prognosis was worse in older children, with residual deficit related to deep infarction. In contrast to the study of Barron et al. (1992), none of the seven neonates reported by Rivkin et al. (1992) was systematically ill, and in none of the infants were conditions felt to predispose to CVT. Either an unexplained seizure or unexplained lethargy was the presenting manifestation. No infants developed signs of increased intracranial pressure, and examination showed only hypotonia or areflexia, and all but one (with frontal cerebral dysgenesis) had normal neurodevelopment at 6 months of age. Deep veins were often involved. None of the patients from either study received heparin or died of CVT.

Investigations The advent of sensitive and non-invasive neuroimaging techniques has made the diagnosis of CVT much easier than it was in the 1980s. In some cases, the use of multiple modalities, including angiography, may be necessary to confirm the diagnosis.

Computed tomography A CT scan is generally the first examination performed on patients presenting with symptoms or signs suggestive of CVT. It can reveal typical changes, but in most cases it shows non-specific abnormalities. The frequency of the different abnormalities varies greatly from study to study because of the small size and selected nature of most groups of patients (Zimmerman & Ernst, 1992). A CT scan is normal in 4 to 25% of patients with proven CVT, particularly in patients presenting with isolated intracranial hypertension (Ameri & Bousser, 1992; Rao et al., 1981; Chiras et al., 1985). To diagnose CVT accurately, scans both before and after contrast enhancement are necessary.

CVT in neonates and children Classically, CVT in children is often associated with serious systemic disease, involvement of the deep venous system, and a poor prognosis (Ehlers & Courville, 1936; Kalbag &

Direct signs The empty delta (or triangle) sign (Buonanno et al., 1978) is the best direct sign of SSS thrombosis. It appears on

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Fig. 50.3. Non-enhanced CT scan: spontaneous foci of hyperdensity within the straight sinus (white arrow) and the superior sagittal sinus (black arrow).

contrast-enhanced CT scans as a triangular pattern of enhancement (dilated venous collateral channels) surrounding a central, relatively hypodense area (nonenhancement of the clot) (Fig 50.3). It must be seen on several consecutive slices to be pathognomonic. The empty delta sign is clearly demonstrated in the second week following clinical onset. The frequency of the empty delta sign is about 25%, but it varies greatly from study to study (Ameri & Bousser, 1992; Virapongse et al., 1987; Bousser et al., 1985; Zimmerman & Ernst, 1992; Rao et al., 1981; Chiras et al., 1985; Anxionnat et al., 1994). Falsenegative findings can be explained by the difficulty of detecting the sign on routine CT scans, delay in appearance of the sign and its subsequent resolution, sparing of

the posterior part of the SSS, enhancement of the thrombus due to clot organization, and non-enhancement of the dural walls because of poor collateral supply (Zimmerman & Ernst, 1992; Shinohara et al., 1986). To increase the detection rate, the sign must be carefully looked for (and therefore suspected) by using thin slices (less than 5 mm) and relatively wide window settings. False-positive empty delta signs have been reported in cases of subarachnoid hemorrhage or small subdural hematoma adjacent to a dural venous sinus, septa in the SSS, and high splitting or fenestration of the SSS (Zouaoui, 1988). An empty delta or similar sign can be observed in the straight sinus, the LS (Fig 50.4), and the vein of Galen (Goldberg et al., 1989). In cavernous sinus thrombosis, a postcontrast CT scan shows heterogeneous filling defects of one or both sinuses, with bulging of the lateral wall of the sinus and enlarged orbital veins. Enhancement of the lateral wall is rare (De Slegte et al., 1988; Berge et al., 1994). A fresh thrombus in the lumen of the vein can be identified on non-contrast-enhanced CT scans as a focus of increased density relative to the grey matter in the expected position of the affected vein (Buonanno et al., 1978; Wendling, 1978; Patronas et al., 1981) (Fig. 50.5). In the SSS, vein of Galen, and cortical veins, the focus is seen on successive slices, whereas in veins parallel to the scanning plane (internal cerebral veins, straight sinus), the focus is apparent on a single slice (Zimmerman & Ernst, 1992). This sign, often referred to as ‘cord sign’ has been reported in 2 to 25% of cases (Ameri & Bousser, 1992; Virapongse et al., 1987; Chiras et al., 1985; Anxionnat et al., 1994). The chance to visualize a cord sign is short-lived, since the thrombus becomes isodense within 1 to 2 weeks of its formation (Cure et al., 1994; Cure & Van Tassel, 1994; Virapongse et al., 1987; Zimmerman & Ernst, 1992). The thrombosed veins may be too small to be visualized or may be obscured by artefacts from adjacent bone. The cord sign has also a poor specificity. A spontaneous hyperdensity can be seen within patent veins, particularly in infants with conditions that increase hematocrit such as polycythemia and dehydration (e.g. cyanotic heart disease, infection) (Zimmerman & Ernst, 1992).

Indirect signs Indirect signs include hemorrhagic and non-hemorrhagic infarcts, brain edema, and intense contrast enhancement of the falx and tentorium. They are not specific but should suggest cerebral venous thrombosis. Venous infarcts are observed in about 30% of cases (Virapongse et al., 1987; Bousser et al., 1985; Rao et al., 1981; Chiras et al., 1985; Anxionnat et al., 1994). Focal

Brain venous thrombosis syndromes

hypodensity of poorly defined configuration with or without enhancement, representing edema or bland infarction, is seen more often than hemorrhagic infarction. Isolated gyral, linear, or even round enhancement can be seen. Hemorrhagic infarcts range from a large hematoma to petechial hemorrhages within a hypodensity (Fig 50.6). The features suggestive of venous infarction are the presence of multifocal lesions (not conforming to arterial vascular distribution), subcortical location, and ill-defined configuration, as compared with the more sharply marginated and wedged shape of an arterial infarct. In contrast to other veins, the territory of the galenic system shows a relatively fixed pattern (Meder et al., 1994). Bilateral involvement of the thalamus, basal ganglia, and surrounding white-matter is very suggestive of deep venous thrombosis. Signs suggestive of brain edema, such as small ventricles and sulci and diffuse relative low density of the whitematter, have been reported in 12 to 52% of cases (Virapongse et al., 1987; Rao et al., 1981; Chiras et al., 1985; Anxionnat et al., 1994). These findings are often difficult to distinguish from normal brain, particulary in young patients. Intense contrast enhancement of the tentorium cerebelli and less frequently the falx cerebri (‘shaggy falx’), as a result of the presence of dural venous collaterals or venous stasis, is present in 5 to 19% of cases (Virapongse et al., 1987; Chiras et al., 1985; Anxionnat et al., 1994). A contrastenhanced CT scan may visualize dilated cortical and occasionally transcerebral (Anderson et al., 1987) collateral veins. Unusual findings include hydrocephalus and small subdural hematomas or effusions (Zimmerman & Ernst, 1992).

Fig. 50.4. Enhanced CT scan: empty delta sign. Note the dural enhancement of the falx cerebri.

Magnetic resonance imaging By virtue of its sensitivity to both blood flow and thrombus formation, its multiplanar imaging capability, and its lack of bone-related artefact, MRI has become the imaging modality of choice in the immediate evaluation of CVT. However, a careful study is essential to avoid false-negative or false-positive images. The signals characteristics of venous thrombi evolve in several stages (Mas et al., 1992; Zimmerman & Ernst, 1992; Macchi et al., 1986; McMurdo et al., 1986; Sze et al., 1988; Isensee et al., 1994). In the acute phase (less than 3 to 5 days), the thrombus is isointense on T1- and hypointense on T2-weighted sequences, regardless of field strength. At this stage, the signal may mimic normal flow and be confused with patency. Subsequently, the thrombus becomes strongly hyperintense on both T1 and T2 images (Figs. 50.7

and 50.8). With spin-echo sequences, however, flowing blood, especially slowly flowing blood, can create artifactually high signals that can be mistaken for thrombus formation (Zimmerman & Ernst, 1992; Macchi et al., 1986). The simplest method for eliminating the possibility of flow-related artefacts is to multiply planes and sequences, since changes in intensity within a vessel indicate the presence of flow. Whereas most cases of CVT are obvious with routine spin-echo techniques because intraluminal hyperintensity is present on all sequences and in all planes over a broad segment of the vessel, in certain cases (especially those involving short segments of clots or partial thrombosis), interpretation of MRI scans may not be so easy and specialized techniques may be necessary (Zimmerman & Ernst, 1992; Sze et al., 1988). After some 2 to 3 weeks, the

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Fig. 50.5. Left lateral sinus thrombosis, enhanced CT scan. 1, normally opacified right lateral sinus; 2, non-opacification of the left lateral sinus contrasting with injection of the sinus wall.

signal characteristics depend on whether the sinus remains occluded or partially or completely recanalizes (Mas et al., 1992; Isensee et al., 1994) (Fig. 50.9). Mas et al. (1992) reported on ten consecutive patients with superior sagittal and/or lateral sinus thrombosis who had been followed by MRI up to 18 months after clinical onset. In only three patients follow-up MRI was entirely normal at 6 months. In the other patients, persistent abnormalities were usually more limited in length, involving only a part of the sinus. Compared with the initial MRI, the signal from the thrombosed sinus was less intense and often heterogeneous but predominantly isointense on T1-weighted images and hyperintense or isointense relative to brain parenchyma on T2-weighted images. A marked decrease in the size of the lateral sinus (probably related to an apparent enlargement of the sinus in the acute phase) was noted in four patients. MRI examinations performed 6 to 12 months later showed little change compared with MRI performed at 6 months. All patients were anticoagulated and had a favourable outcome.

MRI is also a excellent tool for differentiating lateral sinus hypoplasia from lateral sinus thrombosis. In our experience (Mas et al., 1990), the diagnosis of the former was evident on sagittal MRI, which demonstrated frank asymmetry in the sizes of the transverse portions of the sinuses without any abnormal signal suggesting thrombosis in the expected course of the sinuses. MRI is also much more sensitive than CT scan in detecting the complications of CVT, such as hemorrhagic infarction (Figs. 50.10 and 50.11) and edema and the local causes of the disorder, such as tumours or infections. On MRI, venous infarcts are more frequently hemorrhagic (Dormont et al., 1994). Compared with arterial infarcts, parenchymal enhancement is rare and brain swelling more persistent. Subcortical hyperintensity observed on T2weighted images does not always represent venous infarction but may be caused by extravasation due to venous hypertension (Yuh et al., 1994). Diffusion-weighted MRI (Corvol et al., 1998; Keller et al., 1999) and perfusion-weighted MRI (Keller et al., 1999) may

Brain venous thrombosis syndromes

reflect the venous mechanism of cerebral ischemia. In a patient with deep CVT (Keller et al., 1999), DWI demonstrated vasogenic edema which proved to be reversible in follow-up MRI whereas PWI showed areas with extensive venous congestion, but perfusion deficits were missing. In the other case report (Corvol et al., 1998), there were a lack of clear apparent diffusion coefficiant values on DWI, associated with marked FLAIR abnormalities, suggesting vasogenic edema. In recent years, MR angiography (MRA) (two- or threedimensional time-of-flight or phase-contrast techniques) has tended to replace intra-arterial angiography. At present, the major sinuses and veins, such as the superior sagittal, straight, and lateral sinuses, the internal cerebral veins, and the vein of Galen, can be reliably imaged (Mattle et al., 1991) (Fig. 50.12). At the acute phase of CVT, both techniques show a lack of signal whithin the thrombosed veins (Fig. 50.13). With time-of-flight angiograms, subacute thrombus is hyperintense and may be difficult to distinguish from hyperintensity from flow. This is not encountered with phase-contrast angiography (Cure & Van Tassel, 1994; Zimmerman & Ernst, 1992; Osborn, 1994). At the chronic stage, MRA may document venous repermeabilization.

Angiography Angiography is considered the gold standard in diagnosing cerebral venous thrombosis but is now performed only when doubt remains after MRI. This technique should include four-vessel angiography with visualization of the entire venous phase on at least two projections. Frontal films should be obtained with a 10-degree obliquity to avoid overlap of the anterior and posterior portions of the SSS (Zimmerman & Ernst, 1992). Because the dural venous sinuses fill from many sources, venous images obtained from selective injections show filling defects caused by inflow of unopacified blood from other vascular distributions. This can usually be eliminated with crosscompression of the controlateral carotid artery, simultaneous bilateral carotid injection, or arch injection (which does not visualize optimally the cerebral veins). Digital intravenous angiography can visualize only the larger intracranial channels with some degree of reliability. The angiographic diagnosis of extensive dural sinus thrombosis (involving the SSS, LS, and/or straight sinus) is straightforward (Yasargil & Damur, 1974). The sinus fails to fill throughout all or most of its length, and there are dilated, tortuous (corkscrew) collateral cortical and medullary veins extending away from the thrombosed sinus toward alternative outlets for venous drainage (Fig. 50.14). Meningeal, diploic, and scalp veins represent late

Fig. 50.6. Non-enhanced CT scan: left frontal hemorrhagic infarct.

collateral pathways. The cerebral circulation transit time is increased. In SSS thrombosis, an empty triangle can be visualized on frontal views (Fig. 50.15). Deep venous thrombosis, often associated with straight sinus thrombosis, may be accurately diagnosed when the internal cerebral vein, the vein of Rosenthal, or the vein of Galen (which are virtually always present) does not fill on selective angiograms (Zimmerman & Ernst, 1992). Dilated medullary veins extending from the subependymal region towards the cortex may be visualized. When only segments of the sinus are not visualized or show irregular opacification (incomplete thrombosis or partial recanalization), the diagnosis is often difficult, because filling defects in the sinus may be due to inflowing unopacified blood, arachnoid granulations or cavernous nodules, luminal septations or fenestrations, or duplications of the sinuses. In these cases, the diagnosis of partial

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Fig. 50.7. Sagittal T2-weighted MRI (2000/50): superior sagittal sinus thrombosis. Hyperintense signal within the SSS (large arrows). Note the dilated internal cerebral vein (arrowheads) due to the development of a collateral circulation.

thrombosis is supported by the presence of collateral venous drainage and cortical venous thrombosis. Lateral sinus thrombosis may be difficult to distinguish from lateral sinus hypoplasia (which mainly affects its proximal transverse portion). A lack of filling of the proximal portion of the transverse sinus with normal opacification of the more distal portion of the transverse sinus and the sigmoid sinus suggests lateral sinus hypoplasia (see Fig. 50.2), whereas the reverse pattern favours lateral sinus thrombosis (Fig. 50.16). Finding a small sigmoid notch on CT scan or an absent lateral sinus groove on plain X-rays of the skull supports transverse sinus hypoplasia. Absent opacification of the anterior SSS (which is often normally absent) is insufficient in, and of itself, to make the diagnosis of sinus thrombosis. Thrombosis of the cavernous sinus cannot be diagnosed with confidence with arteriography, because the sinus fills very inconsistently in normal conditions. Isolated cortical CVT is extremely rare and difficult to diagnose. The signs are an abrupt termination of a cortical

vein, with dilated collateral veins. Associated infarction and increased signal on MRI in the veins presumed to be thrombosed may confirm the diagnosis.

Other investigations CSF examination is often abnormal. The pressure is usually raised, and there may be an elevation of proteins and red cells and pleocytosis, mainly in patients with focal signs. CSF examination is mainly indicated in patients presenting with symptoms of isolated intracranial hypertension, and normal CT scan to confirm the increase in CSF pressure, to remove CSF when vision is threatened and to exclude meningeal infection (Ameri & Bousser, 1992). Electroencephalography is abnormal in approximatively 75% of cases, but shows non-specific changes. Generalized slowing, more marked on one side, with frequently surimposed epileptic activity is the most common pattern (Ameri & Bousser, 1992). Technetium-labelled red cell scintigraphy has been

Brain venous thrombosis syndromes

(a )

(b )

Fig. 50.8. Coronal T1-weighted MRI (560/60): left lateral sinus thrombosis (curved arrow).

claimed to detect accurately SSS thrombosis (Front et al., 1986). A case has been published of SSS thrombosis demonstrated by indium-111 platelet scintigraphy (Bridgers et al., 1986). These methods are limited by a poor spatial resolution. Ultrasonography has successfully detected SSS thrombosis in infants (Edwards et al., 1987). Venous transcranial colour-coded duplex sonography has been used to monitor the deep cerebral veins and the posterior fossa sinuses in 75 healthy volunteers and eight patients with CVT (Stolz et al., 1999). Increased venous blood velocity or significant side differences in the deep cerebral veins were registered in five of the eight patients and in none of the control group; clinical recovery coincided with decreases in blood flow velocity. Transcranial Doppler ultrasound may detect microembolic signals in the jugular vein in patients with superior sagittal sinus thrombosis (Valdueza et al., 1997). Further studies are needed to assess the value of ultrasonography in diagnosis of CVT and non-ininvasive follow-up of patients.

Fig. 50.9. (a) Coronal-T2-weighted MRI (2025/25) 2 months after clinical onset: partial recanalization of the thrombus leading to a heterogeneous signal from SSS. (b) Control coronal T2-weighted MRI (2000/25) 6 months after clinical onset: normal signal void from SSS.

Etiology Numerous conditions, both intracranial and extracranial, have been implicated to cause or predispose to CVT (Table 50.1). When the thrombosis arises without an obvious cause, an extensive and early work-up is needed because the underlying disease may require treatment in its own right. Even after full investigations, in some 25% of cases the cause remains uncertain. A diagnosis of ‘idiopathic’ cerebral venous thrombosis should be made with caution,

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Fig. 50.10. Coronal T2-weighted MRI: superior sagittal sinus thrombosis (black arrow) with venous infarcts (white arrows). Axial T2weighted MRI (2000/100). Deep venous thrombosis: hyperintense signal in the deep venous cerebral territory (periventricular whitematter, basal ganglia, and thalami).

because other features of an underlying disease may only become evident on follow-up and after repeated investigations (Ameri & Bousser, 1992; Enevoldson & Ross Russel, 1990).

Local causes Septic intracranial venous thrombosis has markedly declined with the advent of antibiotics (Southwick et al., 1986), and in the majority of recently published series sepsis no longer predominates. Facial and sphenoid air sinus infections often precede cavernous sinus thrombosis, and the major pathogens include Staphylococcus aureus, other gram-positive organisms, and anaerobes. Septic lateral sinus thrombosis is almost exclusively a complication of otitis media and/or mastoid infection. Organisms causing this infection include Proteus species, Escherichia coli, S. aureus, and anaerobes. Septic thrombo-

sis of the superior sagittal sinus most frequenly accompanies bacterial meningitis or air sinus infection. Neoplastic occlusion of dural sinuses and cortical veins is a common complication of meningiomas arising in the parasagittal and paratentorial regions. CVT may result from head trauma with fracture crossing one of the major sinuses, and occasionally develops in trauma patients without fractures.

Systemic diseases In addition to the general risk factors of venous thrombosis, a myriad of systemic disorders have been associated with CVT (see Table 50.1), malignancies and inflammatory systemic diseases being the most common. Puerperium remains a frequent cause of CVT, particulary in developing countries. Puerperal CVT was reported to be responsible for 25% of maternal deaths in India and

Brain venous thrombosis syndromes

to complicate 4.5 of 1000 obstetrical admissions (Srinavasan, 1984). In a recent, well-documented Mexican study (Cantù & Barinagarrementeria, 1993), the puerperal state accounted for 60% of all CVTs, whereas in western Europe and North America the pregnant and puerperal state together account for only 5 to 20% of all CVTs (Barnett & Hyland, 1953; Mas et al., 1992; Bousser et al., 1985; Milandre et al., 1988; Kaplan et al., 1991; Rondepierre et al., 1995; Rousseaux et al., 1978). Puerperal infections and dehydration may contribute to the high frequency of CVT in developing countries. Although a few cases of CVT have been reported in all stages of pregnancy, most cases occur in the second or third weeks postpartum. Parity has not be found to influence the risk. In a recent study (Lanska & Kryscio, 1998), CVT was more common in mothers aged 15 to 24 years than in mothers aged 25 to 34 years. Labour and delivery are characteristically normal in occidental countries, whereas in developing countries women who had home delivery and poor prenatal care are more often affected (Cantù & Barinagarrementeria, 1993). Among drugs that have been associated with the occurrence of CVT, oral contraceptives are by far the most common. For most other drugs, there are only one or a few case reports. An etiologic work-up is needed to look for associated conditions. Hereditary coagulation disorders (AT III, protein C, and protein S deficiencies) should be systematically looked for in the absence of an obvious cause because they imply family screening and a long-term treatment (Ameri & Bousser, 1992). In some patients with abnormalities of coagulation, CVT may actually occur only when other more obvious factors (such as pregnancy, oral contraception, or surgery) are superimposed and then incorrectly blamed as causing CVT. Activated protein C resistance due to the factor V Leiden mutation may be the most common inherited coagulation defect associated with CVT. The prevalence of the mutation in a heterozygous form ranged from 15 to 21% in patients with CVT and 2 to 6% in controls in recent studies (Zuber et al., 1996; Lüdeman et al., 1998; Martinelli et al., 1998). The prothrombin-gene mutation is another inherited risk factor for CVT. In two recent case control studies (Martinelli et al., 1998; Reuner et al., 1998), this mutation was found in a heterozygous form in 20 and 8.9% in patients with CVT, compared to 3 and 2.3% in the control groups. Combined effect of the prothrombin gene mutation and the use of oral contraceptive increased the risk of CVT (Martinelli et al., 1998). CVT may complicate (or be the first manifestation of) several systemic inflammatory diseases, such as systemic

Fig. 50.11. Axial T2-weighted MRI (2000/100). Deep venous thrombosis: hyperintense signal in the deep venous cerebral territory (periventricular white-matter, basal ganglia, and thalami).

lupus erythematosus with or without anticardiolipin antibody syndrome, Behçet’s disease, and ulcerative colitis. In Saudi Arabia, Behçet’s disease accounted for about 25% of all CVT in one recent study (Daif et al., 1995).

Prognosis The clinical course and prognosis are variable and unpredictable for a given patient. Some patients in deep coma at presentation may survive without sequelae, whereas others with minor symptoms and signs may worsen progressively and suffer major morbidity. The current case-

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Fig. 50.12. Normal MR venogram (3D time-of-flight). 1, superior sagittal sinus; 2, internal cerebral vein; 3, Rosenthal’s basal vein; 4, great vein of Galen; 5, straight sinus; 6, torcular Herophili; 7, transverse sinus.

fatality rate in Western countries with modern methods of diagnosis and the increasing use of anticoagulation is 10 to 20% on average (Ameri & Bousser 1992; Virapongse et al., 1987; Mas et al., 1992; Thron et al., 1986; Einhäulp et al., 1991; Kaplan et al., 1991; Rondepierre et al., 1995; Daif et al., 1995), certainly better than the estimates of 30 to 50% in the 1960s (Krayenbuhl, 1967). If survival does occur, the prognosis for recovery of function is better than in arterial thrombosis, with 10 to 20% of patients having persisting sequelae including optic atrophy, focal deficits, and epilepsy (Ameri & Bousser, 1992). As previously discussed, thrombosis of the galenic system, cerebellar vein thrombosis, and isolated cortical vein thrombosis carry a much poorer outcome than isolated sinus thrombosis. Prognosis is also largely dependent on the nature of the underlying disease (Ameri & Bousser, 1992; Rondepierre et al., 1995). Others features classically considered to indicate poor outcome include the rate of evolution of thrombosis (Kalbag & Woolf, 1967), the pres-

ence of focal signs or coma, an empty delta sign and hemorrhagic infarction on CT scan (Virapongse et al., 1987), and age at presentation (infants and elderly doing worse). Pulmonary embolism, a possible complication of sinus thrombosis, also carries a poor prognosis (Diaz et al., 1992). The long-term outcome of patients with CVT is scarcely known. Among 77 patients with CVT, 11 (14.3%) remained neurologically impaired (Pretez et al., 1996). Two had blindness due to opticatrophy. The other nine were left with various cognitive or focal deficits. During a mean follow-up of 77.8 months, nine of the 77 patients (11.7%) suffered a second CVT, all but one in the first year (Pretez et al., 1996). Dural arteriovenous fistulas are uncommon lesions in which meningeal and extracranial arteries shunt blood directly into the dural sinuses. Their frequent association and apparent temporal relationship with an occluded dural sinus supports the concept that, at least in some cases, dural fistulas result from recanalization of sinus venous thrombosis with vessels out of the meningeal

Brain venous thrombosis syndromes

Fig. 50.13. MR venogram showing transverse sinus thrombosis (open arrows).

vessel’s territory sprouting into the sinus wall (Graeb & Dolman, 1986; Mas et al., 1992; Houser et al., 1979). The factors that stimulate such development in a minority of patients remain unknown.

1979), but is not generally advocated (Ameri & Bousser, 1992). Anticoagulants are widely used. The role of thrombolytics is currently ill-defined.

Anticoagulants

Treatment The low incidence of CVT, the variability of its natural history, and the multiple causes of the syndrome have made it difficult to evaluate the role of therapy. Treatment should be devoted at the thrombotic process, the consequences of CVT (such as intracranial hypertension) and at the underlying cause.

Treatment of the thrombotic process Treatment directed at the thrombotic process itself has excited much debate. Surgical removal of thrombus from the sinuses has been used occasionally (Estanol et al.,

Anticoagulants are not expected to influence an already formed thrombus, but they should at least theoretically prevent extension of thrombosis in other venous channels. This may be valuable in allowing the development of an adequate collateral drainage and preventing cerebral venous infarction, which is believed to result from extension of thrombus from the sinuses into the cortical veins. There have been several reports of clinical improvement or deterioration temporally related to starting or stopping heparin (Bousser et al., 1985; Thron et al., 1986; Fairburn, 1973). The main argument against the use of anticoagulants is the risk of major hemorrhage into a venous and often already hemorrhagic infarct. Such a complication has been well documented (Barnett & Hyland, 1953; Buchanan & Brazinsky, 1970), but the magnititude of the risk is poorly

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Fig. 50.14. Right internal carotid angiogram (lateral view) showing superior sinus thrombosis. Non-filling of the SSS (large open arrows). Cortical vein thrombosis (small open arrow). Dilated and tortuous (corkscrew) cortical vein (long arrows). Dilated basal vein of Rosenthal acting as collateral drainage pathway (large black arrow).

defined and is likely to have been overestimated. Another argument against the use of anticoagulants is the high frequency of a spontaneous recovery, particularly in patients with CVT limited to the sinuses, who often present with isolated intracranial hypertension. However, there is no way of predicting which patients are going to recover spontaneously, and even the most ‘benign’ forms of isolated ICH can have a sudden dramatic worsening if thrombosis extends from sinuses to cerebral veins (Stam, 1993). Several retrospective studies have suggested that there may be a beneficial effect of heparin treatment (Krayenbuhl, 1954, 1967; Bousser et al., 1985; Levine et al., 1988; Brucker et al., 1998), even despite CT scan evidence of hemorrhagic infarction. The results of these studies, however, are subject to various kinds of bias and are confounding. An illustrative example of ‘confounding by indication’ has been provided by Stam (1993). In his series of 62 patients with CVT, those treated with heparin had better outcomes, but none of the patients in coma at the time of diagnosis had been treated by heparin. When these

patients were excluded from the analysis, the difference between heparin and non-heparin treatment disappeared. Heparin may be both relatively safe and ineffective in less severe patients, who often recover spontaneously. By contrast, heparin may be unsafe in more severe patients, who may benefit most from this treatment. Two randomized placebo-controlled studies of anticoagulation in CVT are available. The first trial with adjusteddose intravenous heparin treatment (Einhäulp et al., 1991) was discontinued after the first 20 patients with angiographically established aseptic CVT were entered because a statistically significant difference in favour of heparin was considered to be established. After 3 months, eight of the ten heparin-treated patients had a complete clinical recovery, and two had slight residual neurological deficits. In the control group, three patients died, six survived with a minor deficit (‘slight or mild’ paresis), and one recovered completely. At the beginning of treatment, CT scan of three patients in the heparin group and of two in the control group showed an ICH. The three patients with ICH in the

Brain venous thrombosis syndromes

heparin group had a favourable outcome, whereas both patients with ICH in the control group died. No additional ICH was detected during heparin treatment, whereas in the control group, three patients (two without initial ICH) had an ICH during treatment. These results are encouraging, but, as pointed out by Stam (1993), the statistically significant difference between the two groups was mainly due to the patients with mild residual deficits in the control group. If patients with a minor residual deficit are considered as cured, poor outcome are three out of ten in the control group vs. zero out of ten in the heparin group, a non-statistically significant difference. In addition, patients were entered into the study about 1 month after the onset of symptoms, at a time when some of the more affected patients may already have died, and when the risk of intracerebral hemorrhage with heparin therapy may have been less than earlier in this disease (Enevoldson & Ross Russel, 1991). In the European controlled multicentre trial (De Bruijn & Stam, 1999), body weight-adjusted subcutaneous nadroparin (180 antifactor Xa units/kg per 24 hours) for 3 weeks followed by 3 months of oral anticoagulation was compared to placebo in 60 patients with cerebral venous thrombosis. At 3 weeks, six of the 60 patients (20%) treated with nadroparin had a poor outcome (death or Barthel index score ⬍15) compared to 7 of the 29 (24%) patients in the control group. At 12 weeks, a poor outcome was observed in 13% in the nadroparin group compared to 21% in the placebo group. A complete recovery was observed in 12% of anticoagulated patients and 28% of the controls. None of these differences was statistically significant. Cerebral hemorrhage on the baseline CT or MRI scans was observed in 15 patients (50%) in the nadroparin group and in 14 (48%) in the control group. New symptomatic cerebral hemorrhage did not occur. The negative results observed in this trial contrast with the results observed in the former study (Einhäulp et al., 1991). Although there is no direct comparison of low-molecular-weight heparin vs. unfractionated heparin in the treatment of CVT, several studies have shown that low-molecular-weight heparin is at least as effective and safe as unfractionated heparin for the initial treatment of venous thromboembolism. The difference in modalities of heparin administration between the two trials is unlikely to explain such difference in efficacy. It is interesting to note that 13% of patients in the nadroparin group in the European trial (De Bruijn & Stam, 1999) compared to 28% in the placebo group had isolated intracranial hypertension, which carries a better prognosis than coma, seizures or focal deficits (Bousser, 1999). Meta-analysis of both trials (De Bruijn & Stam, 1999) shows a modest but clinically important (but not statisti-

Fig. 50.15. Right internal carotid angiogram (frontal view) showing an empty delta sign. The center of the triangle is the unopacified thrombosed sinus (open arrow), and the peripheral enhancement represents dilated venous channels (long arrows).

cally significant) benefit of anticoagulation in CVT. On the basis of current evidence, our policy is to anticoagulate all patients with definite CVT, even with a hemorrhagic infarct, provided there are no contradications because of an underlying (paroxysmal noctural hemoglobinuria) or associated condition. The optimal duration of anticoagulant treatment has not been defined. Our policy is to follow the current recommendations of venous thromboembolism (Kearon et al., 1999).

Thrombolytic treatment Unlike heparin therapy, which inhibits thrombus progression, thrombolytic therapy aims at rapid restoration of

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was observed. Functional sinus patency was achieved in 11 of 12 patients ; the only failure occured in an individual with symptoms of at least 2 months’ duration. A recent open series (Frey et al., 1999) reported 12 patients treated with combined intrathrombus rt-PA and intravenous heparin. Pretreatment MRI disclosed subtle hemorrhagic venous infarction in four patients, obvious hemorrhagic infarction in two, small parenchymal hemorrhage in one and no focal lesion in five. Flow was restored completely in six patients and partially in three. Symptoms improved in these nine patients concomitantly with flow restoration. Flow could not be restored in three patients. In one of them, treatment was stopped when little progress had been made. In the two other patients, hemorrhagic worsening occured; in one of these, the hematoma was evacuated. There is, at present, no proof that thrombolytics are more effective than heparin treatment, and there is no sufficient evidence to recommend local thrombolysis as the first-line treatment for CVT. Thrombolytic treatment should be considered in the subgroup of patients who deteriorate despite adequate anticoagulation and symptomatic treatment, with rapidly progressing thrombosis which involves large parts of the cerebral venous system (Smadja et al., 1997).

Symptomatic treatment Fig. 50.16. Left internal carotid angiogram showing irregular filling of the left transverse sinus (arrowheads) and nonopacification of the left sigmoid sinus (lateral sinus thrombosis).

venous outflow by clot dissolution. Intravenous fibrinolytics have been used ocasionally (Vines & David, 1971). Di Rocco et al. (1981) combined urokinase and heparin in five patients; all had complete clinical recovery. The four patients who had subsequent angiography after recovery showed that the involved sinuses were patent. By contrast, use of the drug has been detrimental in the experience of others (Gettelfinger & Kokman, 1977) because of bleeding into the infarct. Treatment of dural sinus or deep cerebral venous thrombosis by means of selective catheterization and direct instillation of thrombolytic agents into the affected sinus has been recently reported. Horowitz et al. (1995) reported on 12 such treated patients. Good to excellent clinical outcome was achieved in ten of 11 patients (one had inadequate follow-up). Despite the presence of preinfusion infarcts in five patients, four of which were hemorrhagic, no significant complication from therapy

The main consequences of CVT are intracranial hypertension, which may lead to death or visual failure, focal deficits, and seizures. Various methods to reduce CSF pressure have been used (Ameri & Bousser, 1992), the most common being steroids, mannitol, acetazolamide, and therapeutic lumbar punctures. In patients presenting with isolated intracranial hemorrhage, the initial combination of lumbar punction and acetazolamide is recommended (Stam, 1993). This treatment is usually sufficient to rapidly improve headache and vision (assessed by blind spot size, visual acuity, and papilledema). If vision deteriorates, dehydrating agents are added. A minority of patients require shunting procedures. Anticonvulsants may be justified prophylactically because of the risk of status epilepticus and must be given if seizures occur.

Etiologic treatment The underlying disorder, where identifiable, must be treated. In septic CVT, initial treatment with a widespectrum combination of antibiotics (e.g. last-generation cephalosporin and metronidazole or chloramphenicol) is recommended (Dinubile, 1988; Editorial, 1987).

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Table 50.1. Central venous thrombosis: causes and reported associations Systemic diseases Pregnancy and puerperium (Barnett & Hyland, 1953; Kalbag & Woolf, 1967; Enevoldson & Ross Russel, 1990; Mas et al., 1992; Bousser et al., 1985; Milandre et al., 1988; Carroll et al., 1966; Bansal et al., 1980; Estanol et al., 1979; Krayenbuhl, 1954) Drugs Oral contraceptives (Bousser et al., 1985; Rondepierre et al., 1995; Estanol et al., 1979; Gettelfinger & Kokman, 1977; Rousseaux et al., 1978; Buchanan & Brazinsky, 1970; Fairburn, 1973) -asparaginase therapy (Feinberg & Swenson, 1988), heparin- or heparinoid-induced thromboytopenia (Jacquin et al., 1988); hormonal supplement therapy (Knox et al., 1980); ovarian hyperstimulation (Waterstone et al., 1992); androgen therapy (Shiozawa et al., 1982; Jaillard et al., 1994); epsilon-aminocaproic acid (Achiron et al., 1990), danazol (Hamed et al., 1989); parenteral injections (Eikmeier et al., 1989) Malignancies Visceral carcinoma (Barnett & Hyland, 1953; Mas et al., 1992; Sigsbee et al., 1979); carcinoid (Patchell & Posner, 1986) Lymphoma (Averback, 1978; Sigsbee et al., 1979; Meininger et al., 1985); leukemia (Barnett & Hyland, 1953; Meininger et al., 1985; Coquillat & Warter, 1976; Steinherz et al., 1981; David et al., 1975); myeloproliferative disease (Haan et al., 1988) Systemic inflammatory tissue disease Behçet’s disease (Bousser et al., 1985; Daif et al., 1995); systemic lupus erythematosus (Vidailhet et al., 1990); Wegener granulomatosis (Barnett & Hyland, 1953; Enevoldson & Ross Russel, 1990); sarcoidosis (Byrne & Lawton, 1983); temporal arteritis (Coquillat & Warter, 1976) Hematologic disorders Polycythemia (Barnett & Hyland, 1953; Fujimaki et al., 1986; Melamed et al., 1976); paroxysmal nocturnal hemoglobinuria (Valdueza et al., 1997; Johnson et al., 1970; Benoit et al., 1986); sickle-cell disease (Rothman et al., 1986; Feldenzer et al., 1987); hemolytic anemia (Barnett & Hyland, 1953; Krayenbuhl, 1967), posthemorrhagic anemia (Gates, 1986); thrombocythemia (Murphy et al., 1983) Coagulation disorders AT III (Sauron et al., 1982); protein C (Enevoldson & Ross Russel, 1990; Vieregge et al., 1989), protein S (Enevoldson & Ross Russel, 1990; Heistinger et al., 1992) deficiencies; factor V Leiden mutation (Zuber et al., 1996; Lüdeman et al., 1998; Martinelli et al., 1998); prothrombin-gene mutation (Martinelli et al., 1998; Reuner et al., 1998) Antiphospholipid antibodies/lupus anticoagulants (Mas et al., 1992; Levine et al., 1987; Levine et al., 1990; Christopher et al., 1999) Disseminated intravascular coagulation (Smith et al., 1983); hereditary dysfibrinogenemia (Coull & Clark, 1993); plasminogen deficiency (Schutta et al., 1991); cryofibrinogenemia (Dunsker et al., 1970) Severe dehydration of any cause (Garcin & Pestel, 1949; Barnett & Hyland, 1953; Kalbag & Woolf, 1967; Mas et al., 1992) Any surgery (Barnett & Hyland, 1953; Coquillat & Warter, 1976) Infectious disease Bacterial: septicemia (Garcin & Pestel, 1949; Kalbag & Woolf, 1967; Krayenbuhl, 1967; Gates, 1986); endocarditis (Garcin & Pestel, 1949; Kalbag & Woolf, 1967; Krayenbuhl, 1967; Gates, 1986); typhoid (Garcin & Pestel, 1949); tuberculosis (Noetzel & Jerusalem, 1965) Viral: measles (Kalbag & Woolf, 1967); hepatitis (Noetzel & Jerusalem, 1965); encephalitis (Kalbag & Woolf, 1967), herpes; HIV; CMV (Meyohas & Roullet, 1989) Parasitic: malaria (Coquillat & Warter, 1976); trichinosis (Evans & Patten, 1982) Fungal: aspergillosis (Sekhar et al., 1980) Bowel disease Ulcerative colitis (Kalbag & Woolf, 1967; Averback, 1978); Crohn’s disease (Milandre et al., 1992); cirrhosis (Garcin & Pestel, 1949; Coquillat & Warter, 1976) Cardiac disease Congenital heart disease (Barnett & Hyland, 1953; Krayenbuhl, 1967; Coquillat & Warter, 1976); cardiac insufficiency (Barnett & Hyland, 1953; Krayenbuhl, 1967; Towbin, 1973); pacemaker (Girard et al., 1980)

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Table 50.1. (cont.) Others: Nephrotic syndrome (Bousser et al., 1985; Levine et al., 1987); venous thromboembolic disease, Hughes–Stovin syndrome (Hughes & Stovin, 1959); neonatal asphyxia (Gates, 1986); severe exfoliative dermatitis (Kalbag & Woolf, 1967); homocystinuria (Constantine & Green, 1987) Local disease Infection Extradural: mastoiditis; sinusitis, facial cellulitis; osteomyelitis; tonsilitis; stomatitis (Garcin & Pestel, 1949; Kalbag & Woolf, 1967; Krayenbuhl, 1967; Southwick et al., 1986; Coquillat & Warter, 1976; Gates, 1986) Intradural/parenchymal: abscess; empyema; meningitis (Garcin & Pestel, 1949; Kalbag & Woolf, 1967; Krayenbuhl, 1967; Bousser et al., 1985; Southwick et al., 1986; Gates, 1986) Tumours Meningioma, mestastases; carcinomatous infiltration; glomus tumour (Averback, 1978; Garcin & Pestel, 1949; Kalbag & Woolf, 1967; McMurdo et al., 1986; Enevoldson & Ross Russel, 1990; Mones, 1965) Head injury (Barnett & Hyland, 1953; Kalbag & Woolf, 1967; Bousser et al., 1985; Thron et al., 1986; Coquillat & Warter, 1976; Kinal, 1967) Others Neurosurgery (Garcin & Pestel, 1949; Kalbag & Woolf, 1967); cerebral infarction and hemorrhage (Barnett & Hyland, 1953; Kalbag & Woolf, 1967; Melamed et al., 1976); arteriovenous malformation (Enevoldson & Ross Russel, 1990); dural arteriovenous malformation (?) (Enevoldson & Ross Russel, 1990; Garcia et al., 1975; Houser et al., 1979); porencephaly, arachnoid cyst (Garcin & Pestel, 1949; Bousser et al., 1985; Coquillat & Warter, 1976); internal jugular compression (Kalbag & Woolf, 1967) Idiopathic

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51

Carotid occlusion syndromes François Nicoli1 and Julien Bogousslavsky2 Neurology Services, Sainte Marguerite Hospital, Marseilles, France 2 Department of Neurology, University of Lausanne, Switzerland

1

Pathophysiology of carotid ischemic syndromes Occlusion of the internal carotid artery (ICA) remains frequently asymptomatic, especially concerning progression of high grade carotid stenosis to total blockage which left enough time for the progressive development of collateral pathways (Rautenberg et al., 1990). In other cases, ICA occlusions lead either to territorial infarctions related to embolic occlusions of the main intracranial arteries, particularly of the middle cerebral artery and its branches or to hemodynamically induced extraterritorial infarctions. Pial artery occlusions resulting from embolism induce more severe neurological deficits and have a worse neurological prognosis. By contrast, hemodynamically induced infarctions most often lead to repetitive minor strokes and fluctuating symptoms. Different patterns of brain lesion can be observed: (i) pial artery territory infarction or, less frequently, lenticular infarction suggestive of an embolic mechanism; (ii) subcortical terminal supply area infarction or cortico-subcortical watershed infarctions suggestive of an hemodynamically induced infarction (Ringelstein et al., 1983). The bettter the collateral circulation (circle of Willis, leptomeningeal anastomoses, ophthalmic artery, cervical anastomosis between ipsilateral segmental ICA occlusion, above the stump, and a branch of the external carotid artery (ECA) (occipital artery (Bowen et al., 1997) or the ascending pharyngeal artery (Brückman et al., 1987)), the smaller the volume of cerebral infarction and the better the stroke outcome (Takagi & Shinoara, 1981; Hedera et al., 1995).

Embolic mechanism The predominantly embolic nature of strokes following ICA occlusion has been described by several authors.

However, embolus may fire into the MCA just before the definite occlusion of a severe stenotic or ‘nearly occluded’ carotid artery (Kniemeyer et al., 1996). After the carotid oclusion, microemboli from the proximal carotid stump may pass through extracranial anastomotic channels (i.e. via ipsilateral external carotid artery then facial artery then ophthalmic artery (reverse-flow) and carotid arterial system) to lodge in the retinal and cerebral arteries leading preferentially to TIA, or macroemboli shedding from the distal end of the occluded ICA reach directly to the cerebral arteries and induce definite ischemic brain damages (Ringelstein et al., 1983). The source of embolic material may also be the ipsilateral atheromatous common carotid artery or external carotid artery (Countee & Vuayanathan, 1979 ; Bogousslavsky et al., 1981) or the contralateral ICA or exceptionally the vertebrobasilar system via the circle of Willis (Georgiadis et al., 1993 ; Bogousslavsky et al., 1984).

Hemodynamic mechanism Hemodynamically induced brain lesions are believed to be mainly caused by insufficiently collateralized ICA. Patients with ICA occlusion and hemodynamic infarcts have a significantly lower presence of two or three main collateral vessels (ophthalmic artery, anterior and posterior communicating arteries) than those with territorial ischemia (Hedera et al., 1995). The ophthalmic artery is functional only when Willisian collaterals are absent or inefficient (Nighoghossian et al., 1996). Patency of collateral pathways and preserved capacity of vasoreactivity are the major parameters indicating the potential of hemodynamic reserves (Kuwert et al., 1990). The cerebrovascular reserve (CVR) capacity gives information about the quality of this collateralization and may be evaluated using various techniques (positron emission tomography (PET), singlephoton emission computed tomography, xenon computed

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tomography and transcranial Doppler sonography). These methods study the residual capacity of intracerebral arterioles to dilate in response to arterial PCO2 increase (CO2 test) or to intravenous administration of acetazolamide (Diamox test). PET studies have shown that vasodilatation acts as the first compensatory mechanism in order to maintain constant tissue perfusion distal to a hemodynamically significant obstruction (cerebrovascular autoregulation, stage I hemodynamic failure). If tissue perfusion further decreases, the second step, before the misery of perfusion syndrome, is the increase of oxygen extraction ratio to maintain cerebral metabolic rate of oxygen at a constant level (stage II hemodynamic failure) (Kuwert et al., 1990). An exhausted CO2 reactivity is related to an already maximal vasodilatation in response to a reduced cerebral perfusion pressure. Using transcranial Doppler in patients with unilateral ICA occlusion, Widder et al. (1994) have demonstrated a significant correlation between ipsilateral exhausted CO2 reactivity and (i) the probability of recent (⬍3 months) ipsilateral TIA or stroke, and (ii) a contralateral ICA stenosis of 80% or more. This CVR may improve with time because of the development of intracranial collateralization across the circle of Willis and leptomeningeal anastomoses. But, an exhausted CO2 reactivity is more frequent and more durable in bilateral ICA occlusion compared with unilateral ICA occlusion. Consequently, it is recommended to avoid antihypertensive treatment in patients with highly impaired CVR at least during the first 2 to 3 months except if systolic blood pressure reaches to 220 mm Hg or more (Widder et al., 1994). The failure of cerebrovascular autoregulation may be clinically evident in patients with acute ischemic stroke and worsening of their neurological symptoms while sitting upright too early in the postictal period despite the absence of orthostatic hypotension (Caplan & Sergay, 1976). Grubb et al. (1998) obtained similar results using PET but highlight the fact that demonstration of hemodynamic failure at baseline does not prove that all subsequent strokes are hemodynamically mediated. They suggest that low-flow states may predispose to the formation of thrombi or, alternatively, thromboemboli may cause infarction more readily in areas with poor collateral circulation. These pathophysiological data explain that stroke risk increases in patients with progressive high-degree carotid stenosis and continues after occlusion. Indeed, in patients with asymptomatic ICA occlusion followed for a mean of 44 months, the annual stroke and TIA rates were 4.4 and 3.2%, respectively, and the annual mortality was 11.3% (Rautenberg et al., 1990). Some data suggest that progression of carotid stenosis to

occlusion is related to more frequent and more severe vascular risk factors such as high blood pressure, smoking and high plasma glucose level (Bogousslavsky et al., 1985).

Unilateral internal carotid occlusion Stroke patterns Pial infarctions Clinical pictures associated with infarct in each main cerebral arterial territory are already described elsewhere in this book. These infarcts mainly concern middle cerebral artery (MCA) and its branches. A particular condition is represented by the occurence of a large infarct in the MCA territory (laMCA). In the study of Heinsius et al. (1998), ICA occlusion represents the etiology in 40% of laMCA. These authors suggest a more acute development of ICA occlusion in laMCA infarct, owing to a lower frequency of TIA for patients with ICA occlusion in laMCA infarcts than for ICA occlusion in general and to the high proportion of ICA dissection within this group. Emboli or ICA thrombus extended into the circle of Willis may also reach the anterior cerebral artery (ACA) circulation. More rarely, infarcts in the posterior circulation may be observed in relation to ICA occlusion. Unilateral occipital infarction may occur when a fetal posterior artery originates from the occluded ICA (Pessin et al., 1989). Bilateral occipital infarctions may be observed in case of ICA occlusion and persistent trigeminal artery (Gasecki et al., 1994). This artery is rarely present but is the most common of the primitive persistent carotid–basilar connections. It replaces the terminal territory of supply of the basilar artery through the posterior cerebral arteries to both occipital lobes. Exceptionally, ICA occlusion may be associated with a persistent proatlantal artery type I originated from the occluded ICA and leading to the horizontal portion of the ipsilateral vertebral artery (Kolbinger et al., 1993). This rare condition may lead to simultaneous infraand supratentorial infarcts.

Watershed infarctions Watershed infarctions (WSI) (Figs. 51.1–51.3; Bogousslavsky & Regli, 1986b) are related to cerebral ischemia at the junction between territories of supply of major cerebral arteries. Bilateral WSI are associated with severe hypotension as during cardiac arrest, while unilateral WSI are more common in association with severe carotid disease. WSI is rarely the initial manifestation of ICA occlu-

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Fig. 51.1. Anterior watershed territory (between the superficial territory of the anterior and middle cerebral artery). Fifteendegree sections (5 mm interval), after Matsui and Hirano. 1: corresponds to section 11; 2: to section 9; 3: to section 7; 4: to section 5.

Fig. 51.2. Posterior watershed territory (between the superficial territory of the middle and posterior cerebral artery). Fifteendegree sections (5 mm interval), after Matsui and Hirano (1978). 1: corresponds to section 12; 2: to section 10; 3: to section 8; 4: to section 6.

sion (5.2%). But this type of infarction occured in 17% of 154 consecutive patients with ipsilateral ICA occlusion and accounted for 72% of delayed strokes in patients with ICA occlusion (Bogouslavsky & Regli, 1986a). The following factors are significantly associated with WSI in patients with ICA occlusion: severe active heart disease with hypotension and syncope, severe contralateral ICA disease and elevated venous hematocrit values related to heavy smoking (Bogouslavsky & Regli, 1986a ; Bladin & Chambers, 1993). Hypotension seems to be a critical associated factor for the genesis of WSI in these patients since severe carotid stenosis is not sufficient by itself to produce border zone infarction (Hupperts et al., 1997). By the way, the frequent associated heart disease might explain the higher death rate (9.9% per year) of patients with WSI and ICA occlusion compared to those without WSI (2.3% per year).

Anterior WSI infarcts cause mainly crural hemiparesis sparing the face associated, in 50% of the patients, with a decrease in superficial and deep sensation in the same distribution. In dominant hemisphere lesions, there is often transcortical motor aphasia preceded by mutism for 1 hour to 1 week. Isolated word-finding difficulty occurs less frequently. With non-dominant hemisphere lesion, mood disturbances (apathy or euphoria) are usual. Hemianopia is the most common symptom in posterior WSI, always non-congruent, and usually with macular sparing and predominating in the lower quadrant. Brachiofacial hypoesthesia of the cortical type is frequent, but motor weakness is rare and remains mild. In the dominant hemisphere, lesions consisted of either isolated word-finding difficulty or transcortical sensory aphasia or, exceptionally, Wernicke-type aphasia. About one-half of

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anterior choroidal artery territory infarct may occur but is associated with other cortical or subcortical infarcts on the same hemisphere (Mounier-Vehier et al., 1995).

Ocular signs Ocular ischemic syndrome

Fig. 51.3. Subcortical watershed territory (between the deep and superficial territory of the middle cerebral artery). Fifteen-degree sections (5 mm interval), after Matsui and Hirano (1978). 1: corresponds to section 9; 2: to section 8.

the patients showed emotional depression. In nondominant hemisphere lesion, contralateral hemispatial neglect and anosognosia were usual. In subcortical WSI infarcts, brachiofacial of proportional hemiparesis is constant, sometimes associated with hemisensory defect. In dominant hemisphere lesions, expressive speech disturbances with good comprehension and usually good repetition are frequent (Bogousslavsky & Regli, 1986a). Occasionally, hemodynamic recurrent hemiplegia related to a progressive ipsilateral ICA stenosis may occur in patients with contralateral ICA occlusion and large subcortical watershed infarct (Chollet et al., 1996).

Centrum ovale infarcts The centrum ovale (CO) contains the core of the hemispheric white-matter and receives its blood supply from the pial MCA system through perforating medullary branches (MBs), which course toward the lateral ventricles (Bogousslavsky & Regli, 1992). Large infarcts (15 mm or greater) in the core of the CO are associated with severe ICA disease. The pathophysiology of these infarcts may be related to an hemodynamic mechanism since many MBs arise from distributing pial arteries at the cortical border zones. However, an embolic mechanism is also possible (Bogousslavsky & Regli, 1992).

Other subcortical infarcts Emboli from the carotid stump or anterograde extension of the thrombus may occlude the ipsilateral MCA inducing a large, possibly isolated, ipsilateral striatocapsular infarct (Weiller et al., 1990; Donnan et al., 1991). Similarly, an

This is a serious blinding condition caused by reduction of blood flow to the eyeball, which can produce anterior or posterior segment ischemia or both. This condition is associated in about 75% with ipsilateral occlusion or severe ICA stenosis (Mizener et al., 1997). The prognosis for return of vision is usually extremely poor. Severe ocular ischemia manifests by neovascularization of the anterior segment (iris, angle), posterior segment or both, low central retinal artery (CRA) pressure, sluggish circulation on fundus fluorescein angiography. CRA occlusion or anterior ischemic optic neuropathy (AION) may also be observed. Initial complaints are sudden or more rarely gradual loss of vision, amaurosis fugax, ocular/orbital pain. Rarely, ocular ischemic syndrome may be asymptomatic (Mizener et al., 1997).

Optico-cerebral syndrome This syndrome is defined by simultaneous cerebral infarction and monocular blindness due to optic nerve infarction (AION) sparing the retina. Optico-cerebral syndrome (OCS) is found in 2.4% of acute strokes with ICA occlusion and seems to be a reliable indicator of this condition (Bogousslavsky et al., 1987). In ICA disease, monocular blindness is usually attributed to fibrinoplatelar emboli in the retinal arteries but optic nerve infarction is uncommon, perhaps because orbital collaterals usually prevent acute ischemia in case of ophthalmic artery occlusion related to ICA thrombosis. Involvement of border zone cerebral arterial territories (anterior or posterior watershed infarcts) and triggering by orthostatic or induced hypotension especially point to a hemodynamic mechanism at the origin of OCS (Bogousslavsky et al., 1987).

Painful ophthalmoplegia Partial unilateral third-, fourth-, and/or sixth-nerve paresis accompanied by retro- or periorbital pain, ipsilateral visual loss and sometimes contralateral hemispheric signs have been reported in association with ICA occlusion (Wilson et al., 1989; Kapoor et al., 1991; Balcer et al., 1997). Oculomotor palsy may be transient or permanent and pupil-involving third-nerve palsy seems constant. Patients may present amaurosis fugax or, more frequently, develop acute CRA occlusion with its typical appearance on optic fundus : diffuse retinal edema sparing the macula (‘cherry-

Carotid occlusion syndromes

red’ spot) associated with attenuated arterioles. These symptoms are consistent with the known blood supply to oculomotor nerves within the cavernous sinus. This is an anastomotic plexus of small arteries which in turn is supplied from branches of the ICA within the cavernous sinus, from several branches of the maxillary artery, as well as from the ophthalmic artery anteriorly, and from the PCAs and basilar artery posteriorly. Thus, it could explain why oculomotor palsy is so unusual after ICA occlusion since occlusion of several of these collateral pathways (occlusion of ECA or ophthalmic artery, fetal origin of the PCA, . . .) is probably required to induce significant ischemia (Kapoor et al., 1991). Periorbital pain may be related to ischemia of trigeminal trunks in their cavernous portion (Koennecke & Seyfert, 1998).

Transient ischemic attacks Transient ischemic attacks may be the only manifestation of ICA occlusion in 7% of the cases. The occurrence of warning TIAs (47%) correlates with a small volume and a deep localization of infarction, and also with a better initial neurological ability and long-term functional prognosis. Delayed ipsilateral TIAs (28%) are associated with ECA stenosis or a stump of the occluded ICA, suggesting a micro-embolic mechanism, but do not predict a poorer functional prognosis. Vertebrobasilar TIAs (20%) are associated with an absent or poor collateral circulation, a contralateral ICA stenosis, and the absence of vertebral atheromatosis, which suggests a hemodynamic mechanism. These vertebrobasilar symptoms correspond to a poorer long-term functional prognosis (Bogousslavsky & Regli, 1983c; Bogousslavsky & Regli, 1985). Transient monocular blindness and triggering of TIA by exertion or standing up suggest a carotid lesion (Bogousslavsky et al., 1986). Retinal TIAs have a better prognosis compared to hemispheric TIAs, which may reflect a thromboembolic mechanism at an earlier period in the development of carotid lesion (Streifler et al., 1995). Hemodynamic TIAs are typically short in duration and clinically stereotyped, often occuring in clusters, while embolic TIAs tend to last longer and are less often multiple (Pessin et al., 1977). The term hemodynamically severe ICA disease should be strictly applied to patients who describe postural, exercise, postprandial or light-induced ischemic events (Barnett, 1997). Thus, several symptoms attributed to hemodynamic compromise during ICA occlusion have been described. They occur during conditions inducing a probable diversion of blood from retina or brain to different parts of the body: orthostatic TIA without systemic orthostatic hypo-

tension (Somerville, 1984); postprandial TIA (Kamata et al., 1994; Levin & Mootha, 1997); transient monocular visual blurring on facial heating or in warm surroundings (hair drier, hot shower, . . .) (Russel & Page, 1983). Monocular transient retinal ischemia occuring on looking into bright light may be related to retinal claudication caused by an increase in metabolic retinal demand that cannot be met owing to an already marginal perfusion. Exercise (climbing) or stooping may induce a rise in venous pressure and consequently a transient visual loss via a decreased retinal perfusion pressure (Russel & Page, 1983). A case of coughinduced transient hemiplegia has been described in a patient with contralateral ICA occlusion, ipsilateral ICA stenosis (50%) and poor collateral blood supply (Okayasu et al., 1993).The mechanism is probably the same as for cough syncope, where the rise in intrathoracic pressure induces an increase of intracranial pressure to a degree sufficient to compromise cerebral blood flow (Mattle at al., 1995). ‘Limb shaking’ is another symptom of hemodynamic failure occuring after ICA occlusion. Patients complain of repetitive and rhythmic involuntary movements of one or both limbs on one side when standing or walking but without any concomitant epileptiform activity on electroencephalograms (Yanagihara et al., 1985). Exceptionally, a transient worsening of a stroke-related hemiparesis during head-turning has been described and related to a web-like atherosclerotic plaque responsible for positional intermittent ICA occlusion (Nehls et al., 1985).

Unilateral double hemispheric infarction This condition is closely associated with tight stenosis or occlusion of the ICA. The most frequent neurological picture mimicks laMCA, but in about half of these patients, three clinical syndromes specific of this double infarction may be observed (Bogousslavsky, 1991). This type of infarction is found in about 5% of first strokes with ICA occlusion, and is most often secondary to embolism in pial arteries from ICA itself. The hemianopia–hemiplegia syndrome is related to ischemic lesions affecting corticospinal pathway (corona radiata or internal capsule) or the motor cortex and optic radiations or occipital cortex. The sensory cortex and pathways are spared explaining the absence of any sensory dysfunction. The acute conduction aphasia (word-finding difficulties, phonemic paraphasias, impaired repetition and normal comprehension) with hemiparesis syndrome is associated with infarcts involving the supramarginalis gyrus, sparing the sensory cortex and the visual pathways, and the motor cortex and underlying white-matter. The acute mixed transcortical aphasia syndrome (non

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fluent spontaneous speech, impaired naming, semantic paraphasias, echolalia, excellent repetition and poor comprehension) is observed in patients with ICA occlusion and precentral/central and posterior watershed infarcts in the dominant hemisphere. Mild hemiparesis usually predominating in the upper limb is constant while hemisensory impairment or lower quadrantanopia may occur.

Moriatic aphasia-sensorimotor hemiparesis This syndrome has been reported in a patient with left ICA occlusion, right hypoplastic A1 segment and subacute infarct in the territory of both ACAs and left MCA (GhikaSchmid et al., 1998). This patient had atypical global aphasia with ‘massive hyperproduction of meaningless sounds, affective facial expressions, emotional lability, and childish and manipulative behaviour shares features with moria’. The combination of this orbito-mesial frontal syndrome to an atypical global aphasia is extremely rare but might be suggestive of an acute carotid occlusion on the dominant side.

Bilateral internal carotid occlusion Compared to patients with unilateral ICA occlusion, those with bilateral ICA occlusion have a higher incidence of vascular risk factors especially concerning heavy smoking (Wade et al., 1987). The estimated annual stroke rate is 13% per year and the annual mortality is about 8%. Despite this severe atheromatosis, these patients may survive with minimal neurological deficits. Collateral circulation is mainly provided by the vertebrobasilar system (Catala et al., 1995), which explains recurrent vertebrobasilar or presyncopal episodes, most of them related to hemodynamic insufficiency (symptoms triggered by orthostatic hypotension or head turning) (Bogousslavsky & Regli, 1983a; Wade et al., 1987; Yanagihara et al., 1989). However, in patients with severe bilateral carotid stenosis or occlusion, some transient vertebrobasilar-like symptoms might be related to bilateral hemispheric border zone ischemia rather than brainstem ischemia (Sloan & Haley, 1990). This concerns transient bilateral motor, sensory, or visual impairment without dysarthria, dysphagia, and diplopia.

Common carotid occlusion The incidence of common carotid occlusion (CCO) in patients with ischemic stroke related to atherosclerosis is about 1 to 5%. CCO seems less common than ICAO. As ICA

occlusion, CCO may remain asymptomatic. Symptoms distal to CCO have the same pathophysiology compared to ICA occlusion. However, during CCO, the inability of the external carotid artery to provide blood supply to intracranial structures may explain the higher ipsilateral stroke and contralateral hemisphere TIAs prevalence, the frequency of visual disturbances related to ocular ischemia and the high prevalence of vertebrobasilar TIAs supporting hemodynamic mechanisms (Levine & Welch, 1989). But, an embolic mechanism cannot be ruled out in many patients owing to multifocal large vessel atheroma. Sometimes, the contralateral ECA may supply efficiently, via anastomosis between the superior thyroid arteries, the ipsilateral ECA then, in a retrograde fashion, the patent carotid bifurcation below the CCO, then the ICA (Macchi & Catini, 1995). Rarely, a CCO may produce an isolated complete orbital infarction with sparing of cerebral circulation (Bogousslavsky et al., 1991). Typically, the patient presents with ipsilateral acute painful ophthalmoplegia and blindness. Optic fundus and fluorescein angiography are consistent with diffuse retinal infarction as well as anterior ischemic optic neuropathy. Absent corneal reflex suggests involvement of orbital branches of the ophthalmic nerve and suggests acute ischemia involving the whole orbit content. The blood supply of the orbit is derived from rich anastomoses between ICA and ECA which might explain the higher frequency of visual disturbances related to CCO. However, the association of abnormal orbital anastomotic channels (constitutionally or via embolic occlusions) seems necessary to induce this rare syndrome (Borruat et al., 1993).

Intracranial internal carotid occlusion The estimated prevalence of intracranial atherosclerotic disease (IAD) in patients with stenosis of the extracranial ICA varies between 20 and 50%. IAD is an independent risk factor for subsequent stroke in medically treated patients with symptomatic ICA stenosis that can be reduced by carotid endarterectomy (Kappelle et al., 1999). Siphon occlusion of the ICA seems to have the highest rate of progressing course (neurological worsening during the first days of the hospital stay) followed by stem occlusion of the MCA, extracranial ICA occlusion, branch occlusion of the MCA and isolated ICA plaques (Toni et al., 1995). But, no significant difference has been reported between groups with extra- or intracranial occlusion in functional outcome, delayed strokes, TIAs and death. Patients with intracranial stenosis or occlusion of the ICA

Carotid occlusion syndromes

but without proximal atheromatosis are younger and significantly show fewer risk factors compared with patients presenting extracranial ICA occlusion (Bogousslavsky & Regli, 1983b). This suggests that non-atheromatous factors may participate in the pathogenesis of isolated siphon obstruction. The lesion of the siphon may be embolic and resolve spontaneously (Bodosi et al., 1981). Progressive occlusions of the intracranial portions of ICAs are established phenomena in moya-moya disease which is decribed in another chapter of this book.

Carotid dissection The overall frequency of ischemic events related to carotid dissection is 50 to 95%, but the onset of stroke is ⱕ7 days in 82% of the cases in a series of 80 patients with carotid dissection (Biousse et al., 1995). These patients are usually younger than those with atheromatous carotid stenosis. In this study, ICA occlusion occurs in 29% of the patients and is symptomatic in 78% of the cases during a 6-month follow-up. Very suggestive local symptoms such as head or neck pain, Horner’s syndrome, and tinnitus frequently precede cerebral infarction, and are associated with symptomatic ICA occlusion on dissection in about 60% of the cases. Painful Horner’s syndrome is the most common ocular sign in ICA dissection (up to 58% of the patients), while transient monocular visual loss has been reported in 6 to 30% of patients and oculomotor nerve palsies in 2.6% of patients with ICA dissection (Biousse et al., 1998). Compressive palsies of the lower cranial nerves (hypoglossal, glossopharyngeal and vagus nerves) related to ICA dissection is a rare condition but also suggestive of this diagnosis in patients with history of recent cervical trauma, neck or retromandibular pain and contralateral hemiparesis (Hommel et al., 1984).

xReferencesx Balcer, L.J., Galetta, S.L., Yousem, D.M.,Golden, M.A. & Asbury, A.K. (1997). Pupil-involving third-nerve palsy and carotid stenosis: rapid recovery following endarterectomy. Annals of Neurology, 41, 273–6. Barnett, H.J.M. (1997). Hemodynamic cerebral ischemia. An appeal for systematic data gathering prior to a new EC/IC trial. Stroke, 28, 1857–60. Biousse, V., D’Anglejean-Chatillon, J., Touboul, P.J., Amarenco, P. & Bousser, M.G. (1995). Time course of symptoms in extracranial carotid artery dissections. a series of 80 patients. Stroke, 26, 235–9.

Biousse, V., Touboul, P.J., D’Anglejean-Chatillon, J., Levy, C., Schaison, M. & Bousser, M.G. (1998). Ophthalmologic manifestations of internal carotid artery dissection. American Journal of Ophthalmology, 126, 565–77. Bladin, C.F. & Chambers, B.R. (1993). Clinical features, pathogenesis, and computed tomographic characteristics of internal watershed infarction. Stroke, 24, 1925–32. Bodosi, M., Gacs, G. & Merei, F.T. (1981). Stenoses of the distal segments of the internal carotid artery. Surgical Neurology, 16, 109–16. Bogousslavsky, J. (1991). Double infarction in one cerebral hemisphere. Annals of Neurology, 30, 12–18. Bogousslavsky, J. & Regli, F. (1983a). Delayed TIAs distal to bilateral occlusion of carotid arteries. Evidence for embolic and hemodynamic mechanisms. Stroke, 14, 58–61. Bogousslavsky, J. & Regli, F. (1983b). Prognosis of symptomatic intracranial obstruction of internal carotid artery. European Neurology, 22, 351–8. Bogousslavsky, J. & Regli, F. (1983c). Warning and delayed transient ischemic attacks in occlusion of the internal carotid artery. Revue Neurologique (Paris), 139, 625–33. Bogousslavsky, J. & Regli, F. (1985). Vertebrobasilar transient ischemic attacks in internal carotid artery occlusion or tight stenosis. Archives of Neurology, 42, 64–8. Bogousslavsky, J. & Regli, F. (1986a). Borderzone infarctions distal to internal carotid artery occlusion: prognostic implications. Annals of Neurology, 20, 346–50. Bogousslavsky, J. & Regli, F. (1986b). Unilateral watershed cerebral infarcts. Neurology, 36, 373–7. Bogousslavsky, J. & Regli, F. (1992). Centrum ovale infarcts: subcortical infarction in the superficial territory of the middle cerebral artery. Neurology, 42, 1992–8. Bogousslavsky, J., Regli, F., Hungerbuhler, J.P. & Chrzanowski R. (1981). Transient ischemic attacks and external carotid artery. A retrospective study of 23 patients with an occlusion of the internal carotid artery. Stroke, 12, 627–30. Bogousslavsky, J., Uske, A. & Regli F. (1984). Carotid artery occlusion. Delayed embolic ischemia from vertebrobasilar atheromatosis. Archives of Neurology, 41, 334–5. Bogousslavsky, J., Regli, F. & Van Melle, G. (1985). Risk factors and concomitants of internal carotid artery occlusion or stenosis. A controlled study of 159 cases. Archives of Neurology, 42, 864–7. Bogousslavsky, J., Hachinski, V.C., Boughner, D.R., Fox, A.J., Vinuela, F. & Barnett, H.J.M. (1986). Clinical predictors of cardiac and arterial lesions in carotid transient ischemic attacks. Archives of Neurology, 43, 229–33. Bogousslavsky, J., Regli, F., Zografos, L. & Uske, A. (1987). Opticocerebral syndrome: simultaneous hemodynamic infarction of optic nerve and brain. Neurology, 37, 263–8. Bogousslavsky, J., Pedrazzi, P.L., Borruat, F.X. & Regli, F. (1991). Isolated complete orbital infarction: a common carotid artery occlusion syndrome. European Neurology, 31, 72–76. Borruat, F.X., Bogousslavsky, J., Uffer, S., Klainguti, G. & Schatz, N.J. (1993). Orbital infarction syndrome. Ophthalmology, 100, 562–8.

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Bowen, J.C., Garcia M., Garrard, C.L., Mankin, C.J. & Fluke, M.M. (1997). Anomalous branch of the internal carotid artery maintains patency distal to a complete occlusion diagnosed by duplex scan. Journal of Vascular Surgery, 26, 164–7. Brückmann, H., Zeumer, H. & Ferbert, A. (1987). Distal stump of the internal carotid artery with ascending pharyngeal artery collateralisation. A potential source for further embolic ischemia. Neuroradiology, 29, 81–3. Caplan, L.R. & Sergay S. (1976). Positional cerebral ischemia. Journal of Neurology, Neurosurgery, and Psychiatry, 39, 385–91. Catala, M., Rancurel, G., Raynaud, C., Leder, S., Kieffer, E. & Koskas, F. (1995). Bilateral occlusion of the internal carotid arteries. Report of a series of 19 cases. Revue Neurologique (Paris), 151, 648–56. Chollet, F., Rolland, Y., Albucher, J.F., Manelfe, C., Marc-Vergnes, J.P. & Guiraud-Chaumeil, B. (1996). Recurrent right hemiplegia associated with progressive ipsilateral carotid artery stenosis. Stroke, 27, 753–5. Countee, R.W. & Vuayanathan, T. (1979). External carotid artery in internal carotid artery occlusion. Angiographic, therapeutic, and prognostic considerations. Stroke,10, 450–60. Donnan, G.A., Bladin, P.F., Berkovic, S.F., Longley, W.A. & Saling, M.M. (1991). The stroke syndrome of striatocapsular infarction. Brain, 114, 51–70. Gasecki, A.P., Fox, A.J., Lebrun, L.H. & Daneault, N. (1994). Bilateral occipital infarctions associated with carotid stenosis in a patient with persistent trigeminal artery. Stroke, 25, 1520–3. Georgiadis, D., Grosset, D.G. & Lees, K.R. (1993). Transhemispheric passage of microemboli in patients with unilateral internal carotid artery occlusion. Stroke, 24, 1664–6. Ghika-Schmid, F., Assal, G., Ghika, J. & Bogousslavsky, J. (1998). Moriatic aphasia: a syndrome of acute carotid occlusion on the dominant side. Neurology, 50, 1511–12. Grubb, R.L., Derdeyn, C.P., Fritsch, S.M. et al., (1998). Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. Journal of the American Medical Association, 280, 1055–60. Hedera, P., Bujdakova, J. & Traubner, P. (1995). Effect of collateral flow patterns on outcome of carotid occlusion. European Neurology, 35, 212–16. Heinsius, T., Bogousslavsky, J. & Van Melle, G. (1998). Large infarcts in the middle cerebral artery territory. Etiology and outcome patterns. Neurology, 50, 341–50. Hommel, M., Pollak, P., Gaio, J.M., Pellat, J., Perret, J. & Chateau, R. (1984). Hypoglossal paralysis due to two aneurysms and one dissecting aneurysm of the internal carotid artery. Revue Neurologique, 140, 415–21. Hupperts, R.M.M., Warlow, C.P., Slattery, J. & Rothwell, P.M. (1997). Severe stenosis of the internal carotid artery is not associated with borderzone infarcts in patients randomised in the European Carotid Surgery Trial. Journal of Neurology, 244, 45–50. Kamata, T., Yokota, T., Furukawa, T. & Tsukagoshi, H. (1994). Cerebral ischemic attack caused by postprandial hypotension. Stroke, 25, 511–13.

Kapoor, R., Kendall, B.E. & Harrison, M.J.G. (1991). Permanent oculomotor palsy with occlusion of the internal carotid artery. Journal of Neurology, Neurosurgery, and Psychiatry, 54, 745–6. Kappelle, L.J., Eliasziw, M., Fox, A.J., Sharpe, B.L. & Barnett, H.J.M. (1999). Importance of intracranial atherosclerotic disease in patients with intracranial stenosis of the internal carotid artery. Stroke, 30, 282–6. Kniemeyer, H.W., Aulich, A., Schlachetzki, F., Steinmetz, H. & Sandmann, W. (1996). Pseudo- and segmental occlusion of the internal carotid artery: a new classification, surgical treatment and results. European Journal of Vascular and Endovascular Surgery, 12, 310–20. Koennecke, H.C. & Seyfert, S. (1998). Mydriatic pupil as the presenting sign of common carotid artery dissection. Stroke, 29, 2653–5. Kolbinger, R., Heindel, W., Pawlik, G. & Erasmi-Korber, H. (1993). Right proatlantal artery type I, right internal carotid occlusion, and left internal carotid stenosis: case report and review of the literature. Journal of the Neurological Sciences, 117, 232–9. Kuwert, T., Hennerici, M., Langen, K.J. et al., (1990). Compensatory mechanisms in patients with asymptomatic carotid artery occlusion. Neurological Research, 12, 89–93. Levin, L.A. & Mootha, V.V. (1997). Postprandial transient visual loss. A symptom of critical carotid stenosis. Ophthalmology, 104, 397–401. Levine, S.R. & Welch, K.M.A. (1989). Common carotid artery occlusion. Neurology, 39, 178–86. Macchi, C. & Catini, C. (1995). Clinical importance of the supraisthmic anastomosis between the superior thyroid arteries in six cases of occlusion of the common carotid artery. Surgical Radiology and Anatomy, 17, 65–9. Matsui, T. & Hirano, A. (1978). An Atlas of the Human Brain for Computerized Tomography. Tokyo: Igaku-Shoin. Mattle, H.P., Nirkko, A.C., Baumgartner, R.W. & Sturzenegger, M. (1995). Transient cerebral circulatory arrest coincides with fainting in cough syncope. Neurology, 45, 498–501. Mizener, J.B., Podhajsky, P. & Hayreh, S.S. (1997). Ocular ischemic syndrome. Ophthalmology, 104, 859–64. Mounier-Vehier, F., Leys, D. & Pruvo, J.P. (1995). Stroke patterns in unilateral atherothrombotic occlusion of the internal carotid artery. Stroke, 26, 422–5. Nehls, D.G., Marano, S.R. & Spetzler, R.F. (1985). Positional intermittent occlusion of the internal carotid artery. Journal of Neurosurgery, 62, 435–7. Nighoghossian, N., Berthezene, Y., Philippon, B., Adeleine, P., Froment, J.C. & Trouillas, P. (1996). Hemodynamic parameter assessment with dynamic susceptibility contrast magnetic resonance imaging in unilateral symptomatic internal carotid artery occlusion. Stroke, 27, 474–9. Okayasu, H., Wakayama, Y., Takahashi, H. & Jimi, T. (1993). A case of cough hemiplegia. Rinsho Shinkeigaku, 33, 740–5. Pessin, M.S., Duncan, G.W., Mohr, J.P. & Poskanzer, D.C. (1977). Clinical and angiographic features of carotid transient ischemic attacks. New England Journal of Medicine, 296, 358–62. Pessin, M.S., Kwan, E.S., Scott, R.M. & Hedges, T.R. (1989). Occipital

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infarction with hemianopsia from carotid occlusive disease. Stroke, 20, 409–11. Rautenberg, W., Mess, W. & Hennerici M. (1990). Prognosis of asymptomatic carotid occlusion. Journal of the Neurological Sciences, 98, 213–20. Ringelstein, E.B., Zeumer, H. & Angelou, D. (1983). The pathogenesis of strokes from internal carotid artery occlusion. Diagnostic and therapeutical implications. Stroke, 14, 867–75. Russel, R.W.R. & Page, N.G.R. (1983). Critical perfusion of brain and retina. Brain, 106, 419–34. Sloan, M.A. & Haley, E.C. (1990). The syndrome of bilateral hemispheric border zone ischemia. Stroke, 21, 1668–73. Somerville, E.R. (1984). Orthostatic transient ischemic attacks: a symptom of large vessel occlusion. Stroke, 15, 1066–67. Streifler, J.Y., Eliasziw, M., Benavente, O.R. et al., (1995). The risk of stroke in patients with first-ever retinal vs hemispheric transient ischemic attacks and high-grade carotid stenosis. Archives of Neurology, 52, 246–9. Takagi, S. & Shinohara, Y. (1981). Internal carotid occlusion: volume of cerebral infarction, clinical findings, and prognosis. Stroke, 12, 835–9. Toni, D., Fiorelli, M., Gentile, M. et al. (1995). Progressing neuro-

logical deficit secondary to acute ischemic stroke. A study on predictability, pathogenesis, and prognosis. Archives of Neurology, 52, 670–5. Wade, J.P.H., Wong, W., Barnett, H.J.M. & Vandervoort, P. (1987). Bilateral occlusion of the internal carotid arteries. Brain, 110, 667–82. Weiller, C., Ringelstein, E.B., Reiche, W., Thron, A. & Buell, U. (1990). The large striatocapsular infarct. A clinical and pathophysiological entity. Archives of Neurology, 47, 1085–91. Widder, B., Kleiser, B. & Krapf, H. (1994). Course of cerebrovascular reactivity in patients with carotid artery occlusions. Stroke, 25, 1963–7. Wilson, W.B., Leavengood, J.M., Ringel, S.P. & Bott, A.D. (1989). Transient ocular motor paresis associated with acute internal carotid artery occlusion. Annals of Neurology, 25, 286–90. Yanagihara, T., Piepgras, D.G. & Klass, D.W. (1985). Repetitive involuntary movement associated with episodic cerebral ischemia. Annals of Neurology, 18, 244–50. Yanagihara, T., Klass, D.W., Piepgras, D.G. & Houser, O.W. (1989). Brief loss of consciousness in bilateral carotid occlusive disease. Archives of Neurology, 46, 858–61.

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Cervical artery dissection syndromes Tobias Brandt1, Erdem Orberk2 and Werner Hacke2 1 2

Department of Neurology, Ludwig Maximilians University, Munich, Germany Neurological Clinic, University of Heidelberg, Germany

Introduction Dissection of a cervico-cerebral artery (CAD) occurs by a rupture within the arterial wall leading to an intramural hematoma. A possible consequence is an acute obstruction of the vessel inducing a high risk for local thrombus formation and cerebral embolism. The clinical spectrum of CAD varies considerably from local pain in the neck or unusual unilateral headaches and a Horner’s syndrome to life-threatening complete hemispheric or brainstem infarction. Symptomatic dissections of the carotid and vertebral arteries have been diagnosed more frequently since the introduction of Doppler sonography and magnetic resonance imaging (MRI) (Saver et al., 1992; Rother et al., 1993; Steinke et al., 1994; Sturzenegger, 1995). Among young and middle-aged patients, CADs are now recognized as an important cause of stroke (Bogousslavsky et al., 1987; Caplan & Tettenborn, 1992; Saver et al., 1992; Kristensen et al., 1997; Brandt et al., 1998). Bogousslavsky found an incidence of 2.5% in 1200 consecutive first stroke patients (Bogousslavsky et al., 1987). Under the age of 45 years the incidence of CAD is much higher at 10–20% and CAD are the second leading cause of stroke in the younger age group (Bogousslavsky & Pierre, 1992; Gautier et al., 1989; Livosky & Rousseau, P., 1991). The mean age of the patients with CAD is 40 to 45 years (Gautier et al., 1989; Schievink et al., 1994b; Brandt et al., 1998). The true incidence of CAD is unknown: an estimation for ICA dissection on the basis of a community study has been 2.6 per 100 000 per year (Schievink et al., 1993b). However, as asymptomatic dissection detected by MRI is well known (Mascalchi et al., 1997; Lefebvre et al., 1996) and, since many patients with isolated pain, but no neurological deficits, are not screened for flow abnormalities on Doppler sonography, the real incidence is probably higher (Schievink et al., 1993b). Incidence of vertebral artery (VA)

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dissection is one-third of ICA dissection (Hinse et al., 1991; Bassetti et al., 1996; Bertram et al., 1999). Extracranial artery dissection is far more frequent than intracranial dissection (Hart & Easton, 1983; Saver et al., 1992). Simultaneous dissection of more than one vessel is found in the minority of patients (less than 15%; Saver et al., 1992; Schievink et al., 1994b). Sites of predeliction are the distal ICA 2–3 centimetres distal to the carotid artery bifurcation and before entrance into the cranium. The VA is most often found dissected in the distal extracranial segment between the C1 and C2 level of the atlas loop before entering the dura (V3 segment) (Caplan et al., 1985; Saver et al., 1992; Hinse et al., 1991). Dissection of the proximal VA (V1segment) is less frequent (Caplan et al., 1985; Saver et al., 1992; Hinse et al., 1991). Familial occurrence of CAD is described but rare (Mokri et al., 1987; Schievink et al., 1994b).

Diagnosis Until the mid-1980s, diagnosis of CAD (Table 52.1) was usually only confirmed by intra-arterial angiography demonstrating a so-called ‘string sign’ with long segmental narrowing or a flame-like shaped occlusion distal to the carotid bifurcation (Fig. 52.1), and infrequently an intimal flap and double lumen in the dissected artery. Clinical diagnosis of CAD is now confirmed mostly by non-invasive techniques such as Doppler sonography, MRI and MRA (Hart & Easton, 1985; Steinke et al., 1994; Sturzenegger, 1995). Doppler sonography is commonly performed as the first diagnostic screening method and is already highly sensitive (⬎90%) in confirming a clinically suspected CAD. A typical finding is a high resistance flow pattern in the distal ICA, which is not specific but is in combination with char-

Cervical artery dissection syndromes

Table 52.1. Diagnosis: Characteristic Doppler and imaging findings Doppler sonography Distal high resistance flow pattern (cw-Doppler, frequent finding, high sensitivity, characteristic follow-up with recanalization ⬎60%), distal stenosis (TCD 2 MHz-probe), mural hematoma, intimal flap, double lumen (very rare, colour-coded duplex), none or insignificant arteriosclerosis on duplex Angiography Flame-shaped or tapered occlusion or long segmental stenosis (string sign) distal to carotid bifurcation, in V3-segment of VA (less frequent on origin of the VA in V1-segment), pseudoaneurysm (5–30%), signs of FMD (10–15%), ICA redundancies (coiling/kinking ca. 30%) CTA/MRI Semilunar mural hematoma (hyperintensity signal on T1weighted MRI) as confirmation of diagnosis, MRI with axial and coronal sections including sensitive fat-suppression sequences; MRI sensitive only from day 3 up to 6–9 months after dissection, CTA early detection possible; no differentiation of complete vessel occlusion of intraluminal thrombus vs. intramural hematoma → course on follow-up

acteristic clinical findings and absence of arteriosclerosis in the carotid bifurcation highly suggestive for CAD (Steinke et al., 1994; Sturzenegger, 1991). Pathognomic findings such as the identification of a mural hematoma or false lumen and an intimal flap of the dissected proximal ICA by colour-coded duplex sonography are very rare (Steinke et al., 1994). MRI (Nguyen Bui et al., 1993; Rother et al., 1993) is usually the diagnostic tool to prove dissection by identification of a semilunar-shaped hematoma in the arterial wall on axial slices 3 days after the event and up to approximately 6 months later (Fig. 52.2). MRI fat-suppression sequences are the most sensitive for hematoma detection. Spiral CT angiography proved also to be diagnostic by demonstrating an intramural hematoma as well as a string sign and might be positive even in the very first days of CAD (Zuber et al., 1994; Egelhof et al., 1996).

Pathogenesis While the clinical and diagnostic criteria for CAD are well established, the exact pathomechanism of arterial dissection is not fully understood. Two principal possibilities are

Fig. 52.1. Dissection of internal carotid artery demonstrated by angiography with long segmental narrowing distal to the bifurcation (string sign).

described: a rupture of the intimal layer of the arterial wall with penetration of intraluminal blood into the wall and compression of the lumen and – more probable – a rupture within the connective tissue and its vasa vasorum of the intramedial layer resulting in dissection of the wall and forming a ‘false lumen’. The intramural hematoma may then penetrate the other layers of the vessel wall and possibly reconnect with the true lumen of the artery (Saver et al., 1992; Guillon et al., 1998). Pathogenesis is also as yet unknown (Schievink et al., 1994b). CAD may occur in otherwise healthy individuals with no risk factors for stroke, and develop spontaneously (Saver et al., 1992). Occasionally, a mild mechanical stress such as sudden head movement, coughing, or sport activities prior to the dissection are reported (Hart & Easton, 1985; Herr et al., 1992; Saver et al., 1992; Brandt et al., 1998).

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Fig. 52.2. Dissection of internal carotid artery proven by MRI (T1weighted) showing a semilunar mural hematoma around the remaining vessel lumen (flow void).

Chiropractic manoeuvres have often been associated with occurrence of CAD (Saver et al., 1992; Guillon et al., 1998). In severe direct trauma of a cervical artery, often combined with fracture in the cervical spine, e.g. by an accident, the cause of the dissection seems to be obvious (Saver et al., 1992). Since the majority of dissections, however, occurs without a history of any relevant trauma, an underlying arteriopathy has often been postulated in these so-called ‘spontaneous’ CAD, particularly because patients are young and several cervico-cerebral vessels might be involved simultaneously (Schievink et al., 1994a). Structural aberrations of the arterial walls and defective connective tissue components in the surrounding extracellular matrix leading to a so-called ‘weakness of the vessel wall’ have been assumed in those patients. Postmortem examinations have rarely been performed, mostly in patients with intracranial dissections leading to

subarachnoid hemorrhage (Adelmann et al., 1974; Caplan et al., 1988; O’Connell et al., 1985; Sasaki et al., 1991; Peters et al., 1995). Tissue specimens of the vessel wall are also rare, as surgery is seldom performed in CAD (Saver et al., 1992). In most cases histopathological examinations showed a normal vascular structure (Savers et al., 1992). In single cases, cystic medial degeneration, FMD, or defects in the internal elastic lamina were reported (Adelmann et al., 1974; Corrin et al., 1981; O’Connell et al., 1985; Caplan et al., 1988, Caplan & Tettenborn, 1992; Sasaki et al., 1991; Saver et al., 1992; Amarenco et al., 1994; Goldstein et al., 1995; Peters et al., 1995). Angiographic signs of FMD are found in up to 15% in patients with CAD. There is also a high incidence of dissections and other neurovascular complications in patients with known heritable connective tissue disorders, such as Ehlers–Danlos (EDS) and Marfan syndrome (Saver et al., 1992; Schievink et al., 1994a; North et al., 1995). A recent study, however, failed to show COL3A1 mutations as a common cause in 40 patients with intracerebral aneurysms and in 18 patients with CAD (Kuivaniemi et al., 1993). Until recently, a connective tissue disorder has never been proven to correlate with CAD in otherwise healthy individuals. An ultrastructural study of the connective tissue components of skin biopsies by electron microscopy detected that two-thirds of 25 patients had spontaneous CAD ultrastructural abnormalities in the collagen and elastic fibres morphology (Brandt et al., 1998). None of these patients had clinical signs of known hereditary connective tissue disorders (Schievink et al., 1994a). This further supports the hypothesis of a primary arteriopathy. Structural defects of the arterial wall and the surrounding extracellular matrix may result in a predisposition to arterial dissections. A definite genetic defect, however, could not yet be identified. It remains unclear, however, even with an assumed underlying connective tissue disorder, why CAD happens at a certain period of time and at a distinct location, and why recurrency rate and family occurrence are usually low. Possibly, a combination of an underlying arteriopathy and temporarily active factors may be necessary for CAD to occur. In the majority of patients with CAD a minor mechanical stress induced by coughing or a sudden head movement, or recent infection is reported and might have played a role by a triggering the mechanism in the pathogenesis of CAD (Caplan et al., 1985; Herr et al., 1992; Saver et al., 1992; Grau et al., 1995; Guillon et al., 1998; Brandt et al., 1998). During infection, microbial agents, or proteolytic, oxidative or autoimmunological mechanisms may additionally damage the arterial wall (Grau et al., 1999).

Cervical artery dissection syndromes

Clinical manifestations CAD can occur as a mono- or oligosymptomatic form with isolated new onset of pain or a cranial nerve deficit but also as a full hemispheric or brainstem syndrome with diagnosis of CAD only on further diagnostic work-up including MRI. Characteristic and possibly differentiating features from other etiologies of stroke are the younger age of patient (⬍50 years, with a maximum of 35–45 years) in association with a painful Horner’s syndrome (Table 52.2). The pain is commonly described as unusual, unilateral, severe or sharp in all localizations of CAD and might occur as an isolated symptom (Biousse et al., 1994, Silbert et al., 1995). With CAD of the ICA the pain is localized in the antero-lateral area of the neck, often including the mastoid area and lateral mandible. In dissection of the vertebral artery, frequency of neck pain with a dorsolateral localization is higher, with up to 50% (Caplan et al., 1985; Hinse et al., 1991; Silbert et al., 1995). Concomitant headaches are severe and mostly described as unusual by the patients, sometimes throbbing but mostly sharp and continous, and in 80% ipsilateral to the CAD. In up to 70% of the patients, headaches are the initial symptoms of CAD (Biousse et al., 1994; Silbert et al., 1995). A pulsatile ipsilateral tinnitus might occur with CAD of the ICA and VA. A local sign of CAD is a Horner’s syndrome by compression of the periadvential sympathetic nerve plexus occurring in up to 50% with ICA dissection (Biousse et al., 1994; Sturzenegger & Steinke, 1996). Another local symptom is an ipsilateral cranial nerve deficit. Involvement of all single cranial nerves is described with dissection of the ICA (12%), but lower cranial nerve deficits are far more frequent (Schievink et al., 1993a; Mokri et al., 1996). Also, isolated cranial nerve deficits are described, e.g. for the hyopglossus nerve. The combination of ipsilateral cranial nerve findings and contralateral hemispheric deficits in dissection of the ICA imitating brainstem ischemia is described as a ‘false localizing sign’ (Hess et al., 1990). Local symptoms often precede ischemic events for several days up to 4 weeks (Biousse et al., 1995). In summary, unusual local neck pain or headaches, in combination with a new onset of an ipsilateral Horner’ syndrome or cranial nerve deficit, could be called the specific warning syndrome of acute CAD and is present initially in approximately 20% of all patients with CAD (Steinke et al., 1994). TIAs associated with CAD are present in 10–20%: amaurosis fugax, and hemispheric symptoms for CAD of the ICA, whereas dizziness, nausea, double vision, or gait abnormalities are present for CAD of the VA with brainstem

Table 52.2. Characteristic clinical signs and symptoms of ICA and VA dissection Symptoms unusual and unilateral sharp neck pain ICA: antero-lateral neck radiating to mandible, mastoid and ear (20–40%) VA: dorsal neck (ca. 50%) Headaches (80%) ICA: unilateral, mostly dull and severe, sometimes throbbing; frontal, retroorbital VA: neck and occiput Pulsatile tinnitus (10–15%, more common in ICA dissection) Transient monocular blindness (10–15% in ICA dissection) TIA (10–20%, in ca. 40% proceeding to cerebral infarction) Signs Horner’s syndrome (ICA dissection: 40–50%, presenting symptom in 20%; VA dissection: central Horner’s syndrome in 20–30%) Cranial nerve deficits (ICA dissection: 5–12% III–XII, contralateral to hemispheric deficits as ‘false localizing sign’, lower cranial nerves more frequent. VA dissection: ⬎50%) Cerebral infarction (40–90% in selected patient populations)

ischemia. TIAs precede cerebral infarction in 20–40% (Biousse et al., 1995; Sturzenegger et al., 1995). Ischemic infarcts of the distal territories are frequent with CAD and are found in 40 to 90% in selected patients (Guillon et al., 1998). Outcome is mostly benign (Saver et al., 1992). Due to distal ICA occlusion, however, also lifethreatening large hemispheric infarction might result. Bogousslavsky and coworkers found CAD of the ICA in 12% out of 208 large MCA infarcts (Heinsius et al., 1998). In a series of 51 patients with basilar artery occlusion in 5 (10%), CAD of the VA was the cause (Brandt et al., 1996). In a 1-year survey of Bertram et al. (1999) 14 of 23 (61%) with CAD of the ICA and three out of ten (30%) with CAD of the VA required intensive care unit treatment. Asymptomatic forms of CAD detected by Doppler sonography or MRI, however, are described and their incidence might be underestimated in cases with isolated neck or head pain (Guillon et al., 1998). Also, manifestation of hereditary connective tissue disorder as cerebrovascular complication is well known (Schievink et al., 1994a). Therefore, all patients with CAD should be examined for signs of a connective tissue disorder as skin and joint hyperextensibility, abnormal scars, and retina abnormalities on funduscopy e.g. as angoid streaks. Recently, a patient of ours with carotid artery dissection, with pronounced ultrastructural collagen fibril aberrations in the skin biopsy on electron microscopy

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corresponding to EDS II and elastic fibre alterations, only on careful dermatological investigation revealed mild cardinal symptoms of EDS II with small pseudomolluscoid scars at the elbows (T. Brandt, unpublished observation). In a reported case of a patient with CAD with no other phenotypic sign but slightly bluish sclerae, a mutation characteristic of osteogenesis imperfecta type I was identified (Mayer et al., 1996).

Treatment and prognosis There is no controlled study for best treatment or management of CAD. Initial empiric treatment, which is generally accepted in acute CAD to prevent secondary embolism, is PTT-guided anticoagulation by intravenous heparin followed by oral warfarin (Saver et al., 1992; Guillon et al., 1998). Cases with an increasing mural hematoma induced by anticoagulation are not described (Guillon et al., 1998). Carotid surgery for treatment of CAD is no longer recommended, with the possible exception of persisting severe stenosis of the proximal ICA. The use of carotid angioplasty by balloon dilation and stenting in selected cases of persisting vessel narrowing mostly after traumatic CAD is described in case reports, but studies in larger series of patients are lacking (De O’Campo et al., 1997; Levy, 1998). Clinical outcome after CAD can vary considerably but is most often benign (Saver et al., 1992; Guillon et al., 1998). In a subgroup of patients, however, CAD might also cause occlusion of the distal ICA resulting in large hemispheric infarction or artery-to artery occlusion of the basilar artery with brain stem infarction (Brandt et al., 1996; Heinsius et al., 1998; Bertram et al., 1999). In a survey of the literature on outcome after CAD of the ICA in 466 patients Saver found, for 76% of the patients, mild or no deficits, in 18% moderate, and in 5% of the patients major deficits or death (Saver et al., 1992). In 116 patients with CAD of the vertebral artery, outcome was comparable with no or mild deficits in 83% of the patients, moderate deficits in 7%, and severe deficits or death in 9% of the patients (Saver et al., 1992). Since embolic pathogenesis of cerebral ischemia as a major complication of CAD is well known, and hemodynamic infarcts are rare, secondary prevention is anticoagulation. Non-invasive diagnostic tools (Doppler, MRA) are used for follow-up. Recanalization rate of CAD is high with up to 85% normalization within 6 weeks to 3 months (Steinke et al., 1994; Guillon et al., 1998). After 6 months, generally no further recanalization is to be expected (Steinke et al., 1994; Guillon et al., 1998). However, in our experience in single cases (6 out of 55 patients) recanaliza-

tion occurred from 9 up to 24 months after CAD. Recommendation to monitor recanalization of vessel occlusion and treatment by anticoagulation should therefore probably be extended to at least 2 years after CAD. Normalization of hemodynamics guides medical therapy. Cessation of anticoagulation is indicated when complete recanalization by Doppler sonography is diagnosed or when no further change of hemodynamics and risk of embolism are to be expected in occluded vessels. MR angiography is used to confirm regular vessel morphology in the distal segments of the ICA not directly accessible for ultrasound. DSA on follow-up is being less frequently performed in most centres because pseudoaneurysms that may develop in 5–40% in patients with CAD are often transient or decreasing in size, and frequently not suitable surgically to treat for distal location (Sommer et al., 1998; Guillon et al., 1999). Furthermore, pseudoaneurysms do not increase the risk of embolus formation (Guillon et al., 1999). However, a higher incidence of intracranial aneurysm associated with occurrence of CAD is described in one study, and exclusion of intracranial aneurysm could be an indication for DSA, but further studies are necessary to prove this coincidence in order for diagnostic recommendations (Schievink et al., 1992). Platelet antiaggregation as secondary prophylaxis is usually prescribed for some further years. Recurrence rate for CAD is low with ⬍10% varying from 4 to 8% (Mokri et al., 1987). In familial occurrence of CAD, however, risk of redissection is as high as 50% (Mokri et al., 1987). Recurrent dissection of the formerly affected artery is very rare and most often occurs in other cervicocerebral arteries (Leys et al., 1995; Bassetti et al., 1996). No risk factors for recurrency besides familial dissection and presence of a hereditary connective tissue disorder have yet been identified (Schievink et al., 1994a). Intense sport activities, however, e.g. trampoline exercises should probably be avoided. The same is true for oral contraceptives known to possibly cause abnormalities in the intima in the arterial wall. The late recurrence of dissections up to 14 years after the initial event with potential ischemic sequela underlines the necessity of close follow-up.

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O’Connell, B., Towfighi, J., Brennan, R.W. et al. (1985). Dissecting aneurysms of head and neck. Neurology, 35, 993–7. Peters, M., Bohl, J. & Tomke, F. (1995). Dissection of the internal carotid artery after chiropractic manipulation of the neck. Neurology, 45, 2284–6. Rother, J., Wentz, K.U., Rautenberg, W. et al. (1993). Magnetic resonance angiography in vertebrobasilar ischemia. Stroke, 24, 1310–15. Sasaki, O., Ogawa, H., Kioke, T. et al. (1991). A clinicopathological study of dissecting aneurysms of the intracranial vertebral artery. Journal of Neurosurgery, 75, 874–82. Saver, J.L., Easton, J.D. & Hart, G.H. (1992). Dissections and trauma of cervicocerebral arteries. In Stroke: Pathophysiology, Diagnosis and Management, ed. H.J.M. Barnett, J.P. Mohr, B.M. Stein, & F.M. Yatsu, Vol. 2, pp. 671–88. New York, NY: Churchill Livingstone. Schievink, W.I., Mokri, B. & Piepgras, D.G. (1992). Angiographic frequency of saccular intracranial aneurysms in patients with spontaneous cervical artery dissection. Journal of Neurosurgery, 76, 62–6. Schievink, W.I., Mokri, B., Garrity, J.A. et al. (1993a). Ocular motor nerve palsies in spontaneous dissections of the cervical internal carotid artery. Neurology, 43, 1938–4. Schievink, W.I., Mokri, B. & Wishant, J.P. (1993b). Internal carotid artery dissection in a community. Rochester, Minnesota, 1987–1992. Stroke, 24, 1678–80. Schievink, W.I., Michels, V.V. & Piepgras, D.G. (1994a). Neurovascular manifestations of heritable connective tissue disorders. A review. Stroke, 25, 889–903.

Schievink, W.I., Mokri, B. & Piepgras, D.G. (1994b). Spontaneous dissections of cervicocephalic arteries in childhood and adolescence. Neurology, 44, 1607–12. Silbert, P.L., Mokri, B. & Schievink, W.I. (1995). Headache and neck pain in spontaneous internal carotid and vertebral artery dissections. Neurology, 45, 1517–22. Sommer, A., Neff, W. & Schwartz, A. (1998). Spontaneous healing of cervical pseudoaneurysm in vertebral artery dissection under anticoagulant therapy. Neuroradiology, 40, 249–51. Steinke, W., Rautenberg, W. & Schwartz, A. (1994). Noninvasive monitoring of internal carotid artery dissection. Stroke, 25, 998–1005. Sturzenegger, M. (1991). Ultrasound findings in spontaneous carotid artery dissection. The value of duplex sonography. Archives of Neurology, 48, 1057–63. Sturzenegger, M. (1995). Spontaneous internal carotid artery dissection: early diagnosis and management in 44 patients. Journal of Neurology, 242, 231–8. Sturzenegger, M. & Steinke, W. (1996). Dissektion der Hirnarterien. Therapeutische Umschau, 53, 544–51. Sturzenegger, M., Mattle, H.P., Rivoir, A. & Baumgartner, R.W. (1995). Ultrasound findings in carotid artery dissection: analysis of 43 patients. Neurology, 45, 691–8. Zuber, M., Meary, E., Meder, J.F. & Mas, J.L. (1994). Magnetic resonance imaging and dynamic CT scan in cervical artery dissections. Stroke, 25, 576–81.

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Syndromes related to large artery thromboembolism within the vertebrobasilar arterial system Louis R. Caplan Beth Israel Deaconess Medical Center, Boston, MA, USA

Commonest location of arterial lesions The most common vascular lesion that causes posterior circulation infarction is located within the proximal portions of the extracranial vertebral arteries (ECVAs) (Caplan 1996). Atherosclerosis most often affects the first few centimetres of the ECVAs after their origin from the subclavian arteries (Hutchinson & Yates, 1956; Caplan, 1996). Sometimes plaques extend from the subclavian arteries into the proximal ECVAs. Occlusive lesions at this site are most common in white men (Gorelick et al., 1985; Caplan, 1996). Hypertension, hypercholesterolemia, coronary artery disease, peripheral vascular occlusive disease, and atherostenotic lesions in the proximal internal carotid arteries often accompany the ECVA lesions (Gorelick et al., 1985; Caplan, 1996; Yates & Hutchinson, 1957). Black people, Asians and women less often have occlusive ECVA disease. ECVA lesions cause transient hypoperfusion. The major mechanism of posterior circulation infarction, in patients with ECVA atherosclerosis, is intra-arterial embolism (Caplan, 1991, 1996; Caplan et al., 1992; Caplan & Tettenborn 1992a; Wityk et al., 1998). Atherosclerosis is unusual in the portion of the ECVA that traverses the transverse foramena or in the distal portions of the ECVA before dural penetration. The predominant lesion within the second and third portions of the ECVA is dissection (Caplan et al., 1985; Caplan & Tettenborn, 1992b; Chiras et al., 1985; Mas et al., 1987; Mokri et al., 1988). Dissections that involve the distal ECVA sometimes extend into the intracranial vertebral artery (ICVA). Thrombus within the lumen of the dissected artery may propagate into the ICVA or embolize intracranially to cause infarction. The second most frequent site of atherosclerosis within the posterior circulation is within the ICVA (Caplan, 1996). The atherosclerotic lesions most often involve the distal

portions of the ICVAs beyond the posterior inferior cerebellar artery (PICA) branches (Caplan, 1996; MuellerKuypers et al.,1997; Shin et al., 1999). Both ICVAs are often involved and become stenotic or occluded. (Caplan, 1996; Mueller-Kuypers et al., 1997; Shin et al., 1999). ICVA atherosclerotic lesions cause symptoms by decreasing perfusion to the medulla, pons and posterior inferior cerebellum and by providing a source for intra-arterial embolism (Koroshetz & Ropper, 1987; Caplan & Tettenborn, 1992a; Caplan, 1996; Mueller-Kuypers et al., 1997). Dissections (Caplan et al., 1988) and dolichoectasia are also important disorders of the ICVAs (Caplan, 1996). The third most frequent location of severe atherosclerotic disease in the posterior circulation is the basilar artery (Caplan, 1996). Basilar artery occlusive lesions may be focal or thrombus may extend along the artery for a distance. These lesions cause local hypoperfusion to the pons and pontine branches. Intrinsic atherosclerosis does occur within the posterior cerebral arteries, but embolism is a much more common cause of PCA territory infarction. (Caplan, 1996; Yamamoto et al., 1999). In this chapter, I comment on the clinical findings and syndromes related to infarction at different locations within the vertebrobasilar circulation that are frequently related to large artery occlusive disease. Branch syndromes in the pons, midbrain, and thalami are discussed in other chapters in this book.

Localization of brain lesions within the posterior circulation Localization within the posterior circulation is simplified by dividing the vertebrobasilar territory into proximal, middle, and distal territories (Caplan et al., 1992; Caplan, 1996). The proximal intracranial posterior circulation

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Lesions within the medulla are most often unilateral and predominantly lateral tegmental. When an infarct is found in the medulla on one side, the ipsilateral ICVA or its branches must have been obstructed at one time. Infarcts in the pons tend to be bilateral and medial – tegmentobasal when the basilar artery is occluded. When a penetrating branch is occluded, the infarcts are unilateral and in the territory of a branch. Infarctions in the midbrain, thalamus and posterior portions of the cerebral hemispheres supplied by the PCAs are due to disease within the distal basilar artery or its penetrating SCA or PCA branches.

Proximal intracranial territory Lateral medullary infarction

Fig. 53.1. Artist’s drawing of the base of the brain showing the intracranial vertebral and basilar arteries and their main branches. The sections are divided into proximal, middle, and distal intracranial posterior circulation territories. ASA ⫽ anterior spinal artery; PICA ⫽ posterior inferior cerebellar artery; AICA ⫽ anterior inferior cerebellar artery; SCA ⫽ superior cerebellar artery; PCA ⫽ posterior cerebral artery. (Drawn by Laurel Cook-Lowe. Reprinted with permission from Caplan, L.R., 1996.)

territory includes regions supplied by the intracranial vertebral arteries (ICVAs) – the medulla oblongata and the posterior inferior cerebellar artery (PICA)-supplied region of the cerebellum. The ICVAs join together to form the basilar artery at the medullopontine junction. The middle intracranial posterior circulation territory includes the portion of the brain supplied by the basilar artery and its penetrating artery branches up to its superior cerebellar artery (SCA) branches – the pons and the anterior inferior cerebellar artery (AICA)-supplied portions of the cerebellum. The distal intracranial posterior circulation territory includes all of the territory supplied by the rostral basilar artery and its SCA, posterior cerebral artery (PCA) and their penetrating artery branches – midbrain, thalamus, SCAsupplied cerebellum, and PCA territories. This distribution is shown diagrammatically in Fig. 53.1.

The symptoms and signs found in patients with lateral medullary ischemia depend on the dorsal–ventral, medial–lateral, and rostro-caudal location of the infarcts. Figure 53.2 shows various location patterns. Vestibulo-cerebellar symptoms and signs are nearly always present in patients with lateral medullary infarcts. Most patients describe feeling dizzy or off-balance. Others report vertigo characterized by the perception that their head and body are turning, rotating, whirling or moving in relation to their environment. Some patients feel as if they are being pulled or are falling towards one side (most often ipsilateral to the lesion); other patients describe a swaying, rolling feeling as if they are moving from side to side. Feelings of tilting or leaning are also frequent. Feeling seasick, or being on a merry-go-round are common descriptors. Dizziness and vertigo are related to involvement of the vestibular nuclei and their connections. The vestibular nuclei and their connections with oculomotor structures including the vestibulo-ocular reflex (VOR), and the vestibular portions of the cerebellum form a functional unit difficult to separate. Patients with vestibular system abnormalities often report visual symptoms that relate to abnormalities of the VOR. Patients describe blurred vision or frank diplopia. In patients who report visual blurring, the most common neurological sign is nystagmus. Visual loss, visual field abnormalities, and extraocular muscle palsies are not found on examination. Some patients report oscillopsia, rhythmic motion or oscillation of objects on which they attempt to focus. Some describe the abnormality as maximal during fixation, while others note that oscillopsia becomes more prominent as they continue to look at objects or print. The abnormality is accentuated in a

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Med. vestib. nuc. D

Nucleus solitarius Nuc. XII

Inf. vestib. nuc.

Lat. cuneate nuc. S

Dors. eff. X

Mandibular DV Desc. root V Restiform body

Tr. sol. Med. long fasic.

Maxillary

Nuc. ambig.

Ophthalamic Roots X Vent. spinocerebellar Lateral spinothalamic

Medial lemniscus

V

Inferior olive

Pyramid

Fig. 53.2. Diagram showing various distribution lateral medullary infarcts. D ⫽ dorsal; S ⫽ superficial; DV ⫽ dorsoventral; V ⫽ ventral. (Reprinted with permission from Caplan, L.R., 1996.)

moving vehicle. Less common is tilting or inversion of the visual environment. Ataxia is also a very common symptom. It can relate to involvement of the vestibular nuclei, the inferior cerebellar peduncle, or the cerebellum itself. Patients describe tilting, veering, or falling to one side when they sit or attempt to stand. Some speak of pulling or traction impelling them to the side. When walking, the pulling and veering sensations become more severe. Truncal imbalance is more prominent than limb ataxia in many patients. Some patients have great difficulty in feeding themselves using the ataxic arm. They overshoot targets and have difficulty pointing accurately to moving targets. On examination, the eyes usually rest in the midline but may drift conjugately to the side contralateral to the medullary lesion. The quick phase of nystagmus then returns the eyes towards the side of the lesion. Nystagmus is nearly always present in patients with lateral medullary

infarcts especially in patients who report dizziness or vertigo. The nystagmus usually has both horizontal and rotational components. The rapid phase of the rotatory nystagmus usually moves the upper border of the iris towards the side of the lesion. Most often, larger amplitude, slower nystagmus is present on gaze to the side of the lesion, while smaller amplitude quick nystagmus is found on gaze directed to the contralateral side. The direction of the nystagmus and ocular drift depend on the rostralcaudal location of the lesion, and which vestibular nuclei are involved (Morrow & Sharpe, 1988). Ocular torsion is also often present; the ipsilateral eye and ear rest in a down position below the contralateral eye and ear (Morrow & Sharpe, 1988). At times, ocular torsion is accompanied by a head tilt and skew deviation with the ipsilateral eye positioned downwards. This combination of findings is referred to as the ocular tilt reaction (Keane, 1992; Dieterich & Brandt, 1992, 1993; Brandt & Dieterich, 1993,

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1994). Deviation of the perception of the visual–vertical axis is even more common than the full ocular tilt reaction. The ocular tilt reaction and pathological tilts of the subjective visual–vertical axis reflect vestibular dysfunction in the roll plane, a prominent manifestation of ischemia in the dorsolateral medulla (Dieterich & Brandt, 1992, 1993; Brandt & Dieterich, 1993). A much rarer oculomotor abnormality is ocular lateropulsion, a strong forced conjugate deviation of the eyes to one side (Kommerell & Hoyt, 1973; Meyer et al., 1980). Ocular lateropulsion and the ocular tilt reaction both correlate with body lateropulsion, that is a feeling that the body is being pulled, usually to the ipsilateral side (Brandt & Dieterich, 1994). Patients with lateral medullary infarcts initially often have difficulty sitting upright without support. They topple, lean, or veer to the ipsilateral side when they sit or stand. In many patients, standing or walking may be impossible during the acute period and several helpers may be needed to support patients in the erect position. When they become able to walk, patients often feel as if they are being pulled to the side of the lesion. They veer, list, or weave to the side especially on turns. Some patients veer to the contralateral side. These patients accommodate to the magnetic feeling pulling them ipsilaterally by leaning or weighting themselves to the contralateral side to balance the gravitational pull. Truncal titubaton is not common and the limbs usually do not show a cerebellar type rhythmic intention tremor. Hypotonia of the ipsilateral arm can, however, be shown by having the patient quickly lower or raise the outstretched hands together, braking the ascent and descent suddenly. The arm on the ipsilateral side often overshoots and is not as quickly braked. In some patients, the ipsilateral arm also makes a slower ascent or descent to facilitate braking. Sensory symptoms and signs are also very important and frequent in patients with lateral medullary ischemia. The most frequent location of symptoms is the ipsilateral face. Pain or dysesthetic feelings in the face are sometimes the earliest and most prominent feature of the lateral medullary syndrome and are diagnostic of a lateral tegmental brainstem localization. The facial pain in lateral medullary ischemia is usually described as sharp jolts or stabs of pain most often in the ipsilateral eye or face. Sometimes the pain persists and is limited to the forehead and frontal scalp region, in which case patients often refer to the abnormal sensation as a headache. At times, the abnormal sensation is described in thermal terms as hot, burning, or scalding. The facial pain in patients with lateral medullary ischemia is probably due to involvement of sensory neurones within the nucleus of the spinal tract of

V (Fisher, 1972). Numbness or loss of feeling in the face may follow improvement of the pain. Although loss of pain and thermal sensation involving the contralateral body and limbs is usually found on examination, most patients with contralateral hypalgesia are unaware of their sensory loss until they are tested. Some notice loss of thermal sensation when they touch hot or cold objects. They then realize that they cannot tell the temperature of objects with their contralateral upper and/or lower limbs. After sensory testing, nearly all patients become quite aware of the contralateral abnormal sensory function. Examination usually shows a decrease in pain and temperature sensation in the ipsilateral face. Touch sensation is usually preserved although patients often report that the tactile stimulus feels different from that on the contralateral face and the ipsilateral trunk. The corneal reflex is usually reduced in the ipsilateral eye, and the corneal stimulus also fails to evoke a contralateral blink. Examination of the trunk and limbs also shows a loss of pain and temperature sensation on the opposite side of the trunk and contralateral limbs with preservation of touch, position and vibration sense. Usually the loss of thermal sensibility is severe. Initially, the contralateral hypalgesia can extend to the jaw but a sensory level may be present on the thorax or abdomen (Soffin et al., 1968). Pain and temperature sensibility may be normal in the arm. Sensory levels may appear during recovery. Occasionally trunk dysesthesiae can be confused with angina pectoris The most common pattern of sensory abnormality is loss of pain and temperature sensation in the ipsilateral face and the contralateral trunk and limbs. This pattern is due to involvement of the spinal tract of V and the crossed lateral spino-thalamic tract. The next most frequent combination is hypalgesia in the ipsilateral face and contralateral face, trunk, and limbs. This pattern of sensory loss is due to the added involvement of the crossed quintothalamic tract which appends on the medial aspect of the spinothalamic tract and carries pain and temperature sensibility fron the contralateral face. In these patients, pain and temperature sensation is reduced on both sides of the face. Although both sides of the face are hypalgesic, patients note that the two sides of the face feel different and that they are more aware of the ipsilateral facial abnormal sensation. Less often, the hypalgesia can be solely contralateral involving the face, arm, and leg or sometimes only the face and arm (Matsumoto et al., 1988). This pattern is due to involvement of the crossed quintothalamic tract and the adjacent spino-thalamic tract with sparing of the spinal tract and nucleus of V. These lesions are usually deep and more ventral than most lateral

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Fig. 53.3. Distribution and localization of pain fibres in the medulla. On the left is a cartoon of the left half of the medulla. Hashed lines point to the location of the lateral spino-thalamic tract and the spinal trigeminal tract and nucleus. The letters S ⫽ sacral, L ⫽ lumbar, T ⫽ thoracic, C ⫽ cervical, and V ⫽ ventral trigeminothalamic tract show the posited location of pain and temperature fibres subserving these body portions within the spinothalamic tract. The cartoons on the right show the patterns of loss of pain and temperature loss found in patients with lesions involving the areas A and B on the cartoon to the left. (Reprinted with permission from Caplan, 1996.)

medullary infarcts. The most lateral and superficial portions of the spinothalamic tract subserving the lower extremity and trunk may be spared (Matsumoto et al., 1988). The least common pattern of sensory loss is hypalgesia only involving the contralateral trunk, arm and leg or parts therof. Figure 53.3 from Matsumoto et al., 1988 shows diagrammatically the anatomical basis for the patterns of involvement of the somatosensory tracts in the lateral medulla. The ipsilateral eye often shows features of Horner’s syndrome. The descending sympathetic nervous system fibres that course through the lateral reticular substance are affected in most patients with lateral medullary infarcts. Usually the resultant Horner’s syndrome is incomplete. Ptosis is the most frquent component; the upper eyelid is usually only slightly drooped but the lower lid is elevated, thus narrowing the palpebral fissure from above and below. The ipsilateral pupil is usually constricted and is smaller than the contralateral pupil but retains normal reactivity to light. Weakness of bulbar muscles innervated by the lower cranial nerves is a very prominent feature in patients whose lateral medullary infarcts extend medially. Involvement of the nucleus ambiguus causes paralysis of the ipsilateral

palate, pharynx and larynx resulting in hoarseness and dysphagia. The paralysis of the muscles of the oropharynx results in food being trapped in the piriform recess of the pharynx. Food and secretions have relatively free access into the air passages. Patients try to extricate the food with a cough or throat-clearing manoeuvre which makes a characteristic crowing-like sound, probably because of the associated laryngeal weakness. Examination shows paralysis of the ipsilateral vocal cord and a lack of elevation of the ipsilateral palate on phonation. The uvula often deviates to the contralateral side. Dysarthria and dysphonia are common. The abnormal sound of the spoken voice is probably best explained by the laryngeal, palatal, and pharyngeal weakness and phonation through retained pharyngeal secretions. Consonants, syllables, and words are not usually slurred or dysrythmic. In some patients dysphagia and aspiration are prominent. Aspiration and pneumonia are very important complications of abnormal pharyngeal function. Usually the abnormality is unilateral. Some patients are able to swallow using the contralateral pharynx. Hiccoughs are also a relatively common and annoying complaint. The mechanism of hiccoughs is not clear. It may relate to ischemia of the dorsal motor nucleus of the

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vagus or the nucleus of the solitary tract, which are located beneath the lateral part of the floor of the IVth ventricle in the dorsal medulla medial to the vestibular nuclei. Headache is a frequent symptom and can precede brain ischemia. Most often the headache is located in the ipsilateral occipital or mastoid regions and may be steady and aching or pulsatile. Headache is most often centered below the external occipital protuberance and radiates to the back of the head and neck usually close to the midline. Occasionally, discomfort is also felt in the shoulder. This type of headache is identical to that described by patients with ECVA dissections who do not have brain ischemia and is most likely related to the arterial pathology, occlusion of the ICVA, rather than to brainstem ischemia. Headache may be caused by dilatation of the ICVA or by distention of collateral vessels. Nausea and vomiting are often present. These symptoms are usually explained by the accompanying vertigo or involvement of a putative vomiting center in the medulla located near the floor of the IVth ventricle adjacent to the nucleus ambiguus and the tractus solitarius. Respiratory dysfunction is an important and often neglected feature of lateral medullary ischemia. Control of inspiration and expiration and their automaticity lies within the ventrolateral medullary tegmentum and the medullary reticular zone. The nucleus of the tractus solitarius also is an important component and is probably the major afferent input to the control centres. The most common abnormality described in patients with lateral tegmental caudal brainstem lesions is failure of automatic respirations, a phenomenon especially apparent during sleep. This failure to initiate respiration has been referred to as Ondine’s curse because it dooms sufferers to eternally remain awake and vigilant in order to breathe; the alternative is death due to nocturnal apnea. Although most patients with Ondine’s curse have bilateral medullary and/or pontine lateral tegmental lesions some have only unilateral medullary infarcts. (Devereux et al., 1973; Levin & Margolis, 1977; Bogousslavsky et al., 1990). Other autonomic functions are also occasionally affected. Abnormalities of sweating, thermal regulation, and vasomotor control are occasionally present. Cardiovascular abnormalities include tachycardia, orthostatic hypotension without cardiac rate acceleration, and intermittent bradycardia (Caplan, 1996). Gastrointestinal autonomic dysfunction includes decreased esophageal motility, gastroesophageal reflux, and gastric retention. Vomiting could relate to altered gastrointestinal motility. Some patients have labile blood pressures, tachycardia, unusual sweating, and arrythmias.

Medial medullary infarction The most consistent finding in patients with medial medullary ischemia is a contralateral hemiparesis. (Currier, 1969; Tyler et al., 1994; Ho & Meyer, 1981; Caplan 1996). Usually the hemiparesis is complete and flaccid at onset. Later, increased tone and spasticity develop. In about one-half of patients, the face is also involved. Facial involvement is probably best explained by caudal looping of supranuclear corticobulbar fibres that synapse at the facial nucleus. These fibres descend into the medulla before turning cranial to go to the nucleus of VII in the lower pons. Facial weakness, when it occurs, is usually slight and transient and rarely persists. The next most frequent signs relate to medial lemniscus ischemia. In some patients despite involvement of the medial lemniscus there are no clinical symptoms or signs referable to that structure. Some patients report paresthesias or less often dysesthesias in the contralateral lower limb and trunk. Less often, sensory symptoms occur in the arm and hand. In many patients with sensory symptoms there are no objective signs of touch, vibration, or position sense loss. Proprioceptive dysfunction with slight loss of position and vibration sense in the contralateral foot are found in some patients on examination. Severe loss of proprioception in the contralateral limbs has not been described in patients with infarction limited to the medial medulla or the medial pons. Ipsilateral tongue paralysis is the least common but most topographically localizing sign of medial medullary infarction. Tongue weakness is probably most often related to involvement of the intraparenchymal XIIth nerve fibres as they pass ventrally to exit at the medullary base rather than to infarction of the hypoglossal nucleus in the tegmentum. Tongue paresis causes slurring of speech especially of lingual consonants Although the caudal portions of the MLF and the medial portions of the inferior olivary nucleus are involved in patients with medial medullary infarction, no consistent clinical findings have been correlated with this neuropathology. The syndrome of the medial medulla consists of three main findings: contralateral hemiparesis, slight contralateral paresthesias and minor loss of posterior column sensory modalities, and ipsilateral tongue paresis.

Hemimedullary infarction Occasional patients have infarction that involves both the lateral and medial medullary territories on one side (Duffy & Jacobs, 1958; Hauw et al.,1976). The symptom complex is

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identical to that found in patients with lateral medullary ischemia with the addition of a hemiparesis contralateral to the lesion. The hemiparesis may develop concurrently with lateral medullary symptoms or signs or can occur later.

Cerebellar infarction in posterior inferior cerebellar artery (PICA) distribution PICA cerebellar infarcts can be divided into: (i) infarction in the territory of the medial branch of PICA (mPICA) affecting mostly the inferior cerebellar vermis, (ii) infarction limited to the lateral branch of PICA (lPICA) affecting mostly the lateral surface of the posterior inferior cerebellar hemisphere, and (iii) full PICA territory infarcts involving both the mPICA and lPICA territories. Full PICA territory infarcts are often accompanied by edema formation and mass effect – so-called pseudotumoral cerebellar infarcts. About one-fifth of PICA territory cerebellar infarcts are accompanied by infarction in the dorsal or dorsolateral medulla (Caplan, 1996). The combination of lateral medullary and PICA cerebellar infarction occurs when the ICVA is occluded and blocks the orifice of both PICA and the lateral medullary penetrators. PICA usually originates more caudally but in some patients these branches arise near each other. Most often mPICA territory infarcts are accompanied by dorsal medullary infarcts since the mPICA branch has some supply to the dorsal medulla (Amarenco & Hauw, 1989; Amarenco et al., 1989; Caplan, 1996). Infarcts in the cerebellum limited to lPICA distribution rarely are accompanied by medullary infarction (Amarenco et al., 1989). Infarcts limited to the medial vermis in the territory of mPICA usually cause a vertiginous labyrithian syndrome that closely mimics a peripheral vestibulopathy (Duncan et al., 1975; Amarenco et al.,1990a,b). Severe vertigo with prominent nystagmus are the major findings. Some patients also have truncal lateropulsion characterized by feelings of magnetic pulling of the trunk to the ipsilateral side. Ocular lateropulsion may also be present. Lateral cerebellar hemisphere PICA territory infarcts are usually characterized by minor degrees of dizziness and gait incoordination with veering to the side of the lesion. Minor limb hypotonia and incoordination are found. A common syndrome is acute unsteadiness with ataxia but without vertigo or dysarthria (Barth et al.,1994). Body sway towards the side of the lesion, ipsilateral limb ataxia, and abnormal rapid alternating movements are also common. Usually the symptoms regress within a month. When the full PICA cerebellar territory is involved head-

ache is usually present in the occiput or high neck on the ipsilateral side. The head may also be tilted with the occiput tending ipsilaterally. Vomiting, gait ataxia, truncal lateropulsion, and limb incoordination are other common findings. The truncal dysfunction is similar to that found in the lateral medullary syndrome; the body is often tilted or pulled ipsilaterally upon sitting or standing. The limb incoordination consists mostly of hypotonia rather than a rhythmic intention tremor as would be found in involvement of the dentate nucleus or its superior cerebellar peduncle efferent pathways. The syndrome of pseudotumoural cerebellar infarction is most often found after large full PICA territory infarcts. After the first day or so, patients develop increased headache, vomiting, and decreased consciousness. At first they become drowsy and later stuporous. Bilateral Babinski signs are an early sign of cerebellar mass effect. Most characteristic of large cerebellar space-taking infarcts are the oculomotor abnormalities which develop. Most common are a conjugate gaze paresis to the side of the lesion or a paresis of abduction limited to the ipsilateral eye. Bilateral VIth nerve paresis may occur. Later bilateral horizontal gaze palsies may develop often accompanied by ocular bobbing. These signs are due to compression of the pontine tegmentum by the swollen cerebellar infarct. Stupor is followed by deep coma when the oculomotor abnormalities become bilateral. Once coma has developed the mortality rate is extremely high. Neuroimaging tests help confirm compression of the posterior fossa cisterns and the IVth ventricle and the development of hydrocephalus.

Vascular lesions and stroke mechanisms in patients with proximal intracranial territory infarction Lateral medullary infarcts are most often explained by intrinsic disease, atherosclerotic stenosis frequently with superimposed thrombosis or arterial dissection of the distal ECVA or the ICVA (Caplan, 1996; Mueller-Kuypers et al.,1997; Graf et al., 1997). Less often cardiogenic or artery-to-artery emboli usually from the ECVA explain lateral medullary infarction. Most often ischemia in the medial medullary base has accompanied lateral medullary ischemia (hemimedullary infarction) and is caused by occlusions of the ipsilateral ICVA (Caplan, 1996; Escourolle et al., 1976). In some patients ischemia involves the medial medulla bilaterally; in these cases the vascular lesion has been either multiple embolic obstructions of ASA branches by cartilaginous or microcrystalline particles derived from drugs made for

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oral consumption that were injected into the vascular system, or presumed occlusion of a dominant ASA branch of one ICVA (Caplan, 1996). Unilateral medial medullary infarction also results from atheromatous branch disease or the vascular pathology within penetrating ASA branches that underlies lacunar infarction in which case the infarct is usually limited to one medullary pyramid (Ho & Meyer, 1981; Caplan, 1996). The most common cause of PICA territory cerebellar infarction is embolism to the ICVA from the heart or the proximal ECVA (Amarenco et al., 1990a,b, 1994; Graf et al., 1997; Caplan, 1996). Less often occlusion of the ICVA is due to in situ atherosclerosis with superimposed thrombosis. PICA branch territory infarcts are almost always embolic, the source being the heart, aorta, or ECVA (Caplan, 1996).

Middle intracranial territory Pontine ischemia due to basilar artery disease Most patients with basilar artery occlusive disease have motor symptoms and signs. The corticospinal tracts in the basis pontis are among the most frequently involved structures. Most patients with symptomatic basilar artery occlusive disease and pontine ischemia have some transient or persistent degree of paresis and corticospinal tract abnormalities (LaBauge et al.,1981; Caplan,1996). Fisher (1988) noted that the initial motor weakness was often lateralized; he referred to this phenomenon as the ‘herald hemiparesis’ of basilar artery occlusion. Ferbert et al. (1990) in a series of 85 patients with basilar artery occlusion noted that hemiparesis was common initially and Kubik and Adams (1946) in a necropsy study noted that paralysis was often more severe on one side and infarction in the basis pontis was also more severe or was limited to one side. Hemiparetic patients with basilar artery occlusion almost always show some motor or reflex abnormalities on the non-hemiparetic side. The abnormality consists of slight weakness, hyperreflexia, or an extensor plantar reflex or abnormal spontaneous movements such as shivering, twitching, shaking or jerking on the relatively spared side. Asymmetry but bilaterality is the rule. Figure 53.4 shows a symmetric bilateral basis pontis infarct in a patient with quadriparesis caused by basilar artery occlusion. Limb adventitious movements are occasionally seen and can be a prominent feature in patients with pontine ischemia. The movements are variable and can include fasciculation-like small movements as well as larger motions such as shivering, shuddering, jerking, or a tremulous like intermittent shaking motion. These movements can be inter-

mittent. Sometimes movement of the limbs or painful stimuli can precipitate a flurry of abnormal movements. At times there are large repetitive jerking and twitching movements especially in limbs contralateral to a hemiparesis (Ropper,1988). Clonic movements tend to occur while the limbs are in extention and are generally of smaller amplitude than those observed in the clonic phase of epileptic seizures (Ropper,1988). Retention of consciousness and the variability of the movements are evidence against an epileptic mechanism. The abnormal movements probably indicate an unstable motor system and are caused by ischemia of neurons and tracts in the basis pontis. Some extensor movements are probably fragments of decerebrate responses. Decerebrate rigidity and stiffness of the limbs are also common findings in patients with bilateral basis pontis infarcts and reflect involvement of descending tracts to the spinal cord. Limb adventitious movements are seldom observed after the acute phase of pontine infarction. Ataxia or incoordination of limb movements is another common motor finding. Ataxia is invariably combined with some degree of paresis and it is always difficult to know how much of the incoordination is explained by weakness. The incoordination is usually more severe in the legs. Toe-to-object and heel-to-shin testing usually shows a rhythmic ‘cerebellar’ type component to the dysfunction. The incoordination is most likely explained by ischemia of the cortico-ponto-cerebellar fibres that cross the basis pontis to enter the cerebellum. In some patients, the brachium pontis, supplied by the AICAs, may be ischemic. The ataxia is invariably bilateral but may be asymmetric and more severe in the weaker limbs. Intention tremor is not common. Weakness of bulbar muscles is very common and is an important cause of morbidity and mortality. The face, pharynx, larynx, and tongue are most often involved. The pattern may be that of crossed motor loss, e.g. one side of the face and the contralateral body but, more often the bulbar muscle weakness is bilateral. Crossed signs are usually due to hemipontine infarcts that involve the tegmentum and base or are restricted to the base. The unilateral cranial nerve motor weakness is explained by involvement of the cranial nerve nuclei in the tegmentum or their exiting intraparenchymatous nerve fibres as they traverse the base of the pons. The bilateral involvement is usually due to involvement of corticobulbar fibres in the dorsal part of the basis pontis near the central tegmental tracts. Bulbar symptoms include facial weakness, dysphonia, dysarthria, dysphagia, and limited jaw movements. Some patients become totally unable to speak, open their

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Fig. 53.4. Myelin-stained section of the midpons showing a large infarct limited to the paramedian portions of the basis pontis in a patient with basilar artery occlusion. (Reprinted with permission from Caplan, L.R., 1996.)

mouth, protrude their tongue, swallow, or move their face at will or on command. Secretions pool in the pharynx and aspiration is an important and serious complication. In some patients there is a disparity between the ability of the patient to move the muscles of the jaw, face, and tongue voluntarily and on command, and movements generated by emotional stimuli or reflex stimulation. Patients with ventral pontine infarcts frequently have exaggerated crying and laughing spells and are hypersensitive to emotional stimulus. These so-called pseudobulbar release phenomena occur in patients in whom clinically the involvement is mostly unilateral as well as those with definite bilateral signs. Despite the inability to voluntarily move the muscles, the jaw, face, and pharyngeal reflexes may be exaggerated and clonic jaw movements or clamping down on a tongue blade may occur as a response to attempts to pry the mouth open and to insert a tongue blade. The most severe motor paralysis characterized by loss of all voluntary movement other than the eyes, when consciousness is retained, is now usually referred to as the

‘locked-in syndrome’ (Nordgren et al.,1971; Caplan,1996). Some patients remain in the ‘locked-in’ state for years. These patients may be able to signal with eye blinks and jaw and other retained movements and to obtain quite high-level communication skills including triggering Morse code using eye and jaw movements. Some patients with pontine ischemia develop palatal myoclonus. Palatal myoclonus is a rhythmic involuntary jerking movement of the soft palate and pharyngopalatine arch which can involve the diaphragm and larynx (Tahmoush et al., 1972; Caplan,1996). This movement disorder usually begins sometimes after the brainstem infarct. The movements of the palate vary in rate between 40 to 200 beats per minute. The movements are readily seen by watching the palate and pharynx when the mouth is open. The movements involve the eustachian tube and make a click that the patient hears. The noise can also be heard by the examiner if a stethoscope is placed on the neck just below the ramus of the mandible. The palatal movement is often associated with an audible voice tremor and fluttering of the diaphragm. Surprisingly, palatal

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myoclonus seldom interferes with swallowing. The posited anatomical lesion usually involves the ‘Guillain–Mollaret triangle’ which includes the dentate nucleus of the cerebellum, the red nucleus in the midbrain, and the inferior olivary nucleus in the medulla and their interconnections (Lapresle & Ben Hamida,1970). At necropsy the commonest lesion found in patients who had palatal myoclonus during life is hypertrophic degeneration of the inferior olive often accompanied by a lesion of the ipsilateral central tegmental tract or the contralateral dentate nucleus. The dentate nucleus and the contralateral inferior olive are somatotopically interrelated. Fibres from the dentate nucleus on one side travel in the brachium conjunctivum and cross in the midline to end in the contralateral red nucleus in the midbrain. The central tegmental tract descends from the red nucleus to the ipsilateral inferior olivary nucleus in the medulla. The central tegmental tract is probably the structure most often involved in pontine infarctions that lead to palatal myoclonus Oculomotor symptoms and signs are common. Few patients with pontine infarction due to basilar artery occlusive disease have completely normal eye movements. Very often recognition and identification of the presence and nature of the eye movement abnormalities localizes the lesion to the pons and, often, to a specific location within the pons.

Conjugate horizontal gaze and VIth nerve palsies Fibres from the cerebral hemisphere frontal eye fields that relate to voluntary horizontal conjugate gaze directed towards the contralateral side descend in the internal capsule and cross in the pons at or near the level of the abducens nuclei. These fibres end in the reticular grey region of the pontine tegmentum near the contralateral abducens nucleus, a region usually called the paramedian pontine reticular formation (PPRF), an area also referred to as the pontine lateral gaze centre. Damage to the abducens nucleus itself probably causes a conjugate horizontal gaze palsy to the ipsilateral side for all lateral eye movements both voluntary and induced by caloric and oculovestibular stimulation (Pierrot-Deseilligny et al., 1981). When the fascicles of the abducens nerve are involved within or outside the pons and not the Vlth nerve nucleus, then the eye movement abnormality is limited to inability to abduct the eye ipsilaterally, a traditional VIth nerve palsy (PierrotDeseilligny et al., 1981; Bronstein et al., 1990a). When only the PPRF is involved, and the more medially placed abducens nucleus is spared, the resulting abnormality is an inability to voluntarily look to the ipsilateral side with preservation of reflex-induced (caloric and oculovestibular) conjugate gaze. (Pierrot-Deseilligny et al.,

1981). The PPRF also mediates ipsilaterally directed saccades within the contralateral hemifield of eye movement. Bilateral lesions of the paramedian pontine tegmentum including the VIth nerve nuclei and the PPRF on both sides cause a complete paralysis of voluntary and reflex eye movements with sparing of vertical gaze which is mediated more rostrally. Patients with horizontal conjugate gaze palsies may, however, have limitation of voluntary up gaze and slowing of vertical saccades. When the basis pontis is infarcted bilaterally and the tegmentum is spared, voluntary conjugate horizontal eye movements may be entirely absent but oculocephalic and caloric stimulation induce full horizontal eye movements. In patients with bilateral horizontal gaze palsies, bilateral medial tegmental pontine lesions are usually found but sometimes the lesions are mostly unilateral but include both MLFs and the pontine tegmental raphe ventral to the MLFs in the midline (Bronstein et al., 1990b).

Internuclear ophthalmoplegia (INO) Ischemic damage to the medial longitudinal fasciculus (MLF) on one side causes an inability to adduct the ipsilateral eye to the contralateral side on conjugate gaze. The abducting eye can move laterally but shows prominent nystagmus. Vertical nystagmus and skew deviation of the eyes often accompanies INOs. In most patients with an INO, the eyes are in a normal conjugate position of gaze at rest but, in some patients, the ipsilateral eye is outwardly deviated, an exotropia. When the INO is bilateral, both eyes may rest in an outwardly deviated rest position Fisher (1967) used the term one-and-a-half syndrome to describe ‘paralysis of eye movement in which one eye lies centrally and fails completely to move horizontally while the other eye lies in an abducted position and cannot be adducted past the midline’. Fisher counted gaze to each side as worth a score of 1, so that normal full gaze to each side would give a score of 2. If the only preserved gaze was with one eye to one side, this would give a score for gaze of 1/2 meaning that 1 1/2 gaze was lost. A unilateral pontine tegmental lesion that includes the PPRF and MLF on the same side causes this syndrome. Lesions of the right PPRF (and/or the abducens nucleus) causes loss of conjugate gaze of each eye on attempted right lateral gaze; the lesion of the nearby right MLF causes additional loss of function so that the right eye does not adduct on attempted gaze to the left. The only preserved eye movement in this example is abduction of the left eye on left lateral gaze which is accompanied by nystagmus of the left eye as it abducts. The one-and-a-half syndrome has also been referred to as ‘paralytic pontine exotropia’ (Sharpe et al. 1974). Fisher (1964, 1967) also introduced the term ‘ocular

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bobbing’ into clinical neurological terminology. He used the term to describe a characteristic vertical motion of the eyes, ‘The eyeballs intermittently dip briskly downwards through an arc of a few millimetres and then return to the primary position in a kind of bobbing action. (Fisher, 1964).’ Bobbing can be bilateral and symmetric or can be predominantly unilateral or asymmetric. Asymmetric bobbing is common in patients with cerebellar lesions and in those in whom there is an asymmetric paralysis of either conjugate gaze or ocular abduction. When bobbing is asymmetric, usually the eye ipsilateral to the side of limited gaze bobs when gaze is directed to that side. Horizontal, gaze paretic nystagmus is common and, when asymmetric, is usually more prominent when gaze is directed to the side of a unilateral pontine tegmental lesion. Dissociated nystagmus, that is nystagmus that is more severe in one eye and not rhythmically concordant in the two eyes, is found in patients with an INO. Nystagmus is usually limited to the eye contralateral to the MLF lesion on gaze to the contralateral side. Vertical nystagmus is common in patients with pontine lesions who have an INO. Rhythmic vertical nystagmus does not occur with rostral brainstem infarcts but is common in patients with lesions at pontine levels (Fisher,1967). Ptosis of the upper eyelids is a very frequent abnormality in patients with pontine infarction. Ptosis in patients with pontine lesions has traditionally been explained by involvement of descending sympathetic fibres that traverse the lateral tegmentum of the pons. However, even in patients with bilateral severe ptosis, the pupils may remain normal-sized and not show the miosis expected with sympathetic dysfunction (Fisher,1967; Caplan,1974). ‘Pontine ptosis’ is usually more severe than that usually found in patients with Horner’s syndrome due to a peripheral sympathetic lesion or a lateral medullary infarct. Lid position is affected by hemiparesis; ptosis can be more or less severe on the hemiparetic side (Caplan,1974). In patients with asymmetric pontine lesions, ptosis is usually more severe on the hemiparetic side. Oblique positioning of one eye above the other with maintenance of the same relative positioning of the eyes in all fields of gaze is referred to as skew deviation. Skew deviation is ocular divergence in the vertical plane. In patients with lesions limited to the pons, skew deviation is usually accompanied by an INO, and an ipsiversive tilt with the ipsilateral eye and ear undermost (Dieterich & Brandt,1993; Brandt & Dieterich, 1994). There may also be an ocular tilt reaction and ocular torsion. The fibres that relate to the vestibulo-ocular reflex in the roll plane course in or near the MLF and go rostrally to the interstitial nucleus of Cajal and the rostral interstitial nucleus of the

MLF (Dieterich & Brandt, 1993). In most patients with caudal pontine lesions, the ipsilateral eye rests below the contralateral eye, as it does in patients with lateral medullary infarcts. The pupils may remain normal or become small in patients with pontine infarcts. In some patients, especially those in coma from large lesions, the pupils are often bilaterally very small (‘pinpoint’). Use of a magnifying glass can show that, despite their very small size, the pupillary response to light is preserved, although the amplitude of the response is slight. The pupillary reflex arc involves more rostral structures that traverse the upper midbrain–diencephalic region. When infarction in the midbrain at the level of the Edinger–Westphal nucleus accompanies pontine infarction, the pupils are usually midposition and fixed to light reaction. Somatosensory abnormalities are not prominent in patients with basilar artery occlusions. Paresthesias on one side of the body and limbs reflects involvement of the contralateral medial lemniscus in the paramedian dorsal portion of the basis pontis. Bilateral paramedian lesions that include the medial lemnisci on both sides can cause bilateral paresthesias. Usually proprioceptive loss is minimal or absent in these patients despite the unilateral or bilateral paresthesias. The far laterally placed spinothalamic tracts usually escape ischemia in patients with basilar artery occlusion. In the rostral pons, the fibres subserving proprioceptive function and the spinothalamic fibres have moved more dorsally and are not usually included in the region of infarction in patients with basilar artery occlusions, since the lesions are more basal and paramedian. Some patients with basilar artery occlusive disease have unusual burning pain in the face usually located in the centre of the face near the midline. The pain may be intermittent and has been likened to having ‘salt and pepper thrown in the face’. (Caplan & Gorelick, 1983). The posited explanation for the pain is involvement of the crossing quinto-thalamic fibres which originate from the nucleus of the spinal tract of V and cross in the midline on their way to be appended medially to the contralateral spinothalamic tracts in the ventrolateral tegmental regions on each side. The explanation for the commonly ocurring perioral paresthesias are not clear. The touch fibres from the main sensory nucleus of V also must cross somewhere in the midline to reach the contralateral sensory lemniscus during their course to the contralateral ventral posterior median (VPM) thalamic nucleus. The spinal tracts and nuclei of V are placed quite dorsally and laterally in the pontine tegmentum and most often are spared in patients with basilar artery occlusions.

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Tinnitus and hearing loss do occur in patients with basilar artery disease and relate to involvement of the central auditory tracts and nuclei (auditory nuclei, lateral lemnisci, trapezoid bodies, inferior colliculi) or to ischemia of the VIIIth nerves or the cochlea. Basilar artery occlusive disease may reduce blood flow to the AICAs, which give off internal auditory artery branches that supply the peripheral inner ear structures and the VIIIth nerves. Sudden unilateral or bilateral deafness can be an important sign of basilar artery occlusive disease but is not very common (Huang et al., 1993). Auditory hallucinations such as hearing a sound like a freight train, seashell, buzzing bees, bells chiming, and organ notes have been described in patients with pontine tegmental lesions usually associated with hearing loss and tinnitus (Cascino & Adams,1986). Alteration in the level of consciousness has long been recognized as an important sign in patients with basilar artery occlusion. An alteration in the level of consciousness was the most common finding during the acute phase among 282 patients with basilar artery occlusion in the review of LaBauge et al. (1981). The reticular activating system that relates to consciousness is located in the paramedian tegmentum of the pons and midbrain on its way to the intralaminar thalamic nuclei (Pappas & Carrion, 1989). Lesions of the medial tegmentum interrupt the reticular activating system, but preservation of one side is enough to cause retention of consciousness. The traditional teaching is that coma in patients with pontine lesions is always accompanied by bilateral eye movement abnormalities, often loss of horizontal gaze. I have, however, seen several patients with retained alertness despite the absence of voluntary horizontal gaze eye movements. This occurrence is explained by the MRI findings of Bronstein et al. (1990b), who showed that some patients with bilateral horizontal gaze abnormalities had involvement of the pontine tegmentum on one side affecting the MLF, PPRF and/or the abducens nucleus with spread to just beyond the midline affecting the contralateral MLF and the midline pontine tegmental raphe but sparing the contralateral lateral gaze centres in the pons. This combination of pontine tegmental raphe and unilateral tegmental lesions can cause bilateral abnormalities of lateral gaze. Sparing of the reticular activating system neurons in the medial tegmentum on one side in these patients accounts for retained alertness.

Anterior inferior cerebellar artery territory infarction The anterior inferior cerebellar arteries (AICAs) are the most variable of the long circumferential cerebellar arteries and they have the smallest zone of supply within the

cerebellum. The AICAs always supply the lateral pontine tegmentum, the brachium pontis, and the flocculus. (Amarenco et al., 1993; Caplan,1996) Figure 53.5 is an MRI that illustrates a unilateral AICA territory infarct involving the basis pontis and brachium pontis. When infarction is limited to unilateral AICA territory, as in the patient whose MRI is shown in Fig. 53.5, the clinical findings are identical to those found in patients with lateral medullary infarcts except that VIIth and VIIIth nerve findings are present rather than symptoms and signs related to Xth nerve (nucleus ambiguus) dysfunction (Adams,1943; Amarenco & Hauw, 1990a). The lesion may involve the facial, vestibular and cochlear nuclei or may affect the VIIth nerve fibres within the lateral tegmentum and base, or affect the VIIIth nerve peripheral fibres or the cochlea and vestibule. Occasionally, there may be accompanying weakness of the contralateral limbs and an extensor plantar sign when the infarct extends to the pontine base as it does in Fig. 53.5. The internal auditory artery is most often a branch of AICA. In some patients, especially diabetics, ischemia of the inner ear structures supplied by the internal auditory artery can herald a full AICA territory infarct (Oas & Baloh, 1992). Tinnitus, hearing loss and vertigo are the most common symptoms related to inner ear ischemia. Amarenco et al. (1993) reported nine patients with AICA territory infarcts identified by MRI. The patients could be clearly divided into two groups: those with infarcts limited to the territory of AICA on one side, and those with infarcts that involved bilateral AICA territory or unilateral AICA territory⫹other brainstem and cerebellar vascular supply territories (AICA⫹infarcts).

Vascular lesions and stroke mechanisms in patients with middle intracranial territory ischemia When pontine ischemia is bilateral, the causative vascular lesion is almost always an intrinsic lesion within the basilar artery – most often atherostenosis with or without superimposed thrombosis. Figure 53.6, a drawing patterned after Kubik and Adams (1946), shows the distribution of infarction in a patient with a long basilar artery occlusion. The paramedian pontine base and tegmentum are infarcted, but the medulla and midbrain are spared. Dissection of the basilar artery can produce a similar syndrome. Sometimes thrombosis begins in one distal ICVA and extends into the basilar artery or the occlusion involves a basilarized ICVA, the contralateral ICVA being hypoplastic or ends in PICA (Caplan, 1996). Bilateral distal ICVA occlusions rarely cause infarction limited to the middle intracranial posterior circulation territory (Caplan,

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1996; Shin et al., 1999). When infarction is limited to the territory of one AICA, the cause is almost always atheromatous branch disease (Amarenco et al., 1993; Caplan,1996). When there is AICA⫹infarction, then basilar artery or bilateral ICVA occlusions are usually present.

Distal intracranial territory Rostral brainstem ischemia as part of the ‘top-of-thebasilar’ syndrome. Occlusion of the rostral portion of the basilar artery can cause ischemia of the midbrain and thalami as well as the temporal and occipital lobe cerebral hemispheral territories supplied by the PCAs. Figure 53.7 is a CT scan that shows bilateral PCA territory occipital lobe infarcts and infarction in the right thalamus in a patient with a top-ofthe-basilar embolus. In many patients infarction is limited to either brainstem or hemispheral structures. Figure 53.8 shows a bilateral PCA territory infarction due to embolism. The major abnormalities associated with rostral brainstem infarction relate to abnormalities of alertness, behavior, memory, and oculomotor and pupillary functions. The most common abnormalities of eye position and movement involve vertical gaze and convergence. (Caplan, 1980, 1996; Mehler, 1988) Voluntary eye movements in the vertical plane are generated by simultaneous activation of the cerebral hemispheral gaze centres. Vertical gaze pathways converge on the periaqueductal grey region just beneath the collicular plate and in the vicinity of the posterior commissure and the interstitial nucleus of Cajal (Buttner-Ennever et al. (1982). There is a cluster of neurons in this region located among the fibres of the MLF that are important in vertical gaze. These neurons are usually referred to as the rostral interstitial nucleus of the MLF or the nucleus of the prerubral field (Buttner-Ennever et al., 1982). Clinically, there is often a disparity between paralysis of voluntary vertical gaze and vertical eye movements induced by vertical oculo-cephalic manoeuvres, simultaneous caloric stimulation of both ear canals or Bell’s phenomenon. Some patients have a loss of all voluntary and reflex vertical eye movements. Reflex movements are sometimes preserved despite loss of voluntary vertical eye movements. The pathways that subserve up and down gaze are not identical. Either up gaze or down gaze can be selectively involved, but in most patients both directions of vertical gaze are involved together. Upgaze and vertical gaze palsies are more common than down gaze palsies (Buttner-Ennever et al.,1982; Caplan,1996). In experimental animals and humans, lesions in the pretectal region

Fig. 53.5. T2-weighted MRI showing an infarct in the distribution of the anterior cerebellar artery on one side. The black arrow points to the basis pontis portion of the infarct and the white arrow points to the brachium pontis portion of the infarct. (Reprinted with permission from Caplan, 1996.)

near the posterior commissure are necessary to produce upgaze palsies (Buttner-Ennever et al.,1982). The lesions that cause upgaze palsies are either bilateral, or unilateral but involve fibres in the posterior commissure. Oculomotor afferents that carry information for upgaze emanating from the rostral interstitial nucleus of the MLF and the interstitial nucleus of Cajal decussate from one side of the brain to the other in the posterior commissure explaining why posterior commissure lesions cause an upgaze palsy affecting both eyes. Lesions that cause selective downgaze palsies are rare and have all been bilateral and rostral to the oculomotor nuclei involving regions bordering on the dorsomedial portion of the red nuclei in the distribution of the thalamic–subthalamic arteries (Buttner-Ennever et al., 1982; Caplan, 1996). Monocular elevation palsies also occur, but are rarely reported; they may be ipsilateral or contralateral to the lesion (Hommel & Bogousslavsky, 1991). If the lesion affects the efferent upgaze fibres of the rostral interstitial

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Fig. 53.6. Artist’s drawing patterned after Kubik and Adams (1946) showing a basilar artery occlusion in the cartoon on the right. On the left are cartoons of the midbrain (a), rostral pons (b), caudal pons (c) and medulla (d ). The shaded areas show the distribution of infarction in the pons. (Reprinted with permission from Caplan, 2000.)

nucleus of the MLF just after leaving that nucleus and before the fibres decussate, the monocular elevation palsy will be ipsilateral. If the lesion involves fibres after the decussation but before reaching the oculomotor nucleus, the elevation palsy affects the contralateral eye (Hommel & Bogousslavsky, 1991). Vertical one-and-a-half syndromes also occur. This deficit consists of a bilateral upgaze palsy and monocular downgaze palsy or bilateral downgaze palsy and monocular upgaze palsy. The causative lesions are combinations of those that cause the vertical gaze palsies described. Asymmetric or unilateral lesions in the midbrain tegmentum and posterior thalami can cause ocular tilt reactions that are contraversive, that is, the contralateral eye and ear are down. The abnormalities include skew deviation, ocular torsion, and abnormal estimation of the visual vertical (Dieterich & Brandt, 1993; Brandt & Dieterich, 1994). At times, very small amplitude lightening-like movements occur spontaneously and on attempted horizontal and vertical gaze. Convergence abnormalities are also very common in

patients with rostral midbrain lesions. Usually one or both eyes are hyperconverged as if there was increased tone or overactivity of structures that subserve the coordination of bilateral ocular adduction that we call convergence. The hyperconvergence may be unilateral or bilateral so that one or both eyes may rest inward or down and inward at rest. On attempted upgaze, the eyes may show adductor contractions causing convergence movements. Asking patients to peer inward at the tip of their nose or at the examiner’s finger placed at a near fixation site often leads to a further increase in the convergence and may provoke some bilateral synchronous adductor movements of the eyes. Having the patient watch an upwardly directed optokinetic tape also stimulates convergence movements. Some call the bilateral convergence movements ‘retractory nystagmus’ but the movements are not true nystagmus and do not usually cause significant retraction of the globe although they superficially give that impression. The increased tone and activity of adductor movements is probably responsible for the so-called pseudosixth phenomenon. This term has been used to describe failure of full abduction on lateral gaze in patients with upper brainstem lesions and in the absence of a lesion that could affect the sixth nerve (Caplan, 1980). Pseudosixth palsy can be unilateral or bilateral. Close inspection of eye movements in the abducting eye shows that there are often inwarddirected small movements of the eye as it abducts. Often, the contralateral eye is hyperadducted. Covering the contralateral hyperadducted eye and asking the patient to look further laterally sometimes enables further abduction excursion of the open eye. Two different phenomena explain failure of ocular abduction in this syndrome: (i) dysconjugate gaze with fixation by the hyperadducted eye. When the patient looks laterally, they first fixate with the hyperadducted eye. This fixation will stop any further lateral eye movement since the patient has already fixated on the object with the adducted eye. Covering the hyperadducted eye then encourages fixation with the abducting eye; and (ii) convergence vectors counter and neutralize the lateral excursion of the eye. The sum of the laterally directed gaze vector and the inwardly directed convergence vector is less than full abduction. Retraction of the upper eyelid to widen the palpebral fissure has been called Collier’s sign when the abnormality is due to a rostral mesencephalic lesion near the level of the posterior commissure (Collier, 1927). In some patients both lids are retracted but one eye may have normal lid position or ptosis. Lesions in the rostral brainstem often affect the pupillary light reflex so that the pupils react slowly and incompletely, or not at all to light. The pupils are often small at rest in

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Fig. 53.7. CT scan showing a bilateral infarct involving the occipital lobes and the right temporal lobe and right thalamus. (Kindly submitted by L. Dana DeWitt, MD. Reprinted with permission from Caplan, 1996.)

patients with diencephalic lesions and may be fixed and dilated if the lesions involve the third nerve Edinger– Westphal nuclei. A combination of diencephalic and midbrain lesions cause midposition fixed pupils. In midbrain lesions, the pupil may become eccentric (‘corectopia’) (Caplan, 1980; Selhorst et al., 1976) or assume an oval position (Fisher, 1980). Eccentricity can be transient and fluctuate from minute to minute. Normally when an individual fixates on a very near object there is increased accommodation of the lens, convergence of the visual axes, and pupillary constriction. The reflex pathways and their coordination for these three functions is not well understood. Patients with rostral brainstem infarcts may have abnormalities of any of these three functions on attempted near gaze (Mehler,1988). Abnormalities of alertness and behaviour are common in patients with rostral brainstem infarcts. Lesions that include the reticular activating system in the rostral brainstem most often produce hypersomnolence rather than coma. The reticular activating system courses through the

tegmental regions on both sides of the sylvian aqueduct and the banks of the third ventricle. This region is perfused by the thalamic–subthalamic arteries (also called the thalamoperforating arteries) and the paramedian mesencephalic arteries that branch from the apex of the basilar artery and the initial portion of the basilar communicating artery (mesencephalic artery). Butterfly-shaped bilateral rostral mesencephalic periaqueductal lesions caused by top-of-the basilar artery embolism can cause both prolonged hypersomnolence and third nerve palsies (Facon et al., 1958; Castaigne et al., 1962). Apathy and inertia are also commonly found (Segarra, 1970). Some patients show very little spontaneity and activity. Abnormal reports and hallucinations probably relate to the altered sleep–wake dreaming cycle present in patients with rostral basilar artery territory infarction (Caplan, 1980). Reports often consist of replies to queries that have no relation to reality. The patient may mislocate themselves in place giving the names of far distant geographical locations, and in the personal time dimension,

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Fig. 53.8. Necropsy specimen showing a bilateral infarct involving predominantly the structures on the lower bank of the calcarine fissure – the lingual and fusiform gyri. The lesion on the right is more hemorrhagic. This patient had mitral stenosis and atrial fibrillation. (Reprinted with permission from Caplan, 2000.)

saying that they were presently performing activities that they only had done in their childhood, adolescence, or much earlier in their adult life. Some patients act as if they are performing an activity, for example, talking on the telephone when there is no phone nearby. These reports and behaviours probably represent patients saying and doing what they were daydreaming about at the time. Some may reflect nocturnal dreaming. The reticular activating system and the neural substrates that control the sleep-wake cycle, and dreaming are all intimately related. Clouding of the distinction between dreams and reality may underly some of the unusual reports and behaviours in patients with rostral brainstem infarction. So-called peduncular hallucinations have long been recognized and described in patients with rostral brainstem lesions. (Lhermitte, 1922; Van Bogaert, 1927) The term pedonculaire was used by the French to refer to the general region of the midbrain and not just the cerebral peduncle. Hallucinations also occur in patients with thalamic lesions. The hallucinations are predominantly visual but there may be some minor tactile and auditory components. The

visual hallucinations are often quite vivid and contain colours, objects, and scenes. The hallucinations occur predominantly after sundown and are sometimes quite frightening to the patient (Caplan, 1980, 1996). In most patients with hallucinations the lesions have been large. However, McKee et al. (1990) described a patient with peduncular hallucinations who had very discrete bilateral lesions in the basal portion of the midbrain involving the substantia nigra pars reticulata. The pars reticulata of the substantia nigra has connections with the pedunculopontine nuclei which show increased discharges during REM sleep. Some patients with rostral brainstem infarcts that include the thalamus have prominent and sometimes persistent memory deficits. The amnesia involves both anterograde and retrograde memory and usually includes both verbal and nonverbal memory. Amnesia has developed in patients with infarction in the antero-lateral thalamic territory supplied by the polar (tubero-thalamic) artery (Bogousslavsky & Caplan, 1993; Caplan, 1996), as well as in the territory of the thalamic–subthalamic artery (Bogousslavsky & Caplan, 1993; Stuss et al.,1988). Patients

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with left thalamic infarcts may have more difficulty with memory for language-related activities while patients with right thalamic lesions have more difficulty with visual–spatial memory tasks (Bogousslavsky & Caplan, 1993). In patients with top-of-the-basilar embolism, both territories in the medial thalamus are often infarcted. Patients with polar territory infarcts show more decrease in spontaneity and abulia. They have difficulty generating lists of common objects, for example, colours, items of clothing, fruits, vegetables, cities in their state, etc. Patients with infarction of the thalamic–subthalamic artery territory, especially when bilateral, have severe deficits in anterograde memory formation and some retrograde amnesia. Some of the lesions associated with amnesia involve the mamillo-thalamic tracts. Some of the medially placed thalamic nuclei such as the dorsal median nuclei are important for memory functions. The anterior thalamic nuclei and the dorsal median nuclei have prominent projections to the frontal lobes probably explaining the abulia seen after thalamic infarcts. As in other anatomical regions, abulia and amnesia are usually less severe and less persistent when the lesions are unilateral than when bilateral. Sensory and motor abnormalities are usually absent in patients with top-of-the-basilar infarction unless the proximal PCAs are also occluded. Movement disorders especially hemiballism have been described in some patients with small infarcts and hemorrhages involving the subthalamic nuclei, but hemiballism is extremely rare in patients with well documented top-of-the-basilar infarcts.

Superior cerebellar artery territory infarction Isolated SCA territory infarcts are not common; most often SCA territory infarcts are accompanied by other infarcts in regions supplied by other arteries that arise at the rostral end of the basilar artery. The symptoms and signs in patients with partial SCA territory infarcts are less severe and disabling than those in other cerebellar artery territories and can be overlooked clinically. The classic SCA syndrome is said to consist of: ipsilateral limb ataxia; ipsilateral Horner’s syndrome; contralateral loss of pain and temperature sensibility of the face, arm, leg, and trunk; and contralateral IVth nerve palsy (Mills,1912a,b; Davison et al., 1935; Guillain et al., 1928; Kase et al., 1985; Amarenco & Hauw, 1990b; Caplan, 1996). Abnormal ipsilateral spontaneous involuntary movements also occur (Amarenco & Hauw, 1990b). The classic syndrome is present when the pontine and midbrain tegmentum and superior cerebellar surface are both infarcted. The full syndrome is quite rare. Some patients with SCA territory cerebellar infarcts have relatively minor symptoms of sudden onset with rather

Fig. 53.9. MRI, T2-weighted sagittal image showing a superior cerebellar artery territory infarct. (Reprinted with permission from Caplan, 2000.)

rapid improvement. Slight dizziness, vomiting, ipsilateral limb dysmetria, gait ataxia, and dysarthria are common. Vertigo is usually not prominent in patients with isolated SCA territory infarcts. Limb incoordination, limb ataxia, intention tremor, and dysarthria are more common in SCA territory cerebellar infarcts than in either AICA or PICA territory cerebellar infarcts (Caplan, 1996). The lateral cerebellar hemispheres are related predominantly to limb movements under voluntary control, while the vermis relates more to posture, stance, truncal movements and gait. The dentate nucleus is the major outflow tract of the cerebellum for modulating voluntary limb movements. The dentate nucleus and surrounding cerebellar whitematter are supplied by SCA branches. SCA territory infarcts may involve the superior vermis and a sizeable portion of the hemispheres in addition to the dentate nuclei explaining the frequent occurrence of both limb and gait ataxia in patients with SCA territory infarcts. SCA territory infarcts can involve the entire SCA territory including the rostral pontine and midbrain tegmentum and the SCA supplied cerebellum, involve the full cerebellar territory but spare the brainstem, or be limited to territory supplied by the medial (mSCA) or lateral (lSCA) branches of the SCA.The bilateral SCA territories may be involved. Figure 53.9 is an MRI that shows a unilateral SCA territory infarct. Figure 53.10 shows MRIs in different

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(a )

(b )

Fig. 53.10. MRI T2-weighted images showing bilateral superior cerebellar artery territory infarcts. (a) is an axial section and (b) a coronal section. (Reprinted with permission from Caplan, 2000.)

The clinical findings depend on whether the brainstem territory of the SCA is involved and whether infarction is limited to SCA teritory or also includes structures supplied by other rostral basilar artery branches. Large full SCA cerebellar infarcts can produce a pseudotumoural syndrome but do so less often than the full PICA territory infarcts (Chaves et al., 1994a,b; Kase et al., 1993). Stupor, and symptoms of hydrocephalus are only rarely found in patients with infarcts limited to the SCA cerebellar territory. Branch infarcts have been less often analysed in the SCA territory compared to PICA territory. Amarenco et al. (1991b) reported the findings in patients with isolated lSCA territory infarcts and reviewed previously reported examples. The territory usually infarcted was predominantly in the rostral anterior cerebellum and sometimes included the dorsolateral pontine tegmentum. Nearly all patients had prominent limb ataxia, varying from slight clumsiness to severe incoordination and dysmetria. Dysarthria was also a frequent and prominent finding. Cerebellar gait ataxia and veering and pulling of the trunk to the ipsilateral side, so-called axial lateropulsion also occurred. Axial lateropulsion can be the only main finding in patients with lSCA territory infarction (Bogousslavsky & Regli,1984). Edema and mass effect do not occur and recovery is excellent (Amarenco et al., 1991b). Infarcts limited to the mSCA territory have been less often reported than lSCA territory infarction. Amarenco et al., 1991a) reported a single patient with an isolated paravermal infarct in the territory of the mSCA. This patient who had atrial fibrillation, diabetes, and hypercholesterolemia presented with the acute onset of severe isolated dysarthria. The infarct involved the simplex and superior semilunar lobules in the rostro-medial left cerebellum. Lechtenberg and Gilman (1978) suggested that the paravermal zone of the left cerebellum was the most frequent site of damage among patients with focal lesions who had ataxia of speech. Speech abnormalities are an integral sign in many patients with SCA territory infarcts, no matter whether the lesion involves the full territory or the medial or lateral branches.

Posterior cerebral artery territory infarction planes in a patient with bilateral SCA territory cerebellar infarcts caused by stenosis of the basilar artery located at the SCA origins. SCA territory infarcts are often accompanied by PCA and midbrain and thalamic infarcts in territories supplied by other branches of the rostral basilar artery. Branch infarcts are much more common than full SCA territory infarcts (Caplan, 1996; Kase et al., 1993; Tohgi et al., 1993; Chaves et al., 1994a,b).

The most common finding in patients with PCA territory infarction is a hemianopia. (Mohr & Pessin, 1998; Pessin et al., 1987b; Caplan, 1996, 2000; Yamamoto et al., 1999). Hemianopia is due to infarction of the striate visual cortex on the banks of the calcarine fissure, a region supplied by the calcarine branch of the PCA, or is explained by interruption of the geniculocalcarine tract as it nears the visual cortex. If just the lower bank of the calcarine fissure is involved – the

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lingual gyrus – a superior-quadrant field defect results. An inferior quadrantanopia results if the lesion affects the cuneus on the upper bank of the calcarine fissure. When infarcts are restricted to the striate cortex and do not extend into adjacent parietal cortex, patients are fully aware of the visual defect. Usually described as a void, a blackness, or a limitation of vision to one side, patients usually recognize that they must focus extra attention to the hemianopic field. When given written material or pictures, patients with hemianopia due to occipital lobe infarction are able to see and interpret stimuli normally, although it may take them a bit longer to explore the hemianopic visual field. In patients with occipital lobe infarcts, physicians can reliably map out the visual fields by confrontation. At times, the central or medial part of the field is spared – so-called macular sparing. Optokinetic nystagmus is preserved. Some patients, although they accurately report motion or the presence of objects in their hemianopic field, cannot identify the nature, location, or colour of those objects. When the full PCA territory is involved, visual neglect can accompany the hemianopia. In patients with PCA territory infarcts, lateral thalamic ischemia is the major reason for somatosensory symptoms and signs (Caplan et al., 1988; Georgiadis et al., 1999). The lateral thalamus is the site of the major somatosensory relay nuclei, the ventroposteromedial and the ventroposterolateral (VPM and VPL) nuclei. Ischemia to these nuclei or to the white-matter tracts carrying fibres from the thalamus to somatosensory cortex (postcentral gyrus and the Sensory 2 region in the parietal operculum) produces changes in sensation, usually without paralysis (Georgiadis et al., 1999; Yamamoto et al., 1999). Patients describe paresthesias or numbness in the face, limbs, and the trunk. On examination, touch, pinprick, and position sense are reduced. The combination of hemisensory loss with hemianopia without paralysis is virtually diagnostic of infarction in the PCA territory. The occlusive lesion is within the PCA before the thalamogeniculate branches to the lateral thalamus. Rarely, occlusion of the proximal portion of the PCA can cause a hemiplegia (Benson, Tomlinson, 1971; Hommel et al., 1990; Caplan, 1996). Penetrating branches from the most proximal portion of the PCA penetrate into the midbrain to supply the cerebral peduncle. Proximal PCA occlusions cause hemiplegia due to midbrain peduncular infarction, accompanied by a hemisensory loss due to lateral thalamic infarction and hemianopia due to occipital lobe infarction. The resultant neurological deficit is not easily distinguished clinically from MCA and anterior choroidal artery (AChA) territory infarcts, but separation is made readily by CT and MRI results.

When the left PCA territory is infarcted, several additional findings may occur (Caplan, 1996, 2000).

Alexia without agraphia Infarction of the left occipital lobe and splenium of the corpus callosum is associated with a remarkable clinical syndrome first described by Dejerine (1892) and later amplified by Geschwind and Fusillo (1966). Because the left visual cortex is infarcted, patients see with their right occipital lobe and their left visual field. In order to name what they see, the information must be communicated from the right occipital cortex to the language region in the left temporal and parietal lobes. Infarction of the corpus callosum or adjacent white-matter paths interrupts communication between the right occipital cortex and the left hemisphere. Patients have difficulty naming what they see. The most conspicuous abnormality is in reading. Although usually able to name individual letters or numbers, the patient cannot read words or phrases. Because the speech cortex is normal, they retain the ability to speak, repeat speech, write, and spell aloud. Although they are able to write a paragraph, they often cannot read it back moments later. Usually accompanying the dyslexia is a defect in colour naming. Patients can match colours and shades, proving that their perception of colours is normal. They can also describe the usual colour of familiar objects and can even colour correctly when given an array of crayons. Nonetheless, they are unable to give a colour its correct name.

Anomic or transcortical sensory aphasia (Kertesz et al. 1982) Some patients with left-PCA-territory infarction have difficulty naming objects, and others can repeat but not understand spoken language.

Gerstmann’s syndrome PCA-territory infarction can undercut the angular gyrus, leading to a host of findings, usually lumped together as Gerstmann’s syndrome. These findings include difficulty telling right from left; difficulty in naming digits on their own or on others’ hands; constructional dyspraxia; agraphia; and difficulty in calculating. In any single patient all features may appear together or one or more may occur in isolation.

Altered memory A defect in acquisition of new memories is common when both medial temporal lobes are damaged but also occurs in lesions limited to the left temporal lobe (Victor et al., 1961; Mohr et al.,1971; Benson et al., 1974; Caplan & Hedley-

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White,1974; Geschwind & Fusillo,1966; Ott & Saver, 1993; Mohr & Pessin, 1998; Caplan, 1996). The memory deficit in patients with unilateral lesions is not usually permanent, but has lasted up to 6 months. Patients cannot recall what has happened recently, and when given new information, they cannot recall it moments later. They often repeat statements and questions spoken only minutes before.

Associative visual agnosia (Lissauer, 1890, Rubens & Benson, 1971, Caplan & Hedley-White, 1974) Some patients with left-PCA territory infarction have difficulty in understanding the nature and use of objects presented visually. They can trace with their fingers and copy objects, demonstrating that visual perception is preserved. They often can name objects if the objects are presented in their hand and explored by touch or when verbally described. Infarcts of the right PCA territory are often accompanied by prosopagnosia, difficulty in recognizing familiar faces (Damasio et al., 1982). At times, patients cannot recognize their own spouses, their children, or even their own images in a mirror. Disorientation to place and an inability to recall routes or to read or revisualize the location of places on maps are also common findings in patients with right PCA territory infarcts (Fisher, 1982). Patients with right occipito-temporal infarcts also may have difficulty revisualizing what a given object or person should look like. Dreams may also be devoid of visual imagery. Visual neglect is much more common after lesions of the right than of the left PCA territory. When the PCA territory is infarcted bilaterally, as in Fig. 53.8, the commonest findings are cortical blindness, amnesia, and agitated delirium (Caplan, 1980, 1996). Most often, bilateral PCA territory infarction is due to embolism, with blockage of the distal basilar bifurcation. Cortically blind patients cannot see or identify objects in either visual field but have preserved pupillary light reflexes (Symonds & McKenzie, 1957). Some patients with cortical blindness do not volunteer or admit that they cannot see and seem to avoid barriers in their way. Amnesia due to bilateral medial temporal-lobe infarction may be permanent and closely resembles Korsakoff’s syndrome. Also, infarction of the hippocampus, fusiform, and lingual gyri, usually bilaterally, leads to an agitated hyperactive state that can be confused with delirium tremens (Horenstein et al., 1962; Medina et al., 1974; Caplan, 1980, 1996). When infarction is limited to the lower banks of the calcarine fissures bilaterally, the major findings are prosopagnosia and defective colour vision (Meadows, 1974; Damasio et al., 1980, 1982; Caplan, 1996).

Vascular lesions and stroke mechanisms in patients with distal intracranial territory infarcts The great majority of distal posterior circulation intracranial territory infarcts are caused by embolism from the heart, aorta, and ECVAs and ICVAs (Caplan, 1980, 1996; Mehler, 1988). Many rostral brainstem infarcts that are unilateral and are within the territory of single penetrating branches such as the polar artery, thalamic–subthalamic artery, posterior choroidal artery, and midbrain penetrating arteries are caused by disease of those branches – lipohyalinosis or atheromatous branch disease. Most infarcts that are limited to the lateral thalamus in the territory of the thalamogeniculate arterial pedicle are caused by atheromatous branch disease and not disease of the parent PCA (Caplan et al., 1988). The thalamic–subthalamic (thalamoperforating) arteries of both sides in a third of patients arise from one side or from a common pedicle. (Castaigne et al., 1981). Infarcts in the posterior paramedian thalamus are often accompanied by infarction in the rostral paramedian midbrain tegmentum (Castaigne et al., 1981; Tatemichi et al., 1992). Since the paramedian mesencephalic and thalamoperforating arteries arise from the basilar apex adjacent to each other, some infarcts that involve the rostral midbrain and posterior thalamus are probably related to non-stenosing basilar artery plaques (atheromatous branch disease). Superior cerebellar artery territory infarcts are predominantly embolic especially when infarction is limited to mSCA or lSCA branches (Caplan, 1996; Kase et al., 1993; Tohgi et al., 1993; Chaves et al., 1994a,b; Amarenco & Caplan, 1993; Amarenco & Huaw, 1990b; Amarenco et al., 1990, 1994). When there are bifid or double cerebellar arteries that supply one side, infarcts are sometimes due to branch disease of one of the arteries. Occasional patients with bilateral SCA territory infarcts (as shown in Fig. 53.10, have a stenosing lesion involving the basilar artery affecting the region of the artery from which the SCAs originate. Unilateral PCA territory infarcts are also predominantly embolic. Emboli most often have been documented to arise from the heart and the ECVAs and ICVAs but the aorta may also be a frequent source (Pessin et al., 1987b; Caplan, 1991, 1996; Yamamoto et al., 1999). Occasional patients have an intrinsic atherostenotic lesion within the PCA. These patients often have TIAs characterized by visual, sensory, or visual and sensory symptoms before their strokes (Pessin et al., 1987a; Mohr & Pessin, 1998; Caplan, 1996). Bilateral PCA territory infarcts are almost always embolic especially when there are accompanying rostral brainstem and SCA territory cerebellar infarcts. Occasional patients with thrombosis or dissection involving the distal

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basilar artery can show similar distribution distal intracranial posterior circulation territory infarcts. Embolic infarcts tend to be larger than those caused by intrinsic distal basilar artery disease, and PCA and rostral brainstem infarcts caused by intrinsic basilar artery disease are almost always preceded by TIAs.

Multiple intracranial territory infarcts Often more than one intracranial territory is involved. The clinical symptoms and signs are additives of the syndromes already described that relate to individual territories. When ischemia involves the proximal and distal intracranial territories, sparing the middle territory, the ICVA and distal basilar artery or its branches must have been affected at some time. The most frequent explanations for this distribution are: embolism from the heart, aorta, or ECVA with the embolus first blocking the ICVA then moving or fragmenting to reach the basilar apex or its branches, or intrinsic occlusive disease of the ICVA causing local hemodynamically related ischemia in the proximal intracranial territory and also acting as a source of artery-toartery embolism to the distal basilar artery or its branches. When the middle territory is involved along with other territories (middle⫹infarcts) the cause is predominantly in situ disease, either atherostenotic occlusive disease or dissection. When the proximal and middle territories, or the proximal, middle, and distal terrirtories are all involved the cause is usually occlusive lesions within one ICVA that extend into the basilar artery. Occasionally emboli cause this distribution infarction. Middle and distal territory infarcts are caused more often by in situ basilar artery lesions then by embolism (Caplan, 1996).

Evaluation The ecology of the ischemia (risk factors) and definition of the location of the brain lesions helps to identify the most likely vascular lesions and stroke mechanisms. Clinicians should attempt to localize the brain ischemia to the various intracranial posterior circulation territories discussed. This is done by using a combination of the clinical signs and brain imaging. MRI is much more effective in localizing posterior circulation lesions than CT. The clinical signs should not be ignored but instead coupled with the neuroimaging results. A patient with symptoms that indicate a lateral medullary syndrome might have a small infarct on MRI in the territory of one PCA unsuspected

clinically. This patient has a proximal and distal territory infarct. In other patients clinical signs, for example, a hemianopia, may be present but no PCA territory infarct is shown by CT or MRI. Definition of the localization of the brain ischemia, when coupled with risk factor assessment is very helpful in predicting the most likely cardio-cerebrovascular–hematological lesions causing the posterior circulation ischemia (Caplan,1996). Most patients with posterior circulation ischemia require non-invasive vascular evaluation (CT, MRA, and/or extracranial and transcranial ultrasound) (Caplan, 1996). Many patients will also need echocardiography, the exception being some hypertensive patients who have branch territory disease.

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Mehler, M.F. (1989). The rostral basilar artery syndrome: diagnosis, etiology, prognosis. Neurology, 39, 9–16. Meyer, K., Baloh, R., Krohel, G. et al. (1980). Ocular lateropulsion as a sign of lateral medullary disease. Archives of Ophthalmology, 98, 1614–16. Mills, C.K. (1912a). Preliminary note on a new symptom complex due to a lesion of the cerebellum and cerebello-rubro-thalamic system; the main symptoms being ataxia of the upper and lower extremities on one side, and on the other side deafness, paralysis of emotional expression in the face, and loss of the senses of pain, heat, and cold over the entire half of the body. Journal of Nervous and Mental Diseases, 39, 73–6. Mills, C.K. (1912b). Cerebello-tegmental lesion from occlusion of branches of the superior cerebellar artery. Transactions of the American Neurological Association, 38, 24–5. Mohr, J.P. & Pessin, M.S. (1998). Posterior cerebral artery disease. In Stroke Pathophysiology, Diagnosis, and Management, 3rd edn, ed. H.J.M. Barnett, J.P. Mohr, B.M. Stein & F. Yatsu, pp. 481–502. New York: Churchill-Livingstone. Mohr, J.P., Leicester, J., Stoddard, L., et al. (1971). Right hemianopia with memory and colour deficits in circumscribed left posterior cerebral artery territory infarction. Neurology, 21, 1104–13. Mokri, B., Houser, O.W., Sandok, B.A. & Piepgras, D.G. (1988). Spontaneous dissections of the vertebral arteries. Neurology, 38, 880–5. Morrow, M.J. & Sharpe, J.A. (1988). Torsional nystagmus in the lateral medullary syndrome. Annals of Neurology, 24, 390–8. Mueller-Kuypers, M., Graf, K.J., Pessin, M.S., DeWitt, L.D. & Caplan, L.R. (1997). Intracranial vertebral artery disease in the New England Medical Center Posterior Circulation Registry. European Neurology, 37, 146–56. Nordgren, R.E., Markesbery, W.R., Fukuda, K. & Reeves, A.G. (1971). Seven cases of cerebromedullospinal disconnection: the ‘locked-in-syndrome’. Neurology, 21, 1140–8. Oas, J.G. & Baloh, R.W. (1992). Vertigo and the anterior inferior cerebellar artery syndrome. Neurology, 42, 2274–9. Ott B. & Saver, J.L. (1993). Unilateral amnestic stroke. Six new cases and a review of the literature. Stroke, 24, 1033–42. Pappas, C. & Carrion, C. (1989). Altered levels of consciousness and the reticular activating system. Barrow Neurological Institute Quarterly, 5, 2–8. Pessin, M.S., Kwan, E.S., DeWitt, L.D. et al. (1987a). Posterior cerebral artery stenosis. Annals of Neurology, 21, 85–9. Pessin, M.S., Lathi, E., Cohen, M., et al. (1987b). Clinical features and mechanism of occipital infarction. Annals of Neurology, 21, 290–9. Pierrot-Deseilligny, C., Chain, F., Serdaru, M. et al. (1981). The ‘oneand-a-half’ syndrome: electro-oculographic analyses of five cases with deductions about the physiologic mechanisms of lateral gaze. Brain, 104, 665–99.

Ropper, A.H. (1988). ‘Convulsions’ in basilar artery occlusion. Neurology, 38, 1500–1. Rubens, A. & Benson, F. (1971). Associative visual agnosia. Archives of Neurology, 24, 305–16. Segarra, J.M. (1970). Cerebral vascular disease and behavior. I, the syndrome of the mesencephalic artery. Archives of Neurology, 22, 408–18. Selhorst, J., Hoyt, W., Feinsod, M. et al. (1976). Midbrain corectopia. Archives of Neurology, 33, 193–5. Sharpe, J., Rosenberg, M., Hoyt, W. et al. (1974). Paralytic pontine exotropia. Neurology, 24, 1076–81. Shin, H-K., Yoo, K-M., Chang, H.M. & Caplan, L.R. (1999). Bilateral intracranial vertebral artery disease in the New England Medical Center Posterior Circulation Registry. Archives of Neurology, 56, 1353–8. Soffin, G., Feldman, M. & Bender, M.B. (1968). Alteration of sensory levels in vascular lesions of lateral medulla. Archives of Neurology, 18, 178–90. Stuss, D.T., Guberman, A., Nelson, R. & La Rochele, S. (1988). The neuropsychology of paramedian thalamic infarction. Brain and Cognition, 8, 348–78. Symonds, C. & McKenzie, I. (1957). Bilateral loss of vision from cerebral infarction. Brain, 80, 415–55. Tahmoush, A., Brooks, J. & Keltner, J. (1972). Palatal myoclonus associated with abnormal ocular and extremity movements: a polygraphic study. Archives of Neurology, 27, 431–40. Tatemichi, T., Steinke, W., Duncan, C. et al. (1992). Paramedian thalamo-peduncular infarction: clinical syndromes and magnetic resonance imaging. Annals of Neurology, 32, 162–71. Tohgi, H., Takahashi, S., Chibra, K. et al. (1993). Cerebellar infarction. Clinical and neuroimaging analysis in 293 patients. Stroke, 24, 1697–701. Tyler, K., Sandberg, E. & Baum, K.F. (1994). Medial medullary syndrome and meningovascular syphilis: a case report in an HIVinfected man and a review of the literature. Neurology, 44, 2231–5. Van Bogaert, L. (1927). L’hallucinose pedonculaire. Revue Neurologique, 43, 608–17. Victor, M., Angevine, J., Mancall, E. et al. (1961). Memory loss with lesions of hippocampal formation. Archives of Neurology, 5, 244–63. Wityk, R.J., Chang, H-M., Rosengart, A. et al. (1998). Proximal extracranial vertebral artery disease in the New England Medical Center Posterior Circulation Registry. Archives of Neurology, 55, 470–8. Yamamoto, Y., Georgiadis, A.L., Chang, H-M. & Caplan, L.R. (1999). Posterior cerebral artery territory infarcts in the New England Medical Center Posterior Circulation Registry. Archives of Neurology, 56, 824–32. Yates, P.O. & Hutchinson, E.C. (1957). Carotico-vertebral stenosis. Lancet, 1, 2–8.

54

Spinal stroke syndromes Matthias Sturzenegger Inselspital Neurological Clinic and Policlinik, Berne, Switzerland

Introduction The causes of spinal ischemia are as multiple as those of cerebral infarction and frequently, especially in young individuals, no definite etiology can be delineated. The concepts are also basically the same: reduced arterial blood supply may cause territorial infarctions in the case of vessel occlusion or embolism, or watershed infarctions in the case of generalized ischemia. This may be transient (spinal transient ischemic attacks, TIA) or permanent (cord infarction). If venous drainage is reduced or venous pressure increased, a congestive myelopathy may evolve which contrary to arterial disease usually shows a fluctuating and chronic progressive course.

Blood supply to the spinal cord At the fetal stage the spinal cord is provided with an extensive arterial network guaranteeing arterial blood supply. This extensive network, however, gradually regresses during maturation.

Arterial Three main levels of arterial blood supply can be differentiated: (i) The vertebral arteries and the segmental arteries arising from the aorta give rise to the radicular arteries; the numbers and locations of radiculomedullar arteries contributing to the cord supply are quite variable, individually they form the spinal region (cervical, thoracic, lumbar and sacral)(Fig. 54.1). (ii) The radiculomedullar arteries feed the extrinsic intraspinal arterial network consisting of the three longitudinal discontinuous channels (anterior and pair of posterior spinal arteries) connected among each other via the spinal arterial plexus (vasa coronae) (Fig. 54.2 and 54.3). (iii) The intrinsic (intramedullary) arterial

supply arises from this (perimedullary) spinal arterial plexus and these vessels are endarteries i.e. without collaterals: the sulcocommissural arteries and the circumferential perforating (or penetrating)(medullary) arteries (Fig. 54.3) (Lazorthes et al., 1971; Romanes, 1965). (i) Modern techniques of spinal arteriography allowing susperselective injection of radicular arteries have demonstrated the enormous variability with respect to the main contributing arteries to the extrinsic spinal arterial network. The vertebral arteries at different levels support the cervical spinal cord which has the best arterial supply of the four spinal cord segments. Not only from the intracranial (V4) section or from the PICA in the posterior fossa can main arterial trunks descend to form the spinal arteries, in the cervical region segmental radicular arteries are also most numerous and are additionally supplied by a rich perispinal anastomotic arterial network among the neck arteries (occipital, inferior thyroidal, ascending cervical, costocervical, deep cervical and supreme intercostal) arising from the external carotid and subclavian artery. The number of segmental spinal arteries (or more precise: spinal branch of the posterior ramus of the segmental artery (Fig. 54.2), giving rise to the posterior and anterior radiculomedullar arteries feeding the perimedullary network is very variable. Whereas in the fetal stage each of the 31 pairs of segmental arteries contributes to the spinal cord vascularization, in the adult only a few (six to ten) are preserved as radiculo-medullary arteries, i.e. with true supply to the spinal cord (Lazorthes et al., 1971). They are especially rare in the thoracic region; the spinal cord between Th 3 and Th 11 thus is sparsely supplied with branches from intercostal arteries. In the lumbosacral region, the spinal cord receives most of its blood supply through a single large anterior radiculomedullar artery (so called great radicular artery of Adamkiewicz)(Fig. 54.1) variously arising between Th 9 and L2 segmental levels (in

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Fig. 54.1. Overview of the extrinsic arterial blood supply to the spinal cord. The main feeders to the intraspinal arterial network are the individually formed segmental (cervical, thoracic, lumbar and sacral) arteries arising from the vertebral and other cervical arteries as well as from the aorta or iliac arteries. (Drawing by the author.)

Spinal stroke syndromes

Fig. 54.2. Segmental view of the extrinsic arterial blood supply to the spinal cord and vertebral body. Radicular arteries arising from the segmental arteries at various levels, feed to the anterior and posterior radiculomedullar arteries, which join to form the discontinuous anterior spinal and the pair of posterior spinal arteries. (Drawing by the author.)

75%; between T5 and L2 in 100%) on the left (80%) or right side. With a high origin of this main artery, there is additional supply to the lumbosacral cord by lumbar or sacral radiculomedullar arteries arising from iliac arteries. The radicular arteries play a fundamental role (feeders) in spinal cord vascular malformations. Because only few of them are engaged in the adult’s cord blood supply (via radiculomedullar arteries), an occlusion may lead to extensive cord infarction involving several cord segments. The thoracolumbar cord, which depends almost exclusively on the artery of Adamkiewicz is more often involved in ischemic disease than the cervical cord which has more extensive and anastomotic arterial supply, as outlined above. MR imaging of spinal ischemic syndromes has disclosed frequently associated anterior vertebral body infarction which in certain instances is more easily delineated than the cord ischemia and thus may be the confirmatory diagnostic sign (Faig et al., 1998). Anterior and posterior central arteries to the vertebral body arise from

the segmental artery or the radicular artery (Fig. 54.2) thus explaining combined ischemia. (ii) The extrinsic intraspinal perimedullary arterial network is more extensively laid out in the region of the cervical and lumbar intumescence. The three longitudinal channels (anterior and pair of posterior spinal arteries) are discontinuous. Around the medullar conus the three longitudinal channels are anastomosing (Lazorthes et al., 1971). The capacity of the connecting spinal arterial plexus (vasa coronae) is crucial to determine the extent of a cord infarction in the case of occlusion of a radicular/radiculomedullar artery. (iii) The sulcocommissural arteries (also: central sulcal arteries) are numerous (200–240), arise from the anterior spinal artery and enter the spinal cord in a perpendicular fashion through the anterior median fissure. They supply, alternately, the left and the right centrospinal region including most parts of the spinal segmental grey matter and the anterolateral columns in a centrifugal way (Fig.

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Fig. 54.3. Three-dimensional view of the intrinsic arterial blood supply of the spinal cord, in an oblique cord cross-section. The anterior and posterior spinal arteries are connected via the spinal arterial plexus. From this network, the spinal cord endarteries, the central sulcal (or sulcocommissural) arteries and the circumferential perforating medullary arteries arise. (Drawing by the author.)

54.3). Since there is no intrinsic anastomotic network, this area has the characteristics of a watershed area and is especially susceptible to ischemia. The capillary network is more developed in the grey than in the white-matter according to its greater demand for oxygen and much higher metabolic rate (Gilles & Nag, 1971; Friedman & Flanders, 1992). The circumferential perforating (also penetrating) (medullary) arteries arise from the perimedullary spinal arterial plexus (vasa coronae). In the posterior part they are supplied by the posterior spinal arteries which supply the posterior third of the cord’s cross-section including the tips of the posterior horns and the posterior columns in a centripetal way (Fig. 54.3).

Venous The extensive epimedullary (intrathecal) intraspinal venous plexus is connected to the longitudinally anastomosing epidural (extrathecal) venous plexus draining into the vertebral bodies and also through numerous radicular veins into an extensive perispinal venous plexus. Veins

without valves finally drain into the azygos and pelvic venous system. Even lumbar and sacral intrathecal veins may be anastomosing all the long the cord to the veins of the posterior fossa which may be important in the case of arteriovenous malformations.

Transient ischemic attacks Intermittent symptoms of cord dysfunction, usually paraparesis or quadriparesis should evoke the possibility of a spinal dural arteriovenous malformation (dural arteriovenous fistula (DAV)). Fluctuating symptoms, typically associated with segmental pain are the consequence of borderline venous drainage due to increased venous pressure following arteriovenous shunts. These attacks may herald impending venous infarction (Teale et al., 1992). True spinal TIAs, e.g. due to cardiac embolism, from aortic atheromatous lesions, or intermittent radicular artery compression, are rare events (6%)(Cheshire et al., 1996).

Spinal stroke syndromes

Clinical features according to the pattern of cord ischemia Diagnosis of spinal cord ischemic syndromes clinically is one of exclusion. The different clinical syndromes are classified according to their location in the longitudinal axis and to their extent with respect to the spinal cord crosssection and thus according to the vascular territory presumably involved. Due to the individually very variable vascular anatomy, the presenting symptoms may be heterogeneous, and incomplete or overlapping syndromes are frequent. It is, for example, not possible to clinically distinguish infarction due to interruption of a spinal radicular artery or the anterior spinal artery. Whenever possible, a causal diagnosis should be attempted. Frequently ‘spontaneous’ spinal strokes occur during the night or after an exertion. MRI has made exclusion of other etiologies such as compression or demyelination and, also the proof of ischemia, more easy.

Cervical, thoracic and lumbar ischemia Cervical cord ischemia leads to tetraplegia and pulmonary insufficiency in the case of transverse extension of ischemia. A specially located high cervical anterior spinal artery syndrome may produce painful brachial diplegia (Berg et al., 1998). Thoracic cord ischemia leads to paraplegia and lumbar ischemia to distal plegia of the legs. Bladder and bowel dysfunction is observed with all levels of ischemic lesion.

Transverse spinal cord infarction A total infarction of one or several spinal cord segments produces a syndrome of cord transsection (‘spinal apoplexia’) with flaccid para- or tetraplegia, complete loss of sensation including all sensory qualities below the lesion, and bowel and bladder paralysis. The motor paralysis shows acute onset and rapid progression. It is usually preceded or accompanied by acute pain of spinal belt-like or radicular irradiating character at the corresponding cutaneous level of the lesion. The pain usually subsides rapidly, but may last for several days. The tendon reflexes and abdominal reflexes below the lesion level are lost and the plantar response is indifferent (spinal shock). A Babinski sign develops only later, within days to weeks together with spasticity. The upper border of the spinal cord lesion is indicated by the sensory level on the trunk. In some cases a zone of hyperesthesia may be present in the trunk immediately above the level of complete sensory loss. Intensity and level of motor and sensory dysfunction may change (ascend or

descend) during the evolution of cord ischemia (Garcin et al., 1962). Absent descending sphincter control leads to stool and urine retention. Disruption of sympathetic innervation is the cause of autonomic disturbances which are usually found if the lesion level is higher than Th8. They encompass passive vasodilatation with orthostatic collapse, lung edema in cervical cord transsections, bowel pseudo-obstruction with diffuse abdominal pain, vomiting and distension, disturbed sweating, thermoregulation and piloerection. The prognosis of complete ischemic cord trans-section is poor with little recuperation potential and multiple secondary disabling complications such as decubital ulcers, septic urinary and skin infections, deep vein thrombosis and pulmonary embolism.

Anterior spinal artery syndrome In the typical case the posterior column’s function is preserved due to blood supply from the posterior spinal arteries (Fig. 54.4). These patients present with pronounced para- or tetraparesis or plegia and areflexia below the level of the lesion, autonomic deficits comprising sphincter flaccidity, atonic urinary bladder and paralytic ileus (Foo & Rossier, 1983). Sensation for touch, vibration and position is preserved, but spinothalamic preception of pain and temperature impaired or more frequently lost. This dissociated sensory loss below the lesion, which is most characteristic, may be missed on superficial examination or by an inexperienced examiner. It’s not rare to have such patients suspected of ‘psychogenic paraplegia’ therefore. Onset of motor paralysis is abrupt and progression usually rapid again. Transient radicular or back pain may herald these findings. In some cases touch sensation may also be impaired, which is explained by the involvement of the base of the posterior horns and the juxtacommissural part of posterior columns, which can be supplied by the anterior spinal artery (Garcin et al., 1962). Touch sensation usually is not disturbed to the degree of thermoalgesia. Spasticity eventually ensues, except when ischemia involves anterior horn cells or nerve roots, in which case mixed or lower motor neuron deficits may occur. In certain cases, persistent dysesthesias may develop which are ascribed to residual posterior column sensory input (Triggs & Beric, 1992). Lesions above C3–5 segments interrupting diaphragm innervation may compromise respiration. Orthostatic hypotension may result from lesions superior to the origin of the greater splanchnic nerve at T4–9. In addition to sexual dysfunction, impairment of vasomotor and sudomotor tone and piloerection may occur below the level of the lesion, leading to impaired thermoregulation. Disinhibited sympathetic neurons of the inter-

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Fig. 54.4. Patient with an anterior spinal artery syndrome affecting the legs. (a) Sagittal T2-weighted MRI of the lumbar spinal cord with hyperintense signal within the conus medullaris (arrow). (b) Axial T2-weighted scan showing hyperintense lesion in the territory of the anterior spinal artery (arrow heads). There is left paramedian disc herniation (arrow).

mediolateral cell column may mount an exaggerated response to mildly noxious stimuli such as a distended bladder, resulting in the paroxysmal, generalized hypersympathetic state known as spinal dysautonomia. Many variants or partial forms of the anterior spinal artery syndrome can be observed: Ischemic cell death can be limited to the grey matter of the anterior horn cells due to its greater susceptibility to ischemia (Gilles & Nag, 1971) (Fig. 54.5). The resulting pure motor (pseudopoliomyelitic) syndrome with acute flaccid paralysis, but without sensory and sphincter dysfunctions may present with acute painful brachial diplegia (man-inthe-barrel syndrome)(Berg et al., 1998) when the cervical cord is involved or acute isolated motor paraplegia when the lumbosacral intumescence becomes infarcted. Ischemia may damage the anterior horn motor neurons in a more chronic way and cause a subacute to chronic progressive amyotrophy of the (distal) extremities (arms or legs) which clinically can be difficult to distinguish from

amyotrophic lateral sclerosis. The ‘téphromalacie antérieure’ described by Pierre Marie and Charles Foix (1912) with isolated non-progressive wasting of the hand muscles is a special variant of this syndrome following cervical meningovascular syphilis with syphilitic arteritis. The sulcocomissural artery syndrome is another incomplete anterior spinal artery syndrome presenting as an incomplete hemicord section (partial Brown–Séquard syndrome) with ischemia involving the territory of a sulcocomissural artery. Since the posterior columns are generally spared, deep sensation is preserved. Mostly this clinical variant can be observed at the onset of a complete anterior spinal artery syndrome representing a transitional state (Fig. 54.6). If infarction involves the medullary conus, the clinical presentation is that of a cauda equina syndrome with severe sphincter paralysis and perianal and perineal sensory loss and variable motor and sensory impairments in the legs corresponding to the caudal segments of the spinal cord (L5–S2)(Garcin et al., 1962). Pain and paresthesias are usually not as prominent as in true cauda equina syndrome, such as caused by luxating lumbar disc hernia-

Spinal stroke syndromes

segments involved by ischemia there is loss of all sensory qualities and abolition of the corresponding stretch reflexes due to involvement of posterior horns/roots. Vibration and position sense is lost below a certain level corresponding to the cord lesion which, however, cannot be explained by the dorsal column interruption alone and implicates involvement of additional cord regions such as the dorsal horns (Davidoff, 1989). More often, there is extension of the ischemia to the posterior part of the anterolateral columns and the patients also display some degree of motor palsy and spincter dysfunction (Garcin et al., 1962).The tetra- or paraparesis is never as marked as in the anterior spinal artery syndrome, and the prognosis for motor recovery is much better.

Spinal claudication Fig. 54.5. 17-year-old girl with acute flaccid paraplegia and sensory level at Th 10. Contrast enhanced T1-weighted axial scan at the level of Th 8 showing hyperintense signal changes of the anterior horns (‘owl’s eye’ sign).

tion. Motor deficits, however, develop more rapidly in conus infarction (Fig. 54.4). The so-called centrospinal infarcts are also best considered a subtype of anterior spinal artery syndrome. Patients commonly show a paraplegia with sensory loss and bowel and bladder paralysis. On clinical grounds alone this type of cord ischemia is very difficult to differentiate from transverse infarction. The extension of spinal cord softening observed in this originally histopathologically described syndrome (Nagashima & Shimamine, 1974) does not correspond to a specific arterial territory. The infarcts have a conical shape, with progressive decrease of the infarcted cord volume towards the tip of the lesion. They involve the deep juxtacommissural part of the posterior columns, the grey commissure and the base of the lateral columns. Centrospinal infarcts frequently are prolongations of total transverse infarctions several segments above and below the lesion. They are thought to result from circulation failure in critical border zone areas between the superficial and deep arterial territories.

Posterior spinal artery syndrome Infarcts limited to the territory of the posterior spinal artery are rare and also difficult to recognize clinically (Gutowsky, et al. 1992). Patients report pain usually involving the trunk and legs, and paresthesias in the legs. In the

The so-called spinal claudication is very rare in its pure sense and corresponds to a transient ischemia of the cord during exercise such as walking. The patient may develop weakness and sensory disturbances in the legs and the tendon reflexes may transiently be exaggerated and the plantar response extensor. This syndrome is much rarer than the pseudoclaudication of the cauda equina which is due to spinal stenosis with mechanical squeezing of the lumbosacral nerve roots. Patients become symptomatic during walking especially downwards when reclination causes further spinal canal narrowing due to vertebral body instability or protrusion of flaval ligaments. The symptoms are probably caused purely mechanically but microvascular ischemia is also possible – whatsoever, this is not a cord syndrome and reflexes are usually diminished or absent.

Vesicourethral dysfunction The type of urinary dysfunction depends on the involvement of nuclear and supranuclear neurogenic structures responsible for the delicate regulation of sensory and motor bladder and urethral functions (Siroky et al., 1992). The most frequent alteration, observed with ischemia involving the conus medullaris and thus the motor nuclei to the bladder, is detrusor areflexia with sphincter neuropathy. With supranuclear cord lesions sparing the conus, detrusor hyperreflexia and detrusor–sphincter dyssynergia can be observed on urodynamic recordings. Patients with anterior spinal artery syndrome and preserved touch and position sense have preserved sensation of bladder filling (distention), whereas sensation of urgency is lost. Urgency obviously is mediated by the anterolateral columns (spinothalamic tracts).

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Fig. 54.6. (a) T2-weighted axial MRI at the level of the fifth cervical vertebra showing left hemicord infarction. The patient 5 days previously presented with acute pain in the left shoulder and left hemiplegia. On examination, there was severe palsy of the left deltoid and biceps muscle but only slight motor deficits in the triceps, hand and finger muscles and in the leg. He had right dissociated sensory loss below a level at C7. (b) T2-weighted paramedian sagittal scan. (c) Contrast-enhanced sagittal scan 12 days after symptom onset.

Mechanisms and causes of spinal cord ischemia Spinal cord infarction shares with cerebral infarction a common systemic vascular differential diagnosis that includes hypoxia and ischemia, cardiogenic embolism, vasculitis, atherosclerosis, AVM, collagen and elastin disorders, polycythemia, hypercoagulability, paradoxical embolism via patent foramen ovale and cocaine use (Table

54.1). When it comes to specific vascular territories, however, instead of carotid occlusion one must consider vertebral and radicular artery and aortic disease, whether related to trauma, hypertrophic degenerative changes in the spine, or invasive procedures compromising the spinal circulation. In the individual case it may be very difficult to define the cause for spinal cord ischemia since examination of the feeding arteries of the spinal cord is difficult including the aortic artery. General rules of atheroscelerosis established for brain ischemia are probably equally valid for spinal cord ischemia but not studied in detail, e.g. it makes sense to assume that a smoker with arterial hypertension and diabetes mellitus presenting with anterior spinal artery syndrome probably has intrinsic (microvascular) cord atheromatosis. Arterial causes of cord ischemia

Spinal stroke syndromes

Table 54.1. Causes of spinal ischemia Arterial

Atherosclerosis

Macroangiopathic

Vasculitis

Microangiopathic Systemic lupus

Embolic

Cardiac

Compressive

Arterial Gaseous Toxic Iatrogenic Parasitic Coagulation disorder Tumour Hematoma

Infectious Toxic Iatrogenic

Global ischemia Venous

Osteophytosis Meningovasculitis Cocaine, Heroin Surgery Anesthesia Endovascular Cardiac Severe anemia

Aortic atheromatosis Aortic dissection Atherolosclerosis (vascular risk factors) Periarteritis nodosa, giant cell arteritis, Sarcoidosis, erythematodes, Sjögrens disease, syphilis, Lyme disease Atrial fibrillation, endocarditis Myocardial infarction Cardiac valve or septal disease Aortic or vertebral artery disease Decompression sickness i.v. addicts Aortic surgery Schistosomiasis Primary vertebral metastatic Epidural hematoma Hematomyelia Cervical spondylosis Syphilis, tuberculosis, zoster Aorta, spine, heart, AVM repair Spinal, epidural Arteriography, embolization Arrest, severe arrhythmia Gastric bleeding, aortic rupture, trauma

Spinal AVM Spinal dural fistula External venous thrombosis (inferior caval vein) Fibrocartilagineous emboli (?)

are much more frequent than venous congestion (Cheshire et al., 1996).

Arterial The radicular arteries are the crucial segment in the bloodsupplying chain to the spinal cord. The thoracolumbar cord, which has the poorest radicular artery supply and almost exclusively depends on the artery of Adamkiewicz, is most frequently affected by ischemia. In the literature there is a myriad of etiologies from sports activities such as yoga to interventions such as epidural anesthesia reported to interrupt spinal cord blood supply (Cheshire et al., 1996).

Aortic disease Aortic disease has replaced syphilitic arteritis as one of the most common etiologies for spinal cord infarction (Ross, 1985). This group comprises dissecting aneurysms, athe-

rosclerotic thoracic and abdominal aneurysms, aortic thrombosis, traumatic or degenerative rupture and otherwise asymptomatic aortic atherosclerosis. There are, however, no studies documenting incidence figures. The arteries supplying the thoracic and lumbosacral cord originate in the aorta. Aortic disease can also involve the segmental branches to the cord; it can be the source of an occluding embolus, or it may occlude the origin in the case of aortic dissection or dilating atherosclerotic aneurysm. In the case of aortic coarctation or severe stenotic aortic disease (Leriche syndrome) hypoperfusion or hypotension may be another mechanism. Such patients may show intermittent symptoms on exercise or chronic progressive ischemic myelopathy. The risk to the cord during aortic surgery is greater when complicated by intraoperative hypotension, if the aorta has to be clamped proximal to the renal arteries, and when the time of aortic cross-clamping exceeds 45 minutes (Crawford et al., 1986)

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Vertebral artery disease

Compression

The arteries supplying the cervical cord originate in the vertebral and cervical arteries. Vertebral artery dissection with upper cord ischemia has been documented (Hundsberger et al., 1998). The most reasonable mechanism in the case of cervical cord infarction following neck muscle injection is retrograde vertebral artery transportation of introduced embolic material.

The radicular arteries traverse the intervertebral foramen to join the cord. Laterally or intraforaminally herniated disc material as well as degenerative spondylarthrotic spurs may compress the artery (and the root) on rare occasions. Chronic progressive degenerative stenosis of the (cervical) spinal canal may directly impinge on cord structures causing slowly progressive (mechanic?) myelopathy. Such a canal stenosis may also compress the anterior spinal artery. A minor neck trauma may trigger decompensation of vascular cord supply and cause (cervical) cord stroke.

Inflammatory disease Inflammation may selectively affect the cord-supplying vessels in the case of vasculitis. Vasculitic syndromes that may involve the cord are isolated granulomatous angiitis of the CNS, systemic lupus erythematodes, Sjögrens disease and polyarteritis nodosa, giant cell arteritis and sarcoidosis. An inflammation, usually infectious, of the cerebrospinal fluid compartment may spread to the neighboring vessels (arteries and/or veins). Such a vasculitic complication inducing cord ischemia has been reported and also documented histologically in the case of syphilis (meningovascular syphilis predominantly involving the cervical cord) and other spirochaetal disease such as Borreliosis (Lyme disease), in tuberculous and fungal (cryptococcosis, coccidiomycosis) meningitis, in meningoradiculitis due to varicella zoster virus infection or reactivation, and in parasitic disease with vessel predilection such as schistosomiasis and bilharziosis.

Embolism The most frequent cause of embolic cord ischemia are probably iatrogenic representing complications of surgical or arteriographic procedures (see below). Cardiac embolism is rarely proven and can occur in the course of bacterial endocarditis, cardiac myxoma or in patients with patent foramen ovale (Mori et al., 1993). A well-known and histopathologically well-documented cause of spinal cord arterial (or venous ?) occlusion is fibrocartilagenous embolism (Moorhouse et al., 1992; McLean, 1995). The embolic material seems to derive from (degenerated ?) intervertebral disc. However, it is still a matter of speculation how this material invades the spinal arteries (or veins?). The condition may affect young people, women more often than men, and affects preferentially the cervical cord segment. Coagulation disorders or procoagulant states which are discussed as causes of cerebral infarcts especially in young people, may also be engaged in cord ischemia. Antiphospholipid antibodies and mutations of the prothrombin gene (Mercier et al., 1998) are reported in the literature.

Iatrogenic complications There are many ways by which cord ischemia can result from iatrogenic measures: cardiac surgery, aortic surgery, catheter angiography and other endovascular procedures, spinal anesthesia, and neck muscle injections. Cord ischemia as a consequence of aortic clamping necessary for aortic repair is the most frequent iatrogenic cause and feared complication of aortic surgery. Depending on the extent, location and technique of original disease and repair, thoracic or lumbosacral cord ischemia has been reported to occur in 3% (at the top and bottom of the aorta) to 40% (in the midportion of the aorta) (Conolly, 1998; Crawford et al., 1986; Mawad et al., 1990). Especially in the case of repair of a traumatic aortic rupture cord ischemia is frequent and may be explained by additional hypotensive shock and general hypovolemic hypoperfusion already existing before surgery. Attempts have been made to prevent cord ischemia (Cunningham, 1998) and the use of somatosensory evoked potential to monitor on line spinal cord function during the surgical procedure proved the most useful and effective (Stühmeier et al., 1993) Cardiac surgery, especially coronary artery bypass procedures have been complicated by cord ischemia (Gottesmann et al., 1992). During any arteriographic procedure where the aorta is involved there is a risk of inducing cord ischemia. The catheter tip may dislodge embolic material or break up a plaque. In the case of therapeutic endovascular embolization used particles may take a false way (Görich et al., 1992) and inadvertently occlude a radicular artery or its branch. Cord ischemia complicating peridural or spinal (intradural) anesthesia is rare and may be due to vasospasm, which should be a rare event since general advice is against the use of adrenalin to slow down elimination of the local anesthetic substance. We observed two patients with cervical cord ischemia immediately following cervical neck injection with a cristalloid steroid suspension for neck pain.

Spinal stroke syndromes

Injecting a muscle branch of the vertebral artery and retrograde transport of particulate emboligenic material seems the most probable explanation.

Global ischemia Following severe hypotension alone, e.g. due to cardiac arrest or severe gastric bleeding or aortic rupture, or combined with severe anemia, cord ischemia may result. The thoracolumbar zone is especially vulnerable to hypotensive ischemia (Gilles & Nag, 1971; Cheshire et al., 1996).

Malformation Vascular malformations involving the spinal cord may produce chronic cord syndrome due to the tumour (mass) effect (true angiomas). Hemangioblastomas, for example, predominantly involve the cervical cord. If the mechanism is ischemia, this is usually a venous congestion due to slowed venous drainage as a consequence of increased venous pressure behind the a–v shunt (see below).

Venous Isolated thrombosis of spinal cord veins is an exceptional event (Kim et al., 1984). Venous spinal cord infarcts usually occur in association with a spinal dural arterio-venous fistula (Foix–Alajouanine syndrome) (Teal et al., 1992; Koch et al., 1998).

Vascular malformations Venous spinal cord infarct with dural AVM is also called congestive venous myelopathy (Partington et al., 1992). The arterio-venous shunt in this kind of vascular malformation is situated in or outside the dura mater and is fed by one or several small dural branches of a radicular artery/ies. The veins, which have a severely increased pressure and therefore dilate, drain to the intradural epimedullary plexus and thus transmit the abnormal pressure to the cord parenchyma.

Diagnostic evaluation The availability of magnetic resonance imaging (MRI) to image the spine and the spinal canal content proved most valuable in direct non-invasive diagnosis of all kinds of spinal cord disease including ischemia. Before the advent of MRI, cord infarction could not be directly visualized and the diagnosis was one of exclusion. Myelography was used to exclude extrinsic compression and intrinsic tumours, and computed tomography (CT) to image bony and disc anomalies of the spine and perispinal space. CT fails to

image spinal cord disease and infarction as well due to poor resolution and interference of bone artefacts. Despite extensive work-up with modern laboratory and imaging modalities, the final cause of cord infarction cannot be identified in half of the cases.

Imaging Magnetic Resonance Imaging (MRI) MRI first allows reliably the exclusion of other causes of an acute myelopathy such as extrinsic compression (epidural hematoma, tumour, abscess, disc herniation, etc.) or intramedullary lesion (tumour, cavity such as syringomyelia, vascular malformation, myelitis) non-invasively. Furthermore MRI can demonstrate cord infarction in some but not in all cases. The pattern of parenchymal signal abnormalities basically is the same as for cerebral infarctions (Takahashi et al., 1992). However, the lesion volumes are much smaller and surrounding artefacts (especially movement related, e.g. respiration) are more prominent. In the typical case, acute infarction shows a hyperintense signal on T2-weighted images compared to the surrounding normal cord parenchyma (Figs. 54.4 and 54.6). T1-weighted images can show focal cord swelling with normal or decreased signal intensity. There is no contrast enhancement. After 10 to 20 days, subacute infarction is characterized by disrupted blood brain barrier with diffuse enhancement of the lesion on postcontrast T1-weighted images (Fig. 54.5 and 54.6(c)). T2-weighted signal intensity remains high (Mawad et al., 1990). In the chronic stage, after months, there is cord atrophy on T1-weighted images with absent postcontrast enhancement and normal T2 signal. We know from cerebral infarction that such a sequence of altered MRI signals is not specific for ischemic lesions. Myelitis, granulomatous inflammation, cord contusion or neoplasm, for example, may behave quite similarly (Takahashi et al., 1992). It is the history and evolution of clinical findings which enable diagnosis of cord infarction with high accuracy. It has to be stressed that, in the peracute stage of cord infarction, MRI is usually unrevealing. Positive findings reported are usually on images taken several days after onset of spinal stroke. The earliest time that MRI can disclose cord infarction is unclear. A second MRI scan 10 to 20 days later, when other cord disease has been excluded by an emergency scan soon after onset of infarction, is recommended to prove ischemia. Another finding indicating cord ischemia, even if the cord signal has not changed, is a corresponding vertebral body infarction. Because of a common arterial supply to the posterior part of the vertebral body

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and the cord (Fig. 54.2), bone marrow signal abnormalities best seen on T2-weighted images of delayed scans are characteristic (Faig et al., 1998). The pattern of contrast enhancement can help differentiate spinal cord infarcts from other abnormal conditions. Predominant enhancement of the grey matter, especially the ventral horns, on postcontrast T1-weighted scans in the subacute stage seems to be characteristic (Fig. 54.5) and is consistent with the known greater susceptibility of the grey matter to ischemia (Gilles & Nag, 1971; Friedmann & Flanders, 1992). Due to its appearance, this pattern has been called ‘snake bite’- or ‘owl’s eyes’-like (Mawad, 1990). Months to years later MRI may reveal focal cord atrophy. Main MRI findings indicating ischemia compared to inflammation (myelitis) or demyelination (multiple sclerosis) are: anterior location of T2-hyperintensities (Takahashi et al., 1992), associated vertebral body hyperintensities, and (delayed) contrast enhancement of the grey matter. Development of faster sequences reducing movement artefacts and high field machines with greater resolution will allow more precise imaging of cord infarction in the future. Diffusion weighted imaging which has already dramatically altered the possibilities of imaging peracute strokes in the brain will soon be applicable to the cord too.

Computed tomography (CT) CT examination may be helpful to demonstrate the cause of cord ischemia such as dissecting aneurysm or a cord compression.

Myelography Indications for myelography are acute spinal cord syndromes where MRI is not readily available to exclude cord compression with the need for emergency surgical intervention. Some authors still consider myelography more sensitive than MRI to demonstrate abnormal intradural vessels in the case of spinal dural a–v fistula.

Angiography Selective catheter angiography of the aorta and the branches feeding the intrinsic cord vasculature in experienced and skilled hands is the most sensitive method to show a spinal vascular malformation. The most frequent type, the dural a–v fistula, demonstrates very characteristic features. The occlusion of the anterior spinal artery or of the artery of Adamkiewicz may indicate a vascular origin of an acute cord syndrome. However, these vessels are discontinuous or individually variable and findings inconstant, an absent radicular artery is not synonymous with occlusion.

Ultrasound Ultrasound methods may be used to evaluate the main large arteries responsible for the cord blood supply. Transesophageal echocardiography can show a cardiac embolic source or atheromatosis and dissection of the ascending aorta and of the aortic arch (Walsh et al., 1992). Aortic duplex ultrasound can demonstrate aortic dissection or expanding aneurysm. Doppler/duplex examination in the case of cervical cord ischemia may reveal vertebral artery disease (Hundsberger et al., 1998)

Electrophysiology Findings on electrophysiological studies are not specific, but can help to differentiate an ischemic cause with axonal damage resulting in reduced amplitudes of evoked potentials from a demyelinating cause such as with inflammation resulting in prolonged latencies. Anterior spinal cord infarction leads to loss of F-waves due to anterior horn involvement whereas somatosensory evoked potentials mediated by the intact dorsal roots and posterior columns are normal.

Various If an inflammatory or infectious cause is considered in the differential diagnosis, CSF analysis is mandatory. This may be the case in acute myelopathy in a patient with positive HIV serology or with known lupus erythematodes or with cutaneous signs of zoster. Increased cell count always suggests inflammatory disease, whereas increased protein content may also be seen with tumours or infarction.

Follow-up There are only very few studies evaluating the long-term prognosis of spinal cord infarction and the parameters which determine the potential for recovery (Cheshire et al., 1996). The functional long-term prognosis is generally poor with about half showing some motor improvement usually occuring in the first 2 to 4 weeks, which is of functional significance in less than one third (Foo & Rosser, 1983). Even if incomplete lesions with residual motor functions in the acute stage herald some potential for recovery, most patients remain wheelchair-bound due to residual paresis and absent sensory control. Absent motor recovery after 30 days is a bad prognostic sign for the future (Waters et al., 1993). Vesicourethral dysfunction also has a very low potential for recovery (Siroky et al., 1992). Persistent often severe pain in the paretic limbs and paresthesias seem to

Spinal stroke syndromes

be a frequent and disabling problem in the long term (Triggs & Beric, 1992; Pelser & Van Gijn, 1993)

Treatment There is no effective therapy to reduce the deficits of cord infarction in the acute stage. Secondary prophylaxis with antiplatelet drugs and anticoagulants in selected cases (e.g. cardiac embolic source) are the principal therapeutic options as in brain infarction. There are efforts to develop neuroprotective drugs not only in brain but also in cord infarction. So far the results are not encouraging. Supportive measures are very important in the acute and chronic stages to regulate bladder and bowel functions, to prevent urinary and other infections as well as decubital ulcers and painful joint contractures.

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patient with prior hemihepatectomy. European Journal of Radiology, 15, 65–67. Gottesmann, M.H., Saraya, I. & Tenti, F. (1992) Modified Brown–Séquard syndrome following coronary artery bypass graft: case report. Paraplegia, 30, 178–80 Gutowsky, N.J., Murphy, R.P. & Beale, D.J. (1992). Unilateral upper cervical posterior spinal artery syndrome following sneezing. Journal of Neurology, Neurosurgery and Psychiatry, 55, 841–3. Hundsberger, T., Thomke, F., Hopf, H.C. & Fitzek, C. (1998). Symmetrical infarction of the cervical spinal cord due to spontaneous bilateral vertebral artery dissection. Stroke, 29, 1742. Kim, R.C., Smith, H.R., Henbest, M.L. & Choi, B.H. (1984). Nonhemorrhagic venous infarction of the spinal cord. Annals of Neurology, 1, 379–85. Koch, C., Hansen, H.C., Westphal, M., Kucinski, T. & Zeumer, H. (1998). Congestive myelopathy caused by spinal dural arteriovenous fistulas. Anamnesis, clinical aspects, diagnosis, therapy and prognosis. Nervenartzt, 69, 279–86. Lazorthes, G., Gouaze, A., Zadeh, J.O., Santini, J.J., Lazorthes, Y. & Burdin, P. (1971). Arterial vascularization of the spinal cord: recent studies of the anatomic substitution pathways. Journal of Neurosurgery, 35, 253–69. McLean, J.M., Palagallo, G.L., Henderson, J.P. & Kim, J.A. (1995). Myelopathy associated with fibrocartilaginous emboli: review and two suspected cases. Surgical Neurology, 44, 228–34. Marie, P. & Foix, C. (1912). L’atrophie isolée non progressive des petits muscle de la main. Téphromalacie antérieure. Nouvelle Iconographie de la Salpetrière, 25, 353–63. Mawad, M.E., Rivera, V., Crawford, S., Ramirez, A. & Breitbach, W. (1990). Spinal cord ischemia after resection of thoracoabdominal aortic aneurysms: MR findings in 24 patients. American Journal of Neuroradiology, 11, 987–91. Mercier, E., Quere, I., Campello, C., Mares, P. & Gris, J.C. (1998). The 20210A allele of the prothrombin gene is frequent in young women with unexplained spinal cord infarction. Blood, 92, 1840–1. Moorhouse, D.F., Burke, M., Keohane, C. & Farrell, M.A. (1992). Spinal cord infarction caused by cartilage embolus to the anterior spinal artery. Surgical Neurology, 37, 448–52. Mori, S., Sadoshima, S., Tagawa, K., Iino, K. & Fujishima, M. (1993). Massive spinal cord infarction with multiple paradoxical embolism: A case report. Angiology, 44, 251–6. Nagashima, K. & Shimamine, T. (1974). Anatomopathologic study of ‘pencil-shaped’ softening of the spinal cord. Advances in Neurological Sciences, 18, 153–66. Partington, M.D., Rüfenacht, D.A., Marsh, W.R. & Piepgras, D.R. (1992). Cranial and sacral dural arteriovenous fistula as cause of myelopathy. Journal of Neurosurgery, 76, 615–22. Pelser, H. & van Gijn, J. (1993). Spinal infarction. A follow-up study. Stroke, 42, 896–8. Romanes, G.J. (1965). The arterial blood supply of the human spinal cord. Paraplegia, 2, 199–207. Ross, R.T. (1985). Spinal cord infarction in disease and surgery of the aorta. Canadian Journal of Neurological Science, 12, 289–95. Siroky, M.B., Nehra, A., Vlachiotis, J. & Krane, R.J. (1992). Effect of

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spinal cord ischemia on vesicourethral function. Journal of Urology, 148, 1211–14. Stühmeier, K.D., Grabitz, K., Mainzer B., Sandmann, W. & Tarnow, J. (1993). Use of the electrospinogram for predicting harmful spinal cord ischemia during repair of thoracic or thoracoabdominal aortic aneurysms. Anesthesiology, 79, 1170–6. Takahashi, S., Yamad, T., Ishii, S. et al. (1992). MRI of anterior spinal artery syndrome of the cervical spinal cord. Neuroradiology, 35, 25–9. Teal, P.A., Wityk, R.J., Rosengart, A. & Caplan, L.R. (1992). Spinal

TIAs – a clue to the presence of spinal dural AVMs. Neurology, 42 (Suppl. 3), 341. Triggs, W.J. & Beric, A. (1992). Sensory abnormalities and dysaesthesias in the anterior spinal artery syndrome. Brain, 115, 189–98. Walsh, D.V., Uppal, J.A., Karadis, D.G. & Chandrasekaran, K. (1992). The role of transesophageal echocardiography in the acute onset of paraplegia. Stroke, 23, 1660–1. Waters, R.L., Sie, I., Yakura, J. & Adkins, R. (1993). Recovery following ischemic myelopathy. Journal of Trauma, 35, 837–9.

Index

Note: page numbers in italics refer to figures and tables Aachen Aphasia Test 213 abducens nerve palsy 523 abducens nucleus lesion 77, 676 syndrome 76, 77 abulia 164, 224, 289–90 anterior cerebral artery infarction 227, 446 caudate infarcts 258–9, 432, 446, 473, 474 cingulate gyrus 446 major 199 minor 199 supplementary motor area 446 thalamic hemorrhage 466 thalamic infarction 259 acalculia 311 low-flow infarcts 568 precentral artery territory infarct 415 acetazolamide, low-flow infarct diagnosis 572–83, 574 achromatopsia 102 central 309 cerebral 103 acoustic stimuli 149 acral sensory syndromes 40 activities of daily living 363 acute phase of stroke 366 adrenal steroid secretion, hippocampal 288 affective disorders 285 afferent motor aphasia of Luria 417 age 63 aggressive burst 291 agitation 222–30 akinetic mutism 227 anterior cerebral artery stroke 227–30 brain lesions 224 brainstem stroke 225–6 caudate nucleus infarct 228–30, 473–4 hyperactivity 226 insomnia 201 logorrhoea 226 maniform 170 medial frontal lesions 227–8

705

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Index

agitation (cont.) meningitis 230 middle cerebral artery infarction 226–7 neuroanatomical substrate 223–4 occipital hematoma 607 posterior cerebral artery stroke 224–5 right temporal lobe infarcts 227, 228–9 subarachnoid hemorrhage 230, 621 thalamic stroke 225 top of the basilar syndrome 224 vertebral artery angiography 225 Wernicke's aphasia 227 agnosia 302–3, 306–14 colour 309 face 307–8 finger 311 lesion sites 304–5 non-canonical views 310 object orientation 310 pantomime 314, 316 paralinguistic 313 sensory 294 shape 303, 306–7 sound 312 tactile 313–14 topographical 102, 310 of usage 316 visuospatial 307, 310, 311 see also apperceptive agnosia; associative agnosia; auditory agnosia; prosopagnosia; visual agnosia agrammatism 211, 212–13 agraphesthesia 313 agraphia 216–17 anterior cerebral artery infarction 447–8 aphasic syndromes 217 apraxic 316, 319 cortical lesions 256 finger agnosia 311 left unilateral 319 posterior cerebral artery left-hemisphere infarction 484 precentral artery territory infarct 415 pure 256 subcortical lesions 256 agrypnia 201 airway protection 365 akathisia 170 akinesia caudate nucleus infarct 432 psychic 474 akinetic mutism 164, 192, 194 agitation 227 anterior cerebral artery infarction 446 anterior limb of internal capsule 431 caudate infarcts 474 consciousness disturbance 199, 200 hypersomnia 199 in deep hemispheric stroke 196 differential diagnosis 195 vertical eye movement disturbance 199 akinetopsia 310–11 cerebral 105

alexia 216–17 posterior cerebral artery left-hemisphere infarction 484 preangular 217 precentral artery territory infarct 415 pure 100, 101, 306, 308–9, 318 associative agnosia 303 somesthetic 314 subangular 217 visual agnosia 267 with agraphia 100 without agraphia 606, 685 alien hand sign 319 anterior cerebral artery infarction 448–9 alien hand syndrome 35, 319–21 frontal 320 mixed frontocallosal 320 motor 319–20 sensory 321 Alzheimer's disease 244, 260 antihypertensive therapy 276 lesions in poststroke dementia 275 neuropathological criteria 276 stroke patients 273 amaurosis fugax 11, 13 headache 14 painful ophthalmoplegia 654 repetitive TIAs 6 amino acids neuroexcitatory 296 neurotransmitter release 14 amitriptyline 72 amnesia anterior communicating artery aneurysms 447 arteriovenous malformation 247 caudate infarcts 474 medial temporal 244–5 memory impairment 242 polar artery infarcts 463 posterior cerebral artery infarction 244–5 bilateral 486 left-hemisphere 485 retrograde 246 rostral brainstem infarcts 682–3 thalamic hemorrhage 466 thalamic infarcts 245–7, 259 thalamic–subthalamic artery infarcts 465 transient global 248 visual 103, 245 amphetamine 368, 602 amusia 153, 215, 312 temporal arteries territory infarct 419 amygdala central nucleus 288 emotional functions 294 lateral nucleus 294 ANCA 326, 327, 328 anesthésie doloureuse 462 aneurysms aortic 699 carotid 476 intracranial 619, 664

Index

mycotic 621, 623 seizures 185 anger 291 cardioembolic stroke 289 expression control 288 angiitis granulomatous of nervous system 603, 700 isolated of CNS 502 angiography cerebral venous thrombosis 635–6, 642, 643 CT 661 digital intravenous 635 empty delta sign 635, 643 lateral sinus thrombosis 636, 644 spinal stroke syndromes 702 see also magnetic resonance angiography angiopathy multiple brain infarcts 502 see also cerebral amyloid angiopathy angiotensin receptor gene 288 angular artery territory infarct 418 angular gyrus syndrome 418 anisocoria 113 anomia aphasic syndrome 212, 215–16 colour 309 tactile 314, 447, 448 visual 99–100 anosodiaphoria 292 complete middle cerebral artery pial territory infarct 409 anosognosia 23, 269, 291–2 putaminal hemorrhage 593 sensory alien hand syndrome 321 anterior cerebral artery xxiii, xxiv, xxv, 439–49 A1 segment 439, 440, 442, 443 A2 segment 439, 440 akinetic mutism 199, 200 anatomy 439 atherothrombotic occlusion 444 caudate nucleus blood supply 471 cerebral hemisphere supply 381 cortical branches 439, 441, 442 dissection 443 dysarthria 335 end-zone arteries 439 faciobrachial paresis 25 fornix blood supply 244 frontal lobe irrigation 234 hypoplastic 442 median 442 occlusion 17 perforating branches 380 simultaneous with single artery occlusion 505 thrombosis 442–3 vasospasm 446 vestibular dysfunction 139, 141 anterior cerebral artery infarction 3 abulia 446 agraphia 447–8 akinetic mutism 446 alien hand sign 448–9

aphasia 447 apraxia 256 ideomotor 447, 448 callosal disconnection syndromes 447–8 crossed visuomotor ataxia 448 etiology 442–3 fecal incontinence 447 grasp reflex 447 hemispatial neglect 448 language disorders 447 mirror writing 447 motor deficit 443–6 motor weakness 24 muteness 447 neglect 257 paraparesis 446 pseudoneglect 448 sensory deficit 446 sphincter dysfunction 446–7 stuttering 447 tactile anomia 447, 448 urinary incontinence 446–7 anterior cerebral artery stroke agitation 227–30 delirium 227–30 manic behaviour 227–8 transcortical motor aphasia 214 anterior choroidal artery xxiii, 244, 380 brainstem supply 375, 376 branches 452–3 hemineglect 265 posterior paraventricular corona radiata 452 syndrome 30 vascular territory 451–3 anterior choroidal artery infarctions 451, 453–6 aneurysms 455 arteriovenous malformations 451 ataxia 454 ataxic hemiparesis 454 causes 455–6 cortical signs 454–5 emotional behaviour 455 eye movement 455 gaze 455 hemiballism 455 homonymous hemianopia 453 Horner's syndrome 455 ischemic 455–6 lacunar syndrome 449, 454 motor hemiparesis 453 motor stroke 454 neglect 257 neuropsychological signs 454–5 prognosis 456 ptosis 455 risk factors 455–6 sensorimotor syndrome 454 sensory deficit 453 sensory stroke 454 syndrome 453–5 tumours 455

707

708

Index

anterior choroidal artery infarctions (cont.) visual field defects 453–4 anterior cingulate gyrus 470, 471 damage 236 anterior circulation, acute multiple infarction 422 anterior communicating artery 380, 439–40 aneurysms 238, 239, 317, 442, 623 amnesia 447 memory loss 247–8 callosal branch 442 anterior inferior cerebellar artery (AICA) 52, 668 brainstem supply 375, 376 cerebellar supply 375, 377, 380 course 547 internal auditory artery 144 ischemia 146 medulla blood supply 534, 535 occlusion 150, 524 syndrome 535 classic 546 partial 54–5 zones of supply 133 anterior inferior cerebellar artery (AICA) infarction 54–5, 131, 546–7, 678, 679 causes 547, 679 clinical features 546–7 multiple 507, 508 posterior circulation 549–50 pontine infarcts 561 anterior internal frontal artery 441, 442 anterior ischemic optic neuropathy (AION) 122, 654 anterior operculum syndrome 416, 431 anterior parietal artery territory infarct 416–18 anterior perforated substance 377, 406 anterior spinal artery, brainstem supply 375, 376 anterior temporal artery 244 anterior thalamic peduncle 431 antiaggregation therapy caudate infarcts 475 cervico-cerebral artery dissection 664 see also antiplatelet therapy anticardiolipin antibodies 70, 114 transient monocular blindness type IV 116–17 anticardiolipin antibody syndrome 639 anticoagulants cardiac emboli 554 caudate infarcts 475 cerebral venous thrombosis 641–3 cervico-cerebral artery dissection 664 complications 641–2 lobar hemorrhage 601–2 medullary hemorrhage 538 spinal cord ischemia 703 anticonvulsants mania 291 seizure management 187 stroke recovery 368 withdrawal and status epilepticus 184 antidepressants 368 antihypertensive therapy 282, 368 antinuclear antibodies 326, 327, 328

antiphospholipid antibodies 64 central retinal artery occlusion 119 migraine 70 multiple brain infarcts 503 spinal cord ischemia 700 transient monocular blindness type IV 116–17 antiphospholipid antibody syndrome multiple brain infarcts 502 TIAs 117 transient monocular blindness 117 differential diagnosis 114 antiplatelet therapy prophylactic 554, 560 spinal cord ischemia 703 see also antiaggregation therapy antithrombotic agents brainstem infarcts 560 cerebellar infarcts 554 anxiety 287–9 abnormal fear reactions 293 anger relationship 289 delayed occurrence 292 with denial 295 depression association 287 diagnosis 287 markers 285 prevalence 287 respiratory response 356 risk factors 287 symptoms 14–15 anxiolytics 368 aorta, arteriography 700–1 aortic arch, ulcerated plaques 501 aortic clamping 699, 700 aortic coarctation 622, 699 aortic disease and spinal cord ischemia 699 apathy, poststroke 289–90 aphasia/aphasic syndromes 211–18 acute 212, 213 mixed transcortical 421–2, 655–6 multiple infarction of anterior circulation 422 adynamic 214 agraphia 217 anomic 212, 215–16, 685 anterior cerebral artery infarction 447 apraxia 315 capsuloputaminal syndromes 252 caudate nucleus infarct 432, 475 classification 212, 213 complete middle cerebral artery pial territory infarct 408, 409 delirium 254 depression association 293 dysarthria 335–6 external capsule infarcts 431 fluent 293 global 212, 213, 216 large hemispheric infarcts 494 low-flow infarcts 568 multiple infarcts 503 putaminal hemorrhage 593 simultaneous infarcts in one hemisphere 505

Index

language disturbance 253–4 functional activation 218 lesion overlap 212, 213, 214 middle cerebral artery inferior division territory infarct 411 occlusion 256 superior division territory infarct 410 mixed transcortical 212, 215 multiple infarcts 503–4 non-fluent 214, 293 outcome prediction 365 parietal hematoma 605 persisting 212, 214 posterior cerebral artery left-hemisphere infarction 484–5 precentral artery territory infarct 415 psychiatric assessment 295–6 pure motor 212, 213 putaminal hemorrhage 592–3 recovery 217–18 semantic 216 simultaneous infarcts in one hemisphere 504 striatocapsular 252–4, 255–6, 434 subcortical stroke 216, 252–4 cortical dysfunction 256 subtranscortical 256 tactile 314 temporal hematoma 605 thalamic 254–6 hemorrhage 466 transcortical motor 212, 214, 235, 236 sensory 212, 215 tuberothalamic infarctions 255 white matter lesions 212, 213 see also Broca's aphasia; conduction aphasia; motor aphasia; optic aphasia; Wernicke's aphasia aphemia, precentral artery territory infarct 415 apnea sustained inspiration 353 see also Ondine's curse; sleep apnea apneusis 353, 356 apolipoprotein E (APOE) gene 275 apperceptive agnosia 99, 100, 303, 307 visual 267, 268, 303, 307 apperceptive prosopagnosia 307 apraxia 23, 302, 314–17 conceptual 316 constructional 316–17 parietal hematoma 606 unilateral 319 dressing 317 parietal hematoma 606 frontal of Bruns 164 ideational 316 lesion sites 304–5 of lid closure of Lewandowsky 415 limb kinetic 414 melokinetic 316 orofacial 314, 316 palpatory 314

primary motor/premotor cortex stroke 234 respiratory 202 speech 316 subcortical lesions 256–7 substitutions 314–15 thalamic hemorrhage 466 trunk 164 visuomotor 257 see also gait apraxia; gaze apraxia; ideomotor apraxia aprosodia lateral premotor region stroke 234 middle cerebral artery inferior division territory infarct 411 receptive 313 Arnold's bundle 51 arousal decreased 195 phasic 193 systems 192–3 tonic 193 arrhythmias, congenital 324, 326 arteria termatica of Wilder 442 arterial disease embolic 65 occlusive extracranial 115 thrombotic 65–6 arterial dissection anticoagulation 70 migraine 69–70 arterial hypertension low-flow infarcts 579 raised intracranial pressure 329 arteriosclerosis in parkinsonism 162 see also atherosclerosis arteriovenous fistula, dural 640, 694, 701 arteriovenous malformations amnesia 247 anterior choroidal artery infarctions 455 caudate hemorrhage 476 dural 701 intraventricular hemorrhage 613 lobar hemorrhage 600–1, 603 medullary hemorrhage 538 migraine 64–5 pontine hemorrhage 527 seizures 185 spinal 619 dural 694 spinal cord ischemia 701 artery-to-artery embolism 18 centrum ovale infarcts 420 complete middle cerebral artery pial territory infarct 408 deep perforating arteries 501 lateral medullary infarct 537 posterior cerebral artery infarction 485–6 posterior circulation 506 striatocapsular infarcts 428, 434 articulation defects 334 ascending reticular activating system 192–3, 194 coma-like conditions 199 syncope 199

709

710

Index

ascending reticular activating system (cont.) wakefulness disorders 195 asimultagnosia 487 asomatognosia 321 aspiration cough 343 gag 343 incidence 344–5 pathophysiology 342 pneumonia 343, 345, 349 prevention 346–7, 348, 349–50 silent 342 syndromes 341, 342–47, 348, 349–50 aspirin brainstem infarcts 560 cerebellar infarcts 554 stroke prevention in migraine patients 72 associative agnosia 99, 100, 303, 307 prosopagnosia 303, 307–8 astasia, thalamic 462 astasia–abasia 164 astereognosia 313 cortical stroke 41 astereopsis 105 asterixis 168, 515 central sulcus artery territory infarct 416 midbrain infarcts 516 putaminal hemorrhage 595–6 asymbolia for pain 41 ataxia anterior choroidal artery infarctions 454 appendicular and PICA infarcts 548 central sulcus artery territory infarct 416 cerebellar 516 crossed visuomotor 448 homolateral and crural paresis 55, 57, 583 lateral medullary infarcts 669 pontine ischemia 674 postcommunal posterior cerebral artery infarcts 483 postural 48 sensory 43, 321 truncal 338, 545 see also cerebellar ataxia; gait ataxia; limb ataxia; optic ataxia ataxic hemiparesis 55–6, 454, 583 corona radiata 454 cortical lesions 454 lacunar syndrome 583, 584–5 midbrain infarcts 516 paramedian pontine infarcts 522, 523 pure and ischemic lesion size 586 sensory variants 585 thalamic hemorrhage 465 thalamic infarction 454 unilateral small basal pontine hemorrhage 530 atheroembolism, diffuse disseminated 114 atherosclerosis genetic factors 288 intracranial 656–7 large artery 4 multiple brain infarcts 500–1

PICA infarcts 549 speed of onset of stroke 4 atherothrombosis, midbrain infarcts 517 athetosis 166 athymormia 164, 199 atrial fibrillation 360 attention defects 89 audiometry, pure-tone 146 auditory agnosia 215, 311–13 affective 313 hemispherical strokes 153 temporal lobe infarction 156 auditory association area 215 auditory comprehension deficit 252 auditory cortex, primary 146 auditory dysfunction 144, 146–53, 154, 155–6, 157–8 auditory evoked potentials 148–9 brainstem extended/multiple infarcts 558–9 auditory function, central 148 electrophysiological evaluation 148 psychoacoustic evaluation methods 146, 157 auditory hallucinations brainstem 146 pontine infarcts 678 auditory nerve 144–5 frequency selective fibres 144 auditory pathway descending 146 stroke syndromes 149–53, 154, 155–6, 157–8 auditory perception of language 218 auditory symptoms 147 hemispherical strokes 151–3 hemorrhage 150 large vessel occlusion 149–50 small vessel occlusion 150–1 auditory system 144–6 afferent central 144, 145 blood supply 144–6 auditory transfer loss 318 autonomic dysfunction lateral medullary infarct 536, 537 paramedian massive/large pontine hemorrhage 528 autonomic processing in orbital frontal cortex 239 autonomic system 323–4, 325, 326, 327, 328–32 autoregulation of cerebral vascular bed 491 awareness 193–4 disorders 200–1 axial lateropulsion, PICA infarcts 548 Babinski reflex (sign) 49, 194 bilateral 360 lacunar syndromes 584 large hemispheric infarcts 493 pseudotumoural cerebellar infarct 673 transverse spinal cord infarction 695 balance impairment in basal ganglia lesions 364 Balint's syndrome 83, 98, 104 angular artery territory infarct 418 multiple infarcts 504 posterior cerebral artery bilateral infarcts 487

Index

simultanagnosia 309, 310 ballism 166 paroxysmal complex dyskinesia 169 see also diballism barbiturates 496 basal forebrain 243 damage 238 basal ganglia delayed hemichorea 166 graphomotor pathway 256 lacunes 443 parkinsonism associated with small vessel disease 163 basal ganglia lesions apraxia 257 balance impairment 364 catastrophe reactions 290 hypotonia 364 neurological deficit 364 basal ganglia–nigral network 364 basilar artery xxvi, 668 aneurysm 225–6 apex occlusion 465, 506 atherosclerosis 667 bifurcation 461 aneurysm 622 brainstem supply 375, 376 clot from vertebral artery occlusion 537 dissection 678 distal 488 embolism 4–5 ischemia 146 migraine 69 multiple posterior circulation infarcts 550 occlusion 149, 303, 506, 517, 520, 521–2, 677 basis pontis infarct 675 border zone cerebellar infarcts 551 clinical features 557 pontine infarcts 677, 678 pontine ischemia 674–78 prognosis 525–6 plaques 547 stenosis 525, 526 superior cerebellar artery infarct 684 thrombosis 525, 526–7 brainstem ischemia 560 treatment 559–60 vestibular syndromes 135, 137, 138 see also rostral basilar artery basilar branch atheromatous disease 521–22 basis pontis infarct 675, 676 basolateral limbic circuit 243 beading 602 Becker X-linked muscular dystrophy 324 behavioural abnormalities caudate infarcts 473–4 subcortical stroke 259–60 behavioural initiation loss 236, 237, 238 Behçet's disease 502 cerebral venous thrombosis 639, 645 Bell phenomenon 81

Benedikt's syndrome 167, 515 beta blockers 72 biballism 166 bibrachial paralysis 30, 502 bilharzosis 700 binaural tests 147 Binswanger's disease 274 Biot's breathing 202 bipolar disorder 238 blepharospasm with midbrain infarcts 516 blindness bilateral 11, 12 lone 13 cerebral 91, 92 common carotid occlusion 656 denial 91–2 monocular 11, 12 acute 117–24 low-flow infarcts 567 subarachnoid hemorrhage 622 psychic 294 see also transient monocular blindness blindsight 92 blink reflex brainstem extended/multiple infarcts 559 inferior parietal/superior temporal lobe lesions 95 blood dyscrasia 185 blood flow velocity with low-flow infarctions 565, 566 blood pressure acute stroke 329 systolic 366 border zone infarcts see low-flow infarctions brachial monoparesis 29 brachiocrural deficit 430 bradykinesia, caudate infarcts 474 brain acute lesions 293 arterial cartography 381–2, 385–403 arterial circulation 375, 376, 377–8 bicommissural plane 381, 382 damage and insomnia 201 herniation and putaminal hemorrhage 591 hypoperfusion 502 ischemia protection 566 reperfusion injury 491 vasogenic edema 491 venous anatomy 626–9 brain edema 491–2 cerebral venous thrombosis 633 induced hypothermia 497 middle cerebral artery infarction 364 therapy of postischemic 495–6 brain hemorrhage, primary 590 hematoma enlargement 595 small putaminal hemorrhage 594 brain venous thrombosis syndromes 626 clinical features 630–1 epidemiology 629–30 etiology 637–9, 645–6 investigations 631–37

711

712

Index

brain venous thrombosis syndromes (cont.) pathophysiology 629 prognosis 639–41 treatment 641–4 venous obstruction 629 brainstem xxvi afferent pathways 52 anatomic structures 400 arterial supply 378–9 arterial territories 378, 381, 382, 383–4 arterial trunks supplying 375, 376 auditory evoked responses 148 auditory hallucinations 146 auditory nerve 145 auditory symptoms in strokes 149–51, 158 cerebellar arteries 376, 377 compression PICA infarcts 548 pseudotumoural cerebellar infarcts 553 space-occupying cerebellar infarcts 561 damage level 135 disorders and ataxia 49 dysarthria 337 dysfunction 492 efferent pathways 52 extended ischemia 557–60 clinical features 557–8 electrophysiological testing 558–9 imaging 558 prognosis 560 treatment 559–60 hemorrhage 150 ischemia 18, 326 multilocular 558 rostral 679–83 micturition centre 331 monoamine systems 62 multiple lesions 507 pontomesencaphalic lesions 138 respiratory organization 353, 354 reticular formation 360 sleep-promoting systems 194 swallowing centres 341 vascular disorders 53 vertebrobasilar TIAs 16 brainstem infarction 554 apneusis 356 bilateral weakness 30 lacunar 524 locked-in syndrome 557 mechanisms 559 multiple 557–60 pure motor hemiparesis 26 rostral 102, 481 speed of onset 4 brainstem stroke agitation 225–6 coma 198–9 dysphagia 345–46 respiratory syndromes 356, 357, 358–60 sleep EEG changes 204

stupor 198–9 wakefulness disorders 195 branch retinal artery occlusion 120–1 breath holding, inspiratory 202 breathing ataxic 202 automatic 202, 355 autonomous 356, 357 limbic control 355 periodic 194 sleep disordered 202, 203 volitional 202 voluntary 355 inability 356, 357 see also Cheyne–Stokes breathing; respiration Broca's aphasia 100–1, 211, 212–13, 234 apraxia 315, 316 central sulcus artery territory infarct 416 complete middle cerebral artery pial territory infarct 409 lateral premotor region stroke 234 middle cerebral artery superior division territory infarct 410 multiple infarcts 503–4 putaminal hemorrhage 593 bromocriptine 290 Brown–Séquard syndrome 696 bulbar muscle weakness lateral medullary infarct 671 pontine ischemia 674–5 Bürger's disease 502 CADASIL headache 71 multiple brain infarcts 502 poststroke dementia 275 calcarine arteries 479 calcarine fissure 87 infarction 91 posterior cerebral arteries 486–7 calcific emboli 120–1 calcium channel blockers 72 callosal disconnection syndromes 302, 317–21 anterior 319–21 anterior cerebral artery infarctions 447–8 lesion sites 304–5 posterior 317 tactile anomia 314 callosal fibres 317 callosomarginal artery 441, 442 cancer 328 Capgras illusion (syndrome) 103, 238, 268 brain damage 308 capillary leak syndrome 487 capsular genu syndrome 29, 335 capsular infarction 28 capsular warning syndrome 28, 42 carbon dioxide reactivity in carotid ischemic syndromes 652 carbon monoxide poisoning 100 cardiac arrest 552 cardiac arrhythmia 329 cardiac damage, neurally induced 329 cardiac embolism

Index

acute multiple infarction of anterior circulation 422 anger 289 border zone cerebellar infarcts 551 brainstem extended/multiple infarcts 559 centrum ovale infarcts 420 complete middle cerebral artery pial territory infarct 408 double infarction 421 emotional behaviour 285, 289 hemiparesis 28, 445 lacunar strokes 552 large hemispheric infarcts 490 middle cerebral artery infarcts 411 multiple brain infarcts 501–2 multiple neurological complications 323–4 PICA infarcts 549 posterior cerebral artery infarction 485–6 posterior circulation 506 multiple infarcts 550 speed of onset of stroke 4 spinal cord ischemia 700 spontaneous improvement 6 striatocapsular infarction 428, 434 superior cerebellar artery infarcts 546 TIAs 18–19 cardiac enzyme activity 329 cardiac hypertrophy 324, 326 cardiac myxoma 621 cardiac surgery 700 cardio-myocytolysis 329 cardiomyopathies 323–4 dilated 326 familial hypertrophic 324, 325, 326 cardiopulmonary bypass, low-flow infarcts 578–9 cardiovascular disease life setting incidents 288 watershed infarctions 653 cardiovascular dysfunction 328–30 cardiovascular regulation, neuroanatomy 328–9 carotid aneurysms, caudate hemorrhage 476 carotid angioplasty, cervico-cerebral artery dissection 664 carotid artery angioplasty 70 atheroma 422 common 656 embolism 501 external 656 occlusive disease intracranial low-flow states 570 lower limb weakness 10 movements 18 perfusion insufficiency 18 syndromes 651–57 posterior 679, 681 stenosis atherosclerotic 500 border zone cerebellar infarcts 551 hypoperfusion 317 low-flow infarcts 566 thrombus progression 411 TIA 15, 111

venous phase angiogram 627, 628 see also internal carotid artery carotid bruit 113 carotid disease, centrum ovale infarcts 420 carotid dissection 657 Ehlers–Danlos syndrome 663–4 non-arteritic ischemic optic neuropathy 122 TIAs 114 transient monocular blindness 69 differential diagnosis 114 carotid endarterectomy 70, 500–1 low-flow infarcts 564–5, 578 carotid ischemic syndromes carbon dioxide reactivity 652 embolic mechanism 651 hemodynamic mechanism 651–2 pathophysiology 651–2 PET studies 651–2 catalepsy asymmetric 164 middle cerebral artery inferior division territory infarct 411 cataplexy 194 catastrophe reactions 290 catatonia 164 cauda equina syndrome 696–7 caudate hemorrhage 469, 475–7 clinical features 476–7 prognosis 477 stroke mechanism 475–6 treatment 477 caudate nucleus anatomy 469, 470, 471–2 blood supply 471–2 disconnection from frontal lobes 474 functional neuroanatomy 469, 470, 471 stroke mechanisms 472–3 caudate nucleus infarct 432, 469, 472–5 abulia 258–9, 446 agitation 228–30 clinical features 473–4 depression 446 hemiparesis 30 intellectual deterioration 259 language disturbance 474–5 lenticulostriate arteries 472 memory impairment 247 prognosis 475 psychotic features 229 risk factors 473 speech disturbance 474–5 treatment 475 cavernous angioma caudate hemorrhage 476 lobar hemorrhage 600–1, 603 cavernous sinuses 628–9 thrombosis 631, 636 central post-stroke pain 42–3 central retinal artery occlusion 117–19, 654 amaurotic pupil 118 antiphospholipid antibodies 119 cardiovascular signs 118–19

713

714

Index

central retinal artery occlusion (cont.) cherry-red spot at macula 118 clinical signs 119 differential diagnosis 120 intraocular pressure 118 retinal emboli 118 treatment 119–20, 121 central retinal artery TIAs 11 central sulcus artery territory infarct 416 central syndromes 194 central tegmental tract, palatal myoclonus 676 central vision 88 centrospinal infarcts 697 centrum ovale infarcts 420, 422, 654 white matter 420, 421 centrum semi-ovale, microangiopathic lacunar infarction 576 cerebellar arteries 52, 53 see also anterior inferior cerebellar artery (AICA); posterior inferior cerebellar artery (PICA); superior cerebellar artery (SCA) cerebellar ataxia 48–57 cerebellar hemorrhage 553 definition 48 neurological findings 48 vascular syndromes 53–7 cerebellar diaschisis, crossed 55–6 cerebellar edema 561 cerebellar hemisphere diseases 53 cerebellar hemorrhage 553 cerebellar infarcts 541 motor deficit 24 multiple 507, 508 PICA distribution 673, 674 pseudotumoural 552–3 PICA infarcts 673 ventricular drainage 553 space-occupying 561–2 topographic classification 507 cerebellar lesions, speech disorder 337–8 cerebellar syndromes 53, 516, 540–54 anterior inferior cerebellar artery infarcts 546–7 border zone cerebellar infarcts 550–2 imaging 540–1, 542–3 lacunar infarction 552 multiple posterior circulation infarcts 549–50 posterior inferior cerebellar artery infarcts 547–9 pseudotumoural infarcts 552–3 superior cerebellar artery infarcts 541–6 treatment 553–4 cerebellar system anatomy 49–53 cerebellum xxvi afferent fibres 50 anatomic structures 400 anterior lobe disorders 53 arterial circulation 375, 377, 379–80 arterial territories 385–87 bilateral lesions 103–5 cortex 50 efferent fibres 50 lesion causing contraversive ocular tilt reaction 136 nuclei 50

oculomotor disorders 53 paravermal zone 545 pathways 50 pial anastomotic network 377 rostral 545 saccade calibration 82 smooth pursuit 82 stroke 53–5 subdivisions 49–50 territories 402 vascular disorders 53 vascular supply 52–3 vestibular syndromes 133–5 cerebral akinetopsia 105 cerebral amyloid angiopathy 275 lobar hemorrhage 599–600, 602 multiple brain infarcts 502 cerebral arteries infarction and vestibular dysfunction 139, 141 leptomeningeal branches 381 perforating branches 380–1 territories 412–13 see also anterior cerebral artery; posterior cerebral artery cerebral blindness 91 blindsight 92 cerebral blood flow 491 regional in low-flow infarctions 565, 566, 572–3, 576–7 cerebral compliance 491–2 cerebral cortex afferent connections to cerebellum 50–2 anatomy 87–90 blood supply 87–90 efferent connections 52 extrastriate system 89 physiology 87–90 sleep–wake functions 194 cerebral hemisphere xxiii–xxv anatomic structures 401–2 arterial circulation 377–8 arterial supply 380–1, 382 arterial territories 388–99, 403 bilateral lesions 103–5 dorsal pathway 104–5 ventral pathway 103–4 dominance 195 encoding/retrieval asymmetry 243 left-sided ventral lesions 100–1 oculomotor impairment 82 right-sided ventral lesions 101–3 saccades 82–3 template map of arteries 412–13 unilateral lesions dorsal pathway 98–9 posterior 98–103 ventral pathway 99–100 white matter 420, 421 see also hemispheric infarction; hemispheric infarcts; hemispheric syndrome; hemispherical strokes; left hemisphere; right hemisphere cerebral hemorrhage neurological deficit 5

Index

speed of onset of stroke 4 cerebral hypoperfusion, global 13 cerebral ischemia diagnostic criteria 493 headache 14 cerebral lesions contralateral muscle atrophy 330 neglect 94 cerebral peduncle, anterior choroidal artery supply 452 cerebral perfusion pressure 491, 496 cerebral polyopia 98 cerebral shock, bladder hypotonia 345 cerebral tumours, lobar hemorrhage 601, 604 cerebral vascular bed autoregulation 491 cerebral vasoconstriction, hyperventilation 496 cerebral veins, cortical/deep 626 cerebral venous thrombosis 626, 627, 629 angiography 635–36, 642, 643 anticardiolipin antibody syndrome 639 anticoagulants 641–2 Behçet's disease 639, 645 brain edema 633 cerebrospinal fluid investigation 636 children 631 clinical features 630–1 coagulation disorders 639, 645 cord sign 632 CT imaging 631, 632, 633 diagnosis 630–1 electroencephalography 636 epidemiology 629–30 etiology 637–9, 645–6 hemorrhagic infarct 633, 635 heparin 642–3, 644 idiopathic 637–8, 645 incidence 629–30 intracranial hypertension 644 investigations 631–7 local causes 638, 646 MR angiography 635, 640, 641 MRI 633–5, 636, 637, 638, 639 nadroparin 643 neonates 631 oral contraceptives 639, 645 outcome 643 pregnancy 630, 639, 645 prognosis 639–41 puerperium 638–9, 645 septic 644 shunting procedures 644 signs direct 631–2 indirect 632–3 spontaneous recovery 642 status epilepticus 644 systemic disease 638, 645–6 systemic lupus erythematosus (SLE) 639, 645 Tc-labelled red cell scintigraphy 636–7 thrombolytic therapy 643–4 treatment etiologic 644

symptomatic 644 thrombotic process 641–4 ulcerative colitis 639 ultrasonography 637 venous infarcts 632–3 cerebral visual dysfunction 90–105 abnormal positive visual perceptions/distortions 95–6, 98 bilateral cerebral lesions 103–5 complex visual perception abnormalities 98 hemi-neglect 92–5, 97 unilateral posterior cerebral hemisphere lesions 98–103 visual-field defects 90–2 cerebrospinal fluid cerebral venous thrombosis 636 pressure reduction 644 spinal cord ischemia 702 cerebrovascular disease epilepsy 182, 184 headache characteristics 68–9 parkinsonism 163 silent infarction 187, 189 small vessel 122 status epilepticus 184 cerebrovascular reserve capacity 651 cerebrum, low-flow states 570–2 cervical artery dissection syndromes 660–4 cervico-cerebral artery dissection 660–4 anticoagulation 664 clinical manifestations 663–4 diagnosis 660–1 familial 664 incidence 660 intracranial aneurysm risk 664 oral contraceptives 664 pain 663 pathogenesis 661–2 prognosis 664 prophylaxis 664 recanalization rate 664 recurrence rate 664 risk factors 661–2 secondary prevention 664 spontaneous 662 treatment 664 Charcot–Wilbrand syndrome 204 Charles Bonnet syndrome 204 cheiro-oral-pedal syndrome 38, 40, 41 cheiro-oral sensory loss 416 cheiro-oral syndrome 38, 39, 40, 41 opercular 416, 417 cheiro-retroauricular symptoms 38 cherry red spot 118, 654–5 Cheyne–Stokes breathing 194, 202 bilateral hemispheric stroke 355 paramedian massive/large pontine hemorrhage 527–8 children, cerebral venous thrombosis 631 cholesterol emboli 111, 113, 120, 323 chorea caudate nucleus infarct 432 paroxysmal complex dyskinesia 169 choreoathetosis 166

715

716

Index

chorioretinitis 14 choroid circulation ischemia 13 reduced 14 see also anterior choroidal artery; posterior choroidal artery Churg–Strauss syndrome 327, 328 cingulate gyrus abulia 446 see also anterior cingulate gyrus circle of Willis 377 anterior 442 variation 443 basal perforating branches 439, 440 compensatory mechanism against ischemia 566 low-flow infarctions 573, 574 perforating arteries 429 plial infarctions 652 vascular lesion in low-flow infarcts 564 circumferential perforating arteries 694 Claude's syndrome 79, 514–15 clumsiness dysarthria 336, 522–3 lateral medullary infarct 534 postcommunal posterior cerebral artery infarcts 483 rostral basilar artery syndrome 544 see also dysarthria–clumsy hand syndrome coagulability, altered state 114–15 coagulation disorders 621 cerebral venous thrombosis 639, 645 spinal cord ischemia 700 coagulopathy, posterior cerebral artery thrombosis 486 coarctation of the aorta 622, 699 cocaine 602 subarachnoid hemorrhage 620 coccidiomycosis 700 cochlea 144 internal auditory artery occlusion 150 cochlear nucleus 145 cognitive decline, antihypertensive therapy 276 cognitive functioning 367 cognitive impairment caudate infarcts 473–4 outcome prediction 365 subcortical vascular dementia 260 subcortical vascular disease 260 cognitive organization 235–6 coital cephalagia 67 Collier's sign 680 colour agnosia 309 anomia 101, 103, 308, 309 splenial split signs 318 perception with posterior cerebral artery bilateral infarcts 487 coma 192, 198–9 AICA infarcts 546 behavioural with normal EEG 194 bilateral/basal tegmental pontine hemorrhages 529 cerebellar hemorrhage 553 lobar hemorrhage 603 mortality 199

PICA infarcts 548 pseudotumoural cerebellar infarcts 553 superior cerebellar artery infarct 545 thalamic hemorrhage 466 thalamic–subthalamic artery infarcts 463 coma-like states 192, 199 commissure of Probst 146 common carotid artery occlusion 656 communicating artery see anterior communicating artery; posterior communicating artery comorbid illness 365–7 competing stimuli 148 complement 326 comprehension, subcortical damage 256 compulsive manipulation of tools 449 computed tomography (CT) angiography 661 cerebellar stroke 540, 541 cerebral venous thrombosis 631, 632, 633 spinal stroke syndromes 702 conduction aphasia 212, 215, 504 anterior parietal artery territory infarct 417 apraxia 315 hemiparesis syndrome 655 putaminal hemorrhage 593 confusion definition 222 dream-reality 204 confusional state 222–3 acute 200, 222, 269 agitated 170 middle cerebral artery territory infarct inferior division 411 superior division 410 subarachnoid hemorrhage 621 temporal arteries territory infarct 419 conjugate-gaze palsy 30 connecting spinal arterial plexus 693 connective tissue disorders, cervico-cerebral artery dissection 662, 663–4 consciousness arousal 193 depression 363, 364 disturbance 192, 194–202, 203, 204 frontal hematoma 604 loss and TIAs 12, 15 paramedian massive/large pontine hemorrhage 527 physiology 192–4 pontine infarcts 678 pseudotumoural cerebellar infarcts 552–3 space-occupying cerebellar infarction 561–2 subarachnoid hemorrhage 620–1 thalamic hemorrhage 466 thalamic–subthalamic artery infarcts 463, 465 constructional apraxia 99, 316–17 posterior cerebral artery right-hemisphere infarction 485 unilateral 319, 448 contingency-based learning, orbital frontal cortex 239 copying ability 485 cord sign 632 corectopia, intermittent 515

Index

corneal reflex absence 360 corona radiata adjacent to lateral ventricle infarcts 431 ataxic hemiparesis 454 caudate infarcts 472, 473 posterior paraventricular 452 coronary artery bypass surgery 700 coronary heart disease behavioural risk factors 288, 289 depression 286 corpus callosum anterior cerebral artery 441 diagnostic dyspraxia 449 stroke 317 white matter fibre atrophy 317 see also callosal disconnection syndromes cortex amino acid neurotransmitter release 14 hemiparesis 23 cortical atrophy 575, 576 neglect 365 cortical blindness apperceptive agnosia 303 posterior cerebral artery bilateral infarcts 486, 686 cortical border zone 574, 576 cortical deafness 151, 153, 154, 155, 212, 215 internal capsule hemorrhage 153, 154, 155 putaminal hemorrhage 596 temporal arteries territory infarct 419 cortical depression, spreading 62 cortical dysfunction, subcortical aphasia 256 cortical hypoperfusion 256 hemineglect 265 subcortical stroke 252 cortical infarction hemiparesis 27 pure motor hemiparesis 26 vestibular syndromes 139, 140, 141 cortical ischemia 18 repetitive TIAs 6 cortical lesions agraphia 256 ataxic hemiparesis 454 cortical metabolism in cortical stroke 256 cortical neglect 258 cortical sensory syndrome 418 cortical signs, anterior choroidal artery infarctions 454–5 cortical streams 302, 303 cortical stroke cortical metabolism 256 dysarthria 336 syndromes 17, 57 sensory dysfunction 41 unilateral temporal 151–2 cortico-subcortical circuits 193 cortico-subcortical hemispheric stroke 194 corticobulbar tract 52 lesions 335 supranuclear lesions 30–1 corticocaudate connection dysfunction 474, 476

corticopontine tract 50–1, 52 supranuclear lesions 30–1 corticoreticulospinal motor system 430 corticospinal fibres 22, 334–5 corticospinal syndrome 49 corticospinal tract 22–3, 51–2, 334–5 lesions 23 pseudo-bulbar palsy 31 corticothalamic network damage 364 cough 360 aspiration 343 cervico-cerebral artery dissection 661, 662 Ondine's curse 360 reflexive 342 transient hemiplegia 655 coumarin 527 cranial nerve abnormalities with small unilateral tegmental pontine hemorrhages 529 crossed 529 dysfunction with dysphagia 343 ipsilateral deficit in cervico-cerebral artery dissection 663 ischemia 326 ischemic syndromes 326 lesions and dysarthria 336 paralysis and locked-in syndrome 200 swallowing 341 cranial nerve palsy arterial dissection 326 lower 30–1, 55, 623 compressive 657 paramedian massive/large pontine hemorrhage 528 peripheral 326 pontine ischemia 676 superior cerebellar artery classic syndrome 543 unilateral tegmental infarcts 524 crossed cerebellar diaschisis 55–6 crural monoparesis 29 anterior cerebral artery infarction 444 crural monoplegia 444 crural paresis 444 crus cerebri 51 crying, pathological 31, 290 anterior choroidal artery infarctions 455 pontine ischemia 675 subcortical stroke 260 cryoglobulinemic vasculitis 327, 328 cryoglobulins, serum 328 cryptococcosis 700 deafness 146 large vessel occlusion 149–50 paramedian massive/large pontine hemorrhage 528 temporal arteries territory infarct 419 unilateral 150 word 153, 155–6 see also auditory entries; cortical deafness; hearing deficits; word deafness decerebrate movement 528 decompression sickness 129 decompressive surgery 497

717

718

Index

deep hemisphere stroke, neurobehaviour 252–61 defecation control 331–2 see also fecal incontinence Degos disease 119 Dejerine syndrome 537 Dejerine–Roussy syndrome 170 delirium 192, 199, 200, 222–30 anterior cerebral artery stroke 227–30 aphasia 254 diagnostic criteria 222, 223 incidence 224 middle cerebral artery infarction 226, 227 inferior division territory 411 posterior cerebral artery bilateral infarcts 487 prognosis in elderly 223 rostral basilar artery 225 subarachnoid hemorrhage 621 temporal arteries territory infarct 419 tremens 222 delusions with basal forebrain lesions 238 dementia caudate infarcts 474 memory impairment 244 multiple infarcts 504, 508–9 pre-existing 273 risk factors 508–9 thalamic infarcts 265 see also vascular dementia dementia, poststroke 279–82 Alzheimer pathology 281 brain lesions 280–1 epidemiology 279–80 incidence 273 multifactorial origin 281–2 multiple lacunar infarcts with leukoencephalopathy 280–1 outcome 280 prevalence 281 risk factors 281–2 strategic vascular lesions 280 stroke prevention 282 survival 283 vascular brain lesions 280 white matter changes 281 denial 291, 293 behavioural reactions 292 delayed poststroke depression/anxiety 295 dentate nucleus cavernoma 134, 136 lesions 134 depression 285–7 anosognosia coexistence 292 anxiety association 287 caudate infarcts 446, 474 coronary heart disease 286 delayed occurrence 292 delayed poststroke with denial 295 diagnosis 285–6 hypertension 286 left hemisphere 285, 286 lesion location 286

markers 285 middle cerebral artery superior division territory infarct 410 migraine 72 mortality rate 294 poststroke 235, 293, 367–8 prevalence 286 primary familial 244 right hemisphere syndromes 286 risk factors 286 serotoninergic mechanism 296 severity 286 stroke outcome 294–5 subcortical stroke 265–6 subcortical vascular disease 266 treatment 287 depth perception, stereoscopic 105 descending motor pathways 330 desipramine 368 detrusor hyperreflexia 697 detrusor reflex 331 detrusor–sphincter dyssynergia 331, 697 diabetes brainstem extended/multiple infarcts 559 caudate nucleus infarcts 473 centrum ovale infarcts 420 multiple brain infarcts 501 multiple cerebellar infarcts 509 parkinsonism associated with small vessel disease 163 diagonal band 243, 247–8 diaphragm, asymmetric function 355 diaschisis 217 cortical 257 crossed cerebellar 364 frontal 258 regional 256 subcortical damage 252 diazepam 248 diballism 166 diet, aspiration prevention 346–7, 348 dietary supplements 349 diffusion weighted imaging 540–1, 542–3 diltiazem 72 diplopia 16 rostral basilar artery syndrome 544 transient 14 disseminated intravascular coagulation 502 multiple infarcts 504 distal basilar artery occlusion 488 distal vertebral artery 534, 535 distorted stimuli 148 dizziness rostral basilar artery syndrome 544 superior cerebellar artery infarct 545 see also vertigo dopamine receptor antagonists 368 Doppler sonography, cervico-cerebral artery dissection 661–2, 664 dorsal nucleus hematoma 254 dorsal visual pathway preservation 307 dorsolateral pontine nuclei (DLPN) 79, 83, 84 dorsolateral prefrontal circuit 469, 470

Index

dorsomedial nuclei memory loss 245–6 vascularization 381 dreaming altered 202, 204 cessation 204 reduction 204 rostral brainstem ischemia 681–2 dreams, acting out 204 dressing apraxia 317, 606 drowsiness 195–8 rostral basilar artery syndrome 544 drugs in stroke recovery 368 dural arteriovenous fistula 640, 694, 701 dural arteriovenous malformations 701 dural sinuses 627–9 neoplastic occlusion 638 thrombosis 635, 642 dysarthria 10–11, 16, 334–9 ataxic 337–8 brachial monoparesis 336 brainstem 337 caudate infarcts 474 central sulcus artery territory infarct 416 cerebellar 48, 53, 337–8 cerebellar hemorrhage 553 classification 334, 336, 337, 338 combined upper/lower motor neuron lesions 337 contralateral hemiparesis 335, 336 cortical stroke 336 cranial nerve lesions 336 dysphagia 346 extrapyramidal lesions 338–9 flaccid 336–7 hemiparesis 25 hyperkinetic 338, 339 hypokinetic 338–9 lacunar syndrome 581 lateral medullary infarct 535, 671 lower motor neuron lesions 336–7 pontine ischemia 674–5 pure 29 scanning 338 spastic 335, 336, 337 subclasses 334 subcortical stroke 336 aphasia 216 superior cerebellar artery infarct 545, 693, 684 supranuclear lesions 335, 336 upper motor neuron lesions 334–6, 337 voice 336, 337, 339 dysarthria–clumsy hand syndrome 55, 56, 336, 520, 583 lacunar syndrome 583, 584–5 paramedian pontine infarcts 522–3 small putaminal hemorrhage 594 unilateral small basal pontine hemorrhage 530 dysarthria–facial syndrome 523 dysautonomia 49 dysdiadochokinesia 338 dysgraphia 606

dyskinesia paroxysmal complex 165–6, 169 transient/paroxysmal/episodic/orthostatic 169 dyslexia central 101 deep 217 neglect 92, 100, 309 occipital hematoma 606 surface 217 dysmetria 338 lacunar syndromes 584 recovery 54 dysphagia 341, 342–47, 348, 349–50 brainstem stroke 345–6 cranial nerve dysfunction 343 diagnosis 342–3, 344 dysarthria 346 feeding tubes 346–7, 349 gastrostomy placement 349–50 incidence 344–5 large vessel disease 346 laryngopharyngeal sensory discrimination deficits 342 lateral medullary infarct 535 lesion location 345–6 management 347 pathogenesis 345 pathophysiology 342 pontine ischemia 674–5 progression of stroke syndromes 345 stroke complication 365 TIAs 10 treatment 346–7, 348, 349–50 dysphasia 10–11, 16 deep 215 hemiparesis 30 lacunar syndrome 587 dysphonia lateral medullary infarcts 671 pontine ischemia 674–5 dyspnea 355 dyspraxia, diagnostic 449 dysprosody 211 dystonia 166–7 cephalic 166 choreoathetosis 166 focal hand/foot 166 paroxysmal complex dyskinesia 169 progressive 167 tonic spasms 166–7 ear extinction, paradoxical 148, 318 ECG changes 329 echoes, suppression of perception 151 Edinger–Westphal nucleus 677, 681 Ehlers–Danlos syndrome cervico-cerebral artery dissection 662 type II 663–4 type IV 628 electroconvulsive therapy 287 electroencephalography 636

719

720

Index

electronystagmography 559 electrophysiology of spinal stroke syndromes 702 embolism border zone cerebellar infarcts 551 carotid artery 501 fibrocartilaginous 700 infarction speed of onset 4 intra-arterial 485 intracranial 485–6 large hemispheric infarcts 490 multiple posterior circulation infarcts 550 platelet-fibrin 120, 121 pontine infarcts 521–2 posterior cerebral artery bilateral infarcts 486–8 pulmonary 360, 640 thromboembolism 564 vascular 323–4 see also cardiac embolism; retinal emboli emotion appraisal 288 emotional aptitudes 293–4 emotional behaviour 285 anterior choroidal artery infarctions 455 cardioembolic stroke 289 index 295 emotional lability 290 emotional peak and stroke onset 288 emotional processing, orbital frontal cortex 239 emotional reactions middle cerebral artery inferior division territory infarct 411 quantification 296 respiratory response 356 see also crying, pathological; laughter, pathological emotional status 367–8 emotionalism 290 empathy 239 empty delta sign 631–2, 633 angiography 635, 643 encephalopathy Binswanger's disease 274 diffuse 168 metabolic 223 post-traumatic 269 subcortical arteriosclerotic 56–7 toxic 223 endothelium in migrainous stroke 64 environment, spatial temporal processing 288 environmental dependency syndrome 238 eosinophilic vasculitis 116 ephedrine 620 epilepsy age-specific incidence 184 post-stroke 186 stroke as cause 182 see also seizures; status epilepticus ergotamine 61, 72 erythrocyte sedimentation ratio (ESR) 366 Escherichia coli 638 excitatory burst nucleus 77 executive functions of dorsolateral prefrontal cortex 235 Exner's area 316 external capsule 431–2

external carotid artery 656 extracranial artery-to-intracranial artery (ECA-ICA) anastomoses 566, 569 bypass surgery 572, 578, 579 high-flow bypasses 566 extrapyramidal lesions 338–9 extrathalamic reticulo-frontal afferents 199 extrinsic intraspinal perimedullary arterial network 693 eye deviation complete middle cerebral artery pial territory infarct 409 large hemispheric infarcts 494 low-flow infarcts 568 middle cerebral artery superior division territory infarct 410 eye disease, progressive ischemic 579–80 eye movement anterior choroidal artery infarctions 455 cerebellar ataxia 48 cerebral hemispheres 82–4 conjugate lateral 76 convergence abnormalities 680 disorders 30, 76–84 medial medullary infarct 537 paramedian massive/large pontine hemorrhage 528 lateral 76–9 afferences of premotor structures 79 final common pathway 76–8 premotor structure 77–9 pontine ischemia 675, 676–7 pursuit 83–4 suprareticular structures 82 top of the basilar syndrome 679 vertical 76, 79–82 brainstem afferences 80–2 final common pathway 79–80 paralysis 81 premotor structures 80–2 see also gaze; gaze palsies; locked-in syndrome; one-and-a-half syndrome eyelid apraxia of lid closure of Lewandowsky 415 retraction 515, 680 face agnosia 307–8 paragnosia 308 perception testing 102 facial dysesthesia 670–1 facial pain lateral medullary infarct 535, 536, 670 pontine ischemia 677 trigeminal neuralgia 38–9 facial palsy isolated 335 supranuclear 29 facial paresis isolated 29 medial medullary infarct 672 syndrome 335 facial pulses, low-flow infarcts 569 facial recognition 294 facial sensory symptoms, bilateral 41–2

Index

facial sinus infection 638, 646 facial weakness lateral medullary infarct 536 pontine ischemia 674–5 unilateral 10 faciobrachial paresis 23, 25 faciobrachial sensorimotor deficit 408 factor V Leiden mutation 639 falx cerebri 628 contrast enhancement 633 familial hypertrophic cardiomyopathies 324, 325, 326 family history, caudate nucleus infarcts 473 fear 287–9 abnormal reactions 293 anger relationship 289 decreased experience 292 emotional perception 294 impaired recognition 293 stroke relationship 287–9 fecal continence 331–2 fecal incontinence 331–2 anterior cerebral artery infarction 447 outcome prediction 365 fibreoptic endoscopic evaluation of swallowing (FEES) 342–3 fibrin microemboli 64 plugs 121 fibrinogen 366 fibrinolytic agents intravenous 644 lobar hemorrhage 601–2 fibrocartilaginous embolism 700 finger agnosia 311 flocculonodular syndrome 53 flocculovestibular neurone 79 flocculovestibular tract 82 flunizarine 72 fluoxetine 368 Foix–Alajouanine syndrome 701 Foix–Chavany–Marie syndrome 31, 416 orofacial apraxia differential diagnosis 316 foramen ovale, patent 71, 360 foveal vision 89 Frégoli syndrome 308 frontal apraxia of Bruns 164 frontal artery 441, 442 frontal cortex working memory 243 see also mesial frontal cortex frontal eye field 79 afferences 80 dorsolateral prefrontal cortex 235 lesions 84 saccade triggering 82–3 frontal gait disorder 164 frontal lobe xxiii anatomy 232–4 deficit with caudate nucleus infarct 432 disequilibrium 164 hematoma 603–4, 606 irrigation 234

lesions 232–4 cerebellar-like symptoms 49 neocortical processing 232–3 organizational features 232–4 frontal lobe stroke syndromes 232, 234–40 clinical correlates 234–6, 237, 238–40 clinical presentation 234–6, 237, 238–40 deep white matter pathways 239–40 hypersomnia 196 lateral 234–6 mesial 236, 237, 238 neurorehabilitation 240 outcome 240 recovery 240 ventral 238–9 frontal–striatal–thalamic–frontal parallel circuits 469, 470, 471 frontocaudate circuit disturbance 446 frontopolar artery 441, 442 frontopontine tract 51 frontotemporal hypoperfusion 256 fusiform gyri 102 fusion ability evaluation 148 gag, aspiration 343 gait initiation failure 57 isolated ignition failure 164 parkinsonian 163 gait apraxia 164, 317 magnetic 164 gait ataxia 48 cerebellar hemorrhage 553 cerebellar stroke 540 dysarthria 338 lateral medullary infarcts 536 PICA infarcts 548 superior cerebellar artery infarct 545, 684 gait disorders frontal 164 higher level 163–4 senile 162, 163–4 gaze anterior choroidal artery infarctions 455 conjugate horizontal 676 deviation with putaminal hemorrhage 591 frontal hematoma 604 rostral brainstem infarcts 680–1 top of the basilar syndrome 679 vertical abnormalities in thalamic hemorrhage 466 vertical paralysis 80 gaze apraxia Balint's syndrome 104–5 posterior cerebral artery bilateral infarcts 487 simultanagnosia 309 gaze palsies 30 combined upward-/downward-gaze 515 conjugate 30 dissociated vertical 515 downward-gaze 515 horizontal 523 lateral 30

721

722

Index

gaze palsies (cont.) PICA infarcts 673 pseudosixth 680 temporal hematoma 605 thalamic–subthalamic artery infarcts 473, 465 top of the basilar syndrome 679–80 upward-gaze 515 vertical 524 gender 63 geniculate body 452 medial 146 geniculocalcarine tract 87–8 infarction 91 Gerstmann's syndrome 104, 309, 311 angular artery territory infarct 418 posterior cerebral artery infarction 685 giant cell arteritis headache 71 ischemic optic neuropathy 123 spinal cord ischemia 700 temporal artery biopsy 124 pulse 113 transient monocular blindness differential diagnosis 113–14 vasospastic 116 Glasgow coma scale 360 glaucoma, neovascular 115 globus pallidus anterior choroidal artery supply 452 caudate nucleus inhibitory projections 475 internal nucleus 469 glutamate hippocampal/hypothalamic responsiveness 296 stroke onset 5 glycerol 496 glycine 290 granulomatous angiitis 603, 700 granulomatous arteritis 71 graphesthesia 41 graphomotor pathway, basal ganglia 256 graphomotor pattern transfer 319 grasp 320 instinctive reaction 449 pathological phenomenon 447 reflex 449 anterior cerebral artery infarction 447 graviceptive pathway 135 great radicular artery of Adamkiewicz 691, 692, 693 Guillain–Barré syndrome 324 Guillain–Mollaret triangle 676 hallucinations 202, 204 brainstem strokes 149 hypnagogic 197 middle cerebral artery infarction 226, 227 paramedian massive/large pontine hemorrhage 528 peduncular 197, 682 poststroke psychosis 291 release 95–6 phenomena 204

rostral brainstem ischemia 681–2 visual 95–6 see also auditory hallucinations hallucinosis, peduncular 96, 194, 202, 204 midbrain infarcts 516 haloperidol 248 hand anarchic 320 dystonia 43 thalamic infarcts 462 see also alien hand sign; alien hand syndrome headache 60–73 aneurysmal 66 benign thunderclap 618, 619 biphasic 620 CADASIL 71 cerebellar hemorrhage 553 cerebellar stroke 540 cerebral venous thrombosis 630 cerebrovascular disease subtypes 65–9 cervico-cerebral artery dissection 663 characteristics in cerebrovascular disease 68–9 consciousness loss 66 embolic arterial disease 65 frontal hematoma 604 giant cell arteritis 71 granulomatous arteritis 71 hemorrhage 62 intracerebral hemorrhage 68 ischemic stroke 65 lacunar infarction 71–2 lateral medullary infarct 535, 537, 672 lobar hemorrhage 603 middle cerebral artery 69 non-aneurysmal 66 NSAIDs 72 occipital 620 hematoma 606–7 oral contraceptives 70 pain location 68, 69 pain-sensitive vessels 62 pathophysiology 61–2 periarteritis nodosa 71 PICA infarcts 548, 673 posterior cerebral artery 69 posterior fossa hemorrhage 68 sentinel 66, 619 small vessel disease 71–2 speed of onset 618–19 stroke 64–5 risk 63 subarachnoid hemorrhage 66, 68–9, 618–19 superior cerebellar artery infarct 545 Takayasu's disease 71 temporal arteritis 71 temporal hematoma 604 tension-type 68, 69 thrombotic arterial disease 65–6 thunderclap 66, 67–8 TIAs 14, 65 vasodilatation 62

Index

venous thrombosis 70 see also migraine hearing deficits 146 auditory system involvement 158 paramedian massive/large pontine hemorrhage 528 pontine ischemia 678 see also auditory entries; cortical deafness; deafness; word deafness hearing evaluation 146–9 heart disease see cardiac and cardiovascular entries; coronary heart disease; myocardial infarct heart failure, congestive 323 hemangioblastoma 701 hematological disorders 502–3 hematoma fulminant putaminal hemorrhage 591 intramural 661 hemiachromatopsia 100 hemiakinetopsia 99 hemialexia, left 318 hemianacusia 151–2 hemianesthesia 451 with sensory tract lesion 49 hemianomia, left visual 317–18 hemianopia blindsight 92 complete 90 contralateral 90 hemispheral infarction in posterior cerebral artery territory 483–4 inattention relationship 94–5 large hemispheric infarcts 493 macular-involving 100 macular-splitting 100 partial 90 posterior cerebral artery infarction 684–5 pure alexia 100, 101 simultaneous infarcts in one hemisphere 504 simultaneous with single artery occlusion 506 temporal hematoma 605 watershed infarctions 653–4 hemianopia–hemiplegia 421 syndrome 655 hemianopic defects, bilateral 91, 96 hemiasomatognosia 593 hemiattention 92–3 middle cerebral artery superior division territory infarct 410 parietal hematoma 605 hemiballism 164–6 anterior choroidal artery infarctions 455 paroxysmal 165 subthalamic nuclei infarcts 683 transient 165 hemichorea 165 delayed 166 low-flow infarcts 567 putaminal hemorrhage 595 hemichorea–hemiballism 164–6 putaminal hemorrhage 595 hemiconcern, acute 417–18 hemidystonia 166 delayed 167 thalamic infarcts 462

hemiextinction 418 hemihypesthesia large hemispheric infarcts 493 thalamic hemorrhage 466 hemihypokinesia 164 hemimedullary infarction 672–3 hemimedullary syndrome of Babinski–Nageotte 538 hemimyoclonus 168 hemineglect 92–5, 264–6 anatomoclinical correlations 265 caudate infarcts 474 constructional apraxia 99 mental imagery 264 models 265–6 modular deficit 264–5 neglect dyslexia 100 perception 264, 265 precentral artery territory infarct 415 recovery 266 rehabilitation 266 testing 93–4, 97 visuo-spatial 265 hemiparesis 10, 22, 23–5 anterior cerebral artery infarction 444–5 brachiocrural 27 cardiac embolism 28 caudate infarct 30 cerebral–lesion localization 24 complete middle cerebral artery pial territory infarct 409 cortical infarction 27 crural 653 dysphasia 30 eye-movement disorders 30 flaccid 591 hemimedullary infarction 673 herald 525, 674 hypesthetic ataxic 30 lacunar syndromes 29–30 large hemispheric infarcts 493 lateral medullary infarct 536 low-flow infarcts 568 medial medullary infarct 25, 537, 672 middle cerebral artery infarction 24 superior division territory 410 neuropsychological dysfunction 30 pontine 24–5 postcommunal posterior cerebral artery infarcts 483 posterior cerebral artery occlusion 482 pure motor 25–8, 29, 430, 431 putaminal hemorrhage 591 speech dysfunction 30 striatocapsular infarction 453 subarachnoid hemorrhage 623 thalamic hemorrhage 466 thalamic infarction 30 see also ataxic hemiparesis hemiphenomena, TIAs 10, 16 hemiplegia denial 291 flaccid 568 hyperkinesia contralateral to 170

723

724

Index

hemiplegia (cont.) large hemispheric infarcts 493 middle cerebral artery infarction 451 paramedian pontine infarcts 522 massive/large hemorrhage 528 posterior cerebral artery infarction 685 occlusion 481–2, 516 simultaneous infarcts in one hemisphere 504 simultaneous with single artery occlusion 506 temporal hematoma 605 time of development 3 transient cough-induced 655 unilateral small basal pontine hemorrhage 530 weakness unawareness 23 hemisensory deficit 591 temporal hematoma 605 hemisensory loss anterior parietal artery territory infarct 416 complete middle cerebral artery pial territory infarct 409 middle cerebral artery superior division territory infarct 410 posterior parietal artery territory infarct 418 small unilateral tegmental pontine hemorrhages 529 striatocapsular infarction 433–4 hemisensory neglect 417–18 hemisensory signs in ataxic hemiparesis 56 hemispatial attention 258 hemispatial neglect 321 angular artery territory infarct 418 anterior cerebral artery infarction 448 anterior choroidal artery infarctions 455 left 236 middle cerebral artery superior division territory infarct 410 posterior cerebral artery occlusion 482 hemispheric infarction bilateral 30 double 420–1, 422 unilateral 655–6 posterior cerebral artery 483–4 silent and mania 290 status epilepticus 184 see also left hemisphere; right hemisphere hemispheric infarcts, large 490–7 clinical course 493–4 decompressive surgery 497 epidemiology 490 etiology 490 induced hypothermia 497 mortality prediction 495 pathophysiology 490–2 prognosis 494–5 radiological findings 492–3, 494 secondary hemorrhage risk 495 therapy 495–6 new/experimental 496–7 hemispheric infarcts, multiple 499–509 causes 500–3 frequency 499–500 incidence 499–500

simultaneous 503–8 in one hemisphere 504–5 with single artery occlusion 505–6 hemispheric syndrome, major 6 hemispherical strokes auditory agnosia 153 auditory symptoms 151–3 coma 198 deep 252–61 respiration 355 sleep EEG changes 204 stupor 198 hemolytic uremic syndrome 503 hemorrhagic stroke 5 headache 66–9 Henoch–Schönlein purpura 327, 328 heparin 527 brainstem infarcts 560 cerebellar infarcts 564 cerebral venous thrombosis 642–3, 644 cervico-cerebral artery dissection 664 herald hemiparesis 525, 674 hereditary hemorrhagic telangiectasia 622 herpes zoster 328 Heschl's gyrus 311 Heubner's artery 439, 440–1, 443 caudate nucleus blood supply 471 infarcts 472 occlusion 445 hiccup 360 intractable 168–9 lateral medullary infarcts 671–2 hippocampus adrenal steroid secretion 288 emotional functions 294 infarction 479 memory loss 251 HIV infection, CSF analysis 702 Hollenhorst plaques 120, 121 homolateral ataxia and crural paresis 55, 57, 583, 584–5 homonymous hemianopia 13, 421 anterior choroidal artery infarctions 453 syndrome 30 congruous 93 middle cerebral artery infarction 451 complete pial territory 409 inferior division territory 411 occipital hematoma 607 parietal hematoma 605 posterior cerebral artery occlusion 482 putaminal hemorrhage 591 temporal hematoma 604 homonymous hemifield defects 91 Horner's syndrome 326 anisocoria 113 anterior choroidal artery infarctions 455 ataxia association 49 carotid dissection 657 caudate hemorrhage 477

Index

cervico-cerebral artery dissection 663 lateral medullary infarcts 535–6, 671 rostral basilar artery syndrome 544 superior cerebellar artery classic syndrome 543, 683 hostility 288–9 hydrocephalus communicating 615 intraventricular hemorrhage 613, 615 obstructive after caudate hemorrhage 477 cerebellar infarcts 553 PICA infarcts 548 subarachnoid hemorrhage 623 hydrops, endolymphatic 129 5-hydroxyindoleactetic acid (5HIAA) 296 5-hydroxytryptamine (5-HT) see serotonin hyperactivity agitation 226 logorrhoea 226 neuroanatomical substrate 223–4 hyperacusis 146 brainstem strokes 149 hyperarousal 199 hyperattention syndromes 275 hypercholesterolemia 473 hyperglycemia 366 hyperhydrosis 332 hyperkinesias complex 170 with mutism 194 hyperkinetic movement disorders 164–70 akathisia 170 asterixis 168 athetosis 166 compulsive motor behaviours 170 delayed hemichorea 166 dyskinesia 169 dystonia 166–7 hemichorea–hemiballism 164–6 hyperkinesia complex 170 contralateral to hemiplegia 170 hyperplexia 169 limb shaking 169 maniform agitation 170 mirror movements 169 myoclonus 168–9 pseudoathetosis 166 stereotypies 169 tremor 167–8 hypermotility, non-goal directed 170 hyperperfusion syndrome with leukoencephalopathy 70 hyperplexia 169 hypersomnia/hypersomnolence 195–8 active 195 akinetic mutism 199 circadian 204 daytime 200, 201 deep hemispheric stroke 194, 195–6 frontal lobe syndrome 196 megaphagia 204

mesencephalic stroke 197 paroxysmal 204 passive 195 pontine stroke 197 poststroke 195 presleep behaviour 196 rostral brainstem infarcts 681 with supranuclear vertical gaze defects and confabulatory amnesia 196 tegmental mesencephalic stroke 197 thalamic stroke 196 thalamic–subthalamic artery infarcts 463 hypertension acute stroke 329 arterial low-flow infarcts 579 raised intracranial pressure 329 caudate hemorrhage 475 caudate nucleus infarcts 473 centrum ovale infarcts 420 cerebellar hemorrhage 553 depression 286 intracranial 630, 644 intrathoracic 360 lobar hemorrhage 599 migrainous stroke 63 multiple brain infarcts 501 parkinsonism associated with small vessel disease 163 pontine hemorrhage 527 subarachnoid hemorrhage 622 hyperthermia outcome prediction 366–7 paramedian massive/large pontine hemorrhage 528 hyperthymia, persisting 291 hyperventilation central 360 cerebral vasoconstriction 496 prognosis 360 hypervigilance 199 hyperviscosity syndrome 129 hypesthesia 530 hypesthetic ataxic hemiparesis syndrome 39–40 hyphema, spontaneous 115 hypocapnia 360 hypokinesia 164 hypokinetic movement disorders 162–4 asymmetric catalepsy 164 motor neglect 164 senile gait disorders 163–4 hypophonia 216 hypotension 330 posterior cerebral artery bilateral infarcts 487 spinal cord ischemia 701 systemic border zone cerebellar infarcts 552 low-flow infarcts 568 watershed infarction 4, 653 hypothalamus lesions and thermic dysregulation 332 hypothermia, induced 497 hypotonia 338 basal ganglia lesions 364

725

726

Index

ideomotor apraxia 314–16, 319 anterior cerebral artery infarction 447, 448 complete middle cerebral artery pial territory infarct 409 left unilateral 319 low-flow infarcts 568 IgA vascular deposits 328 imipramine 287 inattention contralateral with occipital hematoma 607 hemianopia relationship 94–5 incontinence 331–2 see also fecal incontinence; urinary incontinence infarction speed of onset 3–5 watershed 4 infection, cervico-cerebral artery dissection 661 infective endocarditis 323, 621 inferior colliculus 145–6 lesion 148 small vessel infarcts 151 inferior mesial frontal cortex 238 inferior parietal artery 441, 442 inferior parietal lobule 265 inferior sagittal sinus 628 inflammatory bowel disease 328 inflammatory disease, spinal cord ischemia 700 infratentorial stroke 360 inhibitory burst neurones 76, 78 inhibitory control of interference loss 228 inner ear hair cells 144 insomnia 199, 200, 201 intellectual impairment deterioration with caudate infarcts 259 poststroke 286 intensive-care units, specialist 365–6 internal auditory artery 144 AICA territory infarct 678 occlusion 150 internal auditory canal 144 internal capsule 51 anterior choroidal artery supply 452 anterior limb anterior lenticulostriate arteries 471 caudate infarcts 472 infarcts 430–1 ataxic hemiparesis 56 hematoma 591–2 hemorrhage and cortical deafness 153, 154, 155 inferior genu infarction 247, 259 lacunes 443 stroke 55–6 dysarthria 335 subcortical infarcts 252 upper part infarcts 431 watershed infarcts 436 white matter connection damage 434 internal carotid artery bruit 113 cervico-cerebral artery dissection 663, 664 disease 443

dissection 3–4, 113, 326, 443 incidence 660 low-flow infarctions 565, 576 migraine 69 site 660 embolic occlusion 490 superior cerebellar artery infarct 545 embolic phenomenon 3 extraterritorial infarctions 651 hemodynamically severe disease 655 occlusion 4, 13, 18 asymptomatic 651 atherothrombotic 576 bilateral 656 carotid dissection 657 centrum ovale infarcts 654 collateral pathway recruitment 566 double infarction 421 intracranial 656–7 low-flow infarcts 568, 570, 571–2 moriatic aphasia–sensorimotor hemiparesis 656 ocular signs 654–5 outcome 571, 573 plial infarctions 652 prognosis 578 risk factors 652 seizures 189 siphon 656–7 stroke rate 652 TIAs 652, 655 unilateral 652–6 unilateral double hemispheric infarction 655–6 watershed infarctions 652–4 perforating branches 380 pseudo-occlusion 565, 573 stenosis diagnostic imaging 573 low-flow infarcts 566 seizures 189 surgical treatment 579 territorial infarctions 651 transient cerebral ischemia 169 international normalized ratio (INR) 601–2 internuclear ophthalmoplegia 76, 77, 82 paramedian pontine infarcts 523 pontine ischemia 676–7 interpeduncular arteries 378 interstitial nucleus of Cajal 138, 139 intra-arterial embolism 485 intracerebral hemorrhage 18 headache 68 hematoma enlargement 5 seizures 182 stroke type 185 see also lobar hemorrhage intracranial aneurysm cervico-cerebral artery dissection 664 ruptured 619 intracranial atherosclerotic disease 656–7 intracranial embolism 485–6

Index

intracranial hypertension benign 630 cerebral venous thrombosis 644 intracranial pressure, raised arterial hypertension 329 barbiturates 496 cerebellar infarcts 554 induced hypothermia 497 intracranial volume 492 large hemispheric infarcts 494 posterior cerebral artery infarction 486 pulmonary edema 329 subarachnoid hemorrhage 66 therapy 495 venous thrombosis 70 intracranial pressure monitoring 496 intralabyrinthine hemorrhage 150 intralaminar nuclei vascularization 381 intraocular hemorrhage 622 intraocular pressure, central retinal artery occlusion 118 intraspinal perimedullary arterial network, extrinsic 693 intraventricular hemorrhage 612–16 blood volume 614 caudate hemorrhage 476 clinical features 612–13 CT scan 613 fulminant putaminal hemorrhage 591 memory loss 247 primary 612, 614, 615 prognosis 613–16 secondary 612–13 surgery 615 thrombolysis 615, 616 tissue plasminogen activator (tPA) 615 treatment 613–16 urokinase 615 ischemic stroke anterior circulation damage 3–4 emotional disturbance 288 headache 65 migraine 63 posterior circulation damage 4–5 isolation syndrome 212, 215 jerks paroxysmal complex dyskinesia 169 thalamic infarcts 462 jerky dystonic unsteady hand syndrome 170 Jervell and Lange Nielsen syndrome 326 Kana 217 Kanji 217 kinesthetic aphasia 417 Kleine–Levine-like syndrome 204 Klüver–Bucy syndrome 294 Kölliker–Fuse nucleus 353, 354 Korsakoff syndrome 247 labyrinthian syndrome, vertiginous 673 labyrinthine hemorrhage 129

lacunar infarction 429–30, 552 ataxic hemiparesis 55 brainstem 524 headache 71–2 isolated facial paresis 29 isolated monoparesis 28–9 microangiopathic 576 multiple brain infarcts 501 multiple with leukoencephalopathy 274–5 speed of onset 4 subcortical vascular dementia 260 voluntary breathing/swallowing inability 357 lacunar syndrome 17–18 acute stroke treatment 587–8 anterior choroidal artery infarctions 449, 453, 454 ataxic hemiparesis 583, 584–5 centrum ovale infarcts 420 classical 587–88, 586 dysarthria 587 dysarthria–clumsy hand syndrome 583, 584–5 dysphasia 587 extended 584 hemiparesis 29–30 homolateral ataxia and crural paresis 583, 584–5 ischemic lesion size 586 midbrain infarcts 516 partial 586 pontine infarcts 520 paramedian 522 pure motor hemiparesis 25 pure motor stroke 583, 584 pure sensory stroke 583, 584 sensorimotor stroke 583, 585–6 stroke pathology 586 thalamic pure sensory syndrome 40 TIAs 587 vascular pathology 586–7 lacunes, giant 429 language anosognosia for impairment 215 articulated 211 auditory perception 218 comprehension 214 distribution 218 function activation 218 laterality 217 left hemisphere 211 superior mesial frontal cortex stroke 236 thalamic aphasia 254–5 language disorders anterior cerebral artery infarction 447 caudate hemorrhage 476 caudate infarcts 474–5 posterior cerebral artery left-hemisphere infarction 484 large artery atherosclerosis brain lesion localization within posterior circulation 667–8 distal intracranial territory 679–87 evaluation 687 infarction speed of onset 4 location 667

727

728

Index

large artery atherosclerosis(cont.) middle intracranial territory 674–9 multiple intracranial territory infarcts 687 proximal intracranial territory 668–74 strokes sparing lower limb 25 large artery disease cerebellar infarcts 507 intracranial occlusive 550 pontine infarcts 521 large artery occlusion border zone cerebellar infarcts 551 brainstem extended/multiple infarcts 559 lacunar strokes 552 large artery thromboembolism see large artery atherosclerosis large vessel disease 18 dysphagia 346 large vessel occlusion, deafness 149–50 laryngopharyngeal sensory discrimination deficits 342 lateral frontotemporal infarctions 576 lateral-gaze palsy 30 lateral geniculate nucleus 87 infarction 90 lateral inferior pontine syndrome 535 lateral lemniscus infarcts 151 lateral orbitofrontal circuit 469, 470, 471 lateral posterior choroidal arteries 479 lateral sinus hypoplasia 636 left lateral sinus thrombosis differentiation 634 lateral sinus thrombosis angiography 636, 644 septic 638, 646 see also left lateral sinus thrombosis lateral thalamus infarction 482–3 ischemia 685 laterality, language 217 laughter, pathological 31, 290 pontine infarcts 524 pontine ischemia 675 subcortical stroke 260 left dorsolateral prefrontal cortex 243 left hemispatial neglect 236 left hemisphere aggressive burst 291 damage compensation by right hemisphere 217, 218 depression 285, 286 infarction 484–5 language 211 lesions and visual agnosia 502 left lateral sinus thrombosis 630, 631, 634 lateral sinus hypoplasia differentiation 634 MRI 637 left sensory–motor hemisyndrome 269 leg see lower limb lemniscal sensation dysfunction 37 lemniscus see lateral lemniscus; medial lemniscal system lenticulostriate arteries 405–6, 428–35, 436–8 anterior 471–2 caudate nucleus infarcts 472 caudate nucleus blood supply 471

comma-shaped infarct 432–4 faciobrachial paresis 25 hemiparesis with dysphasia 30 hypertensive change 428 infarctions 452 lateral 431, 471 caudate nucleus infarcts 472 microaneurysms 428 obstruction sites 432 origin 429, 430 pathology/pathogenesis 428 watershed infarcts 431, 432, 437, 438 lenticulostriate system 43 lenticulostriate territory infarcts 428 apraxia 262 lentiform nucleus 432 infarction 435 leptomeningeal anastomoses 566 leptomeningeal arteries 377 Leriche syndrome 699 leukoencephalopathy hyperperfusion syndrome 70 metabolic–edematous posterior 487 reversible posterior 310 Lewy bodies 163 lexical retrieval 216 Lhermitte's peduncular hallucinosis 202 Libman–Sacks endocarditis 502 limb adventitious movements 674 dysesthesia 670–1 dysmetria 543, 553 incoordination with superior cerebellar artery infarcts 683 movement with superior cerebellar artery infarcts 683 shaking 169 low-flow infarcts 567, 569 supernumerary 269 unilateral motor neglect 320 see also lower limb; motor weakness; upper limb weakness limb ataxia 48 ataxic hemiparesis 55 lateral medullary infarcts 536 superior cerebellar artery classic syndrome 683 infarcts 545, 683, 684 limb weakness anterior cerebral artery infarction 443, 444 lacunar syndromes 584 limbic circuit 470, 471 basolateral 243 lingual discoordination 342 lingual gyri 102 lingual palsy 25 lingual paresthesia 42 lipohyalinosis 18 caudate infarcts 475 deep perforating arteries 274 lacunar strokes 552 pontine lacunes 526 lipoprotein lipase 288

Index

listeriosis 328 lithium 291 lobar hemorrhage 599–609 anticoagulants 601–2 arteriovenous malformation 600–1, 603 cavernous angioma 600–1, 603 cerebral amyloid angiopathy 599–600, 602 cerebral tumours 601, 604 clinical features 603–7 CT scan 599, 600 fibrinolytic agents 601–2 frequency 599 frontal hematoma 603–4, 606 hematoma size 608–9 hypertension 599 management 608–9 non-hypertensive mechanisms 599–603 occipital hematoma 606–7, 608 outcome 607–8 parietal hematoma 605–6, 607 prognosis 607–8 sites 601 status epilepticus 184 surgical therapy 608–9 sympathomimetic drugs 602 temporal hematoma 604–5, 606 vascular malformation 600–1, 603 vasculitis 602–3 locked-in syndrome 192, 200, 201 brainstem infarction 557 midbrain 516 midpontine lesions 356 pontine ischemia 675 logorrhea 226 long latency responses 149 long-lead burst neurones 81 long QT syndromes 325, 326 long-term care costs 363 low-flow infarctions 550–2 anterior border zone 575, 576 blood flow velocity 565, 566 causes 551 clinical features 550–1, 566–9, 570, 571 course 551 diagnostic imaging 572–4 diagnostic techniques 565 EEG 569 epidemiology 565 imaging 565, 574, 575, 576–7 simultaneous technique 576–7 incidence 565 laboratory parameters 565–6 mechanisms 566, 567 pathophysiology 565–6 prognosis 570, 572 subcortical 565, 570, 576–7, 578 extensions 576 superficial 565 terminology 564–5 therapy 578–80

TIAs 567–8 vascular findings 572–4 low-flow states, cerebral 570–2 lower limb movements in sleep 204 weakness 10, 16 low flow TIAs 18 lower motor neuron lesions 336–7 lunar infarcts 185 lupus anticoagulant 70, 114 transient monocular blindness type IV 116–17 Lyme disease 328, 700 lymphoma, intravascular 502 macropsia 98 macula, cherry-red spot 118 macular dysfunction 87 retinal ischemia 14 magnetic resonance angiography 635, 640, 641 magnetic resonance imaging (MRI) cerebellar stroke 540, 541 cerebral venous thrombosis 663–5, 636, 637, 638, 639 cervico-cerebral artery dissection 661 diffusion-weighted 634–5 lateral medullary infarction 537 migraine 64 spin-echo sequences 633 spinal stroke syndromes 696, 698, 701–2 techniques 493 mamillo-thalamic tract damage memory defect 259, 683 mammillary bodies 244 man in the barrel syndrome 502, 696 mania 290–1 anterior cerebral artery stroke 227–8 right hemisphere lesions 285, 290 mannitol 496 maprotiline 368 marche à petit pas 163, 164 Marfan's syndrome 622 cervico-cerebral artery dissection 662 masking level difference 147–8 masseter paresis 131 masseter reflex 559 medial frontal lesions agitation 227–8 motor neglect 445–6 medial geniculate body 146 medial lemniscal system 34, 52 medial medullary infarct 672 medial longitudinal fasciculus (MLF) 76, 77 ischemia 676 rostral interstitial nucleus 80, 81 top of the basilar syndrome 679 medial nuclei vascularization 381 medial parabrachial nucleus 353, 354 medial septal nucleus 243 medial striate arteries 471 medial superior olive 145 medial superior visual area 83–4

729

730

Index

medial temporal infarcts 479 memory loss 244–5 medial vestibular nucleus afferent pathways 79 lateral slow eye movement 77 median artery of corpus callosum 442 medulla arterial supply 378, 534, 535 dorsal respiratory group 353–4 infarcts 668 pain fibre distribution 671 PICA infarcts 547, 548 respiratory function 353–5 ventral respiratory group 353, 354 medullary hemorrhage 538 medullary infarction 534–8 bilateral 538 combined medial and lateral 538 lateral 36–7, 43, 534–7, 668–72 arterial lesions 537 complications 537 distribution 669 with medial medullary infarcts 673 neuroimaging 536–7 neurological findings 535–6 onset 534 partial 535 stroke mechanisms 673 symptoms 534–5 vascular lesions 673 medial 36–7, 43, 537–8, 672 hemiparesis 25 stroke mechanisms 673–4 unilateral 538 vascular lesions 673–4 Ondine's curse 358 see also hemimedullary infarction medullary stroke, sensory dysfunction 36–7 medullary syndrome, dorsal lateral 548 megaphagia 204 melanoma metastasis 604 MELAS agnosia 303 mitochondrial encephalomyopathy 328 multiple brain infarcts 502 simultanagnosia 310 memory arterial blood supply 243–4 autobiographic 242 categories 242 classification 242–3 cognitive processes 242 declarative 242, 243 episodic 242, 243 medial temporal infarction 245 storage 243 thalamic infarcts 246 functional anatomy 243 immediate 242 perceptual 242–3 priming 243

primary 242, 243 procedural 242–3 processes 98 retention 242 retrieval 242 semantic 242, 243 storage 243 short-term 242 verbal 246 visual 246, 457 working 242, 243 memory deficit basal forebrain lesions 238 caudate nucleus infarct 247, 474 emotional perception 293–4 inferior mesial cortex stroke 238 mamillo-thalamic tract damage 259 posterior cerebral artery infarction 685–6 left-hemisphere 484 rostral brainstem infarcts 682–3 stroke 244 ventroamygdalofugal pathway 259 verbal with thalamic hemorrhage 254 memory loss 242, 244–9 anterior communicating artery aneurysms 247–8 behavioural retraining programmes 249 dorsomedial nuclei 245–6 hippocampus 245 inferior genu infarction in internal capsule 247 intraventricular hemorrhage 247 medial temporal infarcts 244–5 reduplicative paramnesia 248 subarachnoid hemorrhage 247–8 thalamic infarction 245–7, 259 transient global amnesia 248 treatment 248–9 meningioma 638 meningitis agitation 230 spinal cord ischemia 700 mental imagery, hemineglect 264 mental state abnormality with occipital hematoma 607 mesencephalic artery infarction and skew torsion 137 paramedian 479 superior 465 vestibular syndromes 135, 137, 138 mesencephalic stroke hypersomnia 197 sensory dysfunction 39 mesencephalon 52 mesial frontal cortex infarction 446 inferior 238 superior 236, 237, 238 mesial frontal syndromes 236, 237, 238 metabolic–edematous posterior leukoencephalopathy 487 metamorphopsia 98 methylphenidate 248–9, 287 poststroke apathy 290 Meyer's loop 87

Index

Meynert decussation 79 mianserine 287 Miarchafava–Bignami disease 317 microangiopathic disease, diffuse 163 microangiopathy of retina, inner ear and brain 502 microatheroma 18 microembolism, pontine infarcts 521–2 micrographia 432 micropsia 98 microscopic polyangiitis 327, 328 micturition disorders 331 neurologic control mechanism impairment 345 midbrain anatomy 512–13 arterial supply 379, 512–13 hemorrhage 150 hiccup 360 ischemic syndromes 514 lesion diagnosis 513 neuro-ophthalmological features 515 oculomotor syndromes 513–15 stroke 39 supranuclear conjugate-/disconjuate-vertical-gaze palsies 515 yawning 360 midbrain infarcts 512–18 auditory symptoms 151 causes 516–18 clinical features 513–18 lacunar syndrome 516 oculomotor palsies 513–15 middle cerebellar peduncle cavernoma 134, 136 middle cerebral artery xxiii, xxiv, xxv anatomy 405–6, 407, 408 anomalies 408 auditory agnosia 311–12 bifurcation pattern 406, 407 caudate nucleus blood supply 471 cerebral hemisphere supply 381 cortical territories 409 course 451–2 deep territory lesions 364 dissection 69 dysarthria 335 emboli and headache 65 embolic occlusion 490 faciobrachial paresis 25 frontal lobe irrigation 234 headache 65, 69 hyperdense sign 492 ideomotor apraxia 316 insular region 406 lesions 442 origin 451 perforating branches 380 radiological description 408 stenosis 566 subcortical infarcts 654 superficial arterial territory 408, 409, 412–13 superficial branches 408 superficial syndromes 405, 408–11, 414–22 superior trunk 409–10

tactile agnosias 313 TIAs 17 trifurcation pattern 406, 407 middle cerebral artery infarction 3, 23, 141 agitation 226–7 apraxia 256 brain edema 364 complete pial territory 408–9 deep white matter 239 delirium 226, 227 hemianesthesia 451 hemiparesis 24, 27 hemiplegia 451 homonymous hemianopia 451 inferior division territory 410–11, 416 low-flow 575, 576 monoparesis 29 multiple 502 neglect 257 plial 652 prognosis 494 radiological findings 492–3, 494 simultaneous in one hemisphere 504–5 simultaneous with single artery occlusion 505–6 superior division territory 409–10, 411, 415 therapy 497 middle cerebral artery occlusion 17, 18, 256 aphasia 256 embolic 490 frontotemporal hypoperfusion 256 low-flow infarct 578 striatocapsular infarction 256 middle internal frontal artery 441, 442 middle latency responses 149 middle temporal area 83–4 midpontine lesions, autonomous breathing 356 migraine 60–73 acephalgic 116 antiphospholipid antibodies 70 arterial dissection 69–70 arteriovenous malformation 64–5 with aura 63, 64, 71 CADASIL 71 without headache 65 basilar artery 69 depression 72 mitral valve prolapse 70–1 neuroimaging 64 patent foramen ovale 71 posterior cerebral artery bilateral infarcts 488 thrombosis 486 secondary to cerebrovascular disease 64–5 stroke predisposition 61 prevention therapy 72 risk factor 63 stroke-induced 64 symptomatic 64–5 vasospasm 62 vertebrobasilar stroke 69

731

732

Index

migraine (cont.) visual field defects 13, 72 migrainous stroke 60–1, 62–4 incidence 62 recurrence risk 72 Millard–Gubler syndrome 30 mirror movements 169 mirror writing 447 misidentification syndromes 308 mitochondrial encephalomyopathies 328 mitral valve prolapse 63 migraine 70–1 monoballism 166 monocular elevation paralysis 81, 515 monoparesis 10 brachial 28, 29 crural 29 isolated 28–9 subarachnoid hemorrhage 623 monoplegia 23 Monro–Kellie doctrine 491–2 mood caudate infarcts 474 emotional perception 293–4 mood behaviour disorders 285–96 acute behavioural changes 295 acute brain lesions 293 anosodiaphoria 292 anosognosia 291–2 anxiety 287–9 behavioural reactions of denial 292 depression 285–7 fear 287–9 mania 290–1 nosognosia 291–3 poststroke psychosis 291 prognostic impact 294–5 pseudodepressive manifestations 289–90 recall of acute event 293 subjective experience 291–3, 292–3 moriatic aphasia–sensorimotor hemiparesis 656 motion perception impaired 89 loss 310–11 motor abnormalities caudate infarcts 475 compulsive behaviours 170 paramedian massive/large pontine hemorrhage 528 postcommunal posterior cerebral artery infarcts 482–3 unilateral dysfunction 16 motor aphasia low-flow infarcts 568 watershed infarctions 653 motor circuit, classical 469, 470 motor cortex 22 faciobrachial paresis 25 primary 234, 235 motor deficit anterior cerebral artery infarction 443–46 central sulcus artery territory infarct 416

small unilateral tegmental pontine hemorrhages 529–30 thalamic hemorrhage 466 motor execution, abnormal 35 motor hemiparesis anterior choroidal artery infarctions 453 central sulcus artery territory infarct 416 pure 523 small putaminal hemorrhage 594, 595 motor impersistence 414–15 motor neglect 23 hypokinetic movement disorders 164 medial frontal lesions 445–6 unilateral limb 320 motor neurons lower 336–7 transsynaptic degeneration 330 see also upper motor neuron lesions motor persistence 415 motor recovery 367 amphetamine 368 motor responses, visual dysfunction 98 motor speech deficit 252–3 motor stroke anterior choroidal artery infarctions 454 centrum ovale infarcts 420 pure 583, 584 capsular 584 ischemic lesion size 586 pontine 584 motor weakness 22 angular artery territory infarct 418 bilateral 30 caudate infarcts 475 face/arm/leg 26–7, 28 hemiparesis 23 leg-predominant 23 rostral basilar artery syndrome 544 severity 364 movement decerebrate 528 involuntary 35, 43 movement disorders 162–70 caudate hemorrhage 477 caudate infarcts 475 centrum ovale infarcts 420 cerebellar ataxia 48 hemiparesis 23 hyperkinetic disorders 164–70 hypokinetic disorders 162–4 midbrain infarcts 516 modification of previous by strokes 170 subthalamic nuclei infarcts 683 superior cerebellar artery classic syndrome 543 TIAs 10 moya-moya disease 476, 502 EC–IC bypass surgery 579 intracranial internal carotid occlusion 657 low-flow infarction 576 multiple neurological complications (MNCs) 323 primary/secondary changes 324

Index

muscle atrophy contralateral to cerebral lesions 330 disease 323–4, 325, 326, 327, 328–32 neuromuscular disorders 324 weakness with anterior cerebral artery infarction 443 bulbar 671, 674–5 upper limb 10, 16 see also hypotonia muscular dystrophy, Becker X-linked 324 mutism anterior cerebral artery infarction 447 middle cerebral artery superior division territory infarct 410 pseudobulbar 455 see also akinetic mutism mycotic aneurysms 621 subarachnoid hemorrhage 623 mydriasis 513, 514 myelography for spinal stroke syndromes 702 myelopathy, congestive venous 701 myocardial infarct caudate nucleus infarcts 473 multiple cerebral infarcts 504 myocardial necrosis, focal 329 myoclonus 168–9 intention 48 sleep 204 see also palatal myoclonus nadroparin 643 narcolepsy 204 nausea 672 neck pain 663 necrotizing vasculitis 328 neglect anterior cerebral artery infarction 257 anterior choroidal artery infarction 257 caudate infarcts 474 cerebral lesions 94 cortical 258 cortical atrophy 365 dyslexia 92, 100, 309 hemisensory 417–18 low-flow infarcts 568 mechanisms 264 middle cerebral artery infarction 257 motor 23, 164 medial frontal lesions 445–46 overlap of lesions 265 right hemisphere stroke 365 simultaneous infarcts in one hemisphere 505 striatocapsular infarction 434 subcortical stroke 257–8 TIAs 11, 12 unilateral 264 spatial with putaminal hemorrhage 591, 593 visuospatial 409 see also hemineglect; hemispatial neglect; motor neglect; visual neglect neologistic jargon 215

neonates, cerebral venous thrombosis 631 neuroleptics in stroke recovery 368 neurological deficit early spontaneous improvement 6 exacerbation 186 severity 363, 364–5 see also multiple neurological complications (MNCs) neuromuscular disorders 324 neuronal death, delayed 5 neuropathy, ischemic monomelic 323–4 neuropsychological dysfunction 364–5 anterior parietal artery territory infarct 416 caudate infarcts 473 centrum ovale infarcts 420 middle cerebral artery infarction inferior division territory 410–11 superior division territory 410 posterior parietal artery territory infarct 418 precentral territory infarct 414 striatocapsular infarction 434–5 thalamic hemorrhage 466 neuropsychological signs with anterior choroidal artery infarctions 454–5 neurosurgical emergencies, EC–IC bypass surgery 579 neurosyphilis 328 nifedipine 72 nightmares, recurrent 204 nociceptors 62 non-steroidal anti-inflammatory drugs (NSAIDs) 72 noradrenaline 368 noradrenergic reuptake inhibitor 368 nortriptyline 287 nosognosia 291–3 behavioural manifestations of denial 292 medical care seeking 293 recall of acute event 293 subjective experience 292–3 NOTCH 3 gene mutations 275 nucleus acumbens 472 nucleus ambiguus 355 lateral medullary infarcts 671, 672 nucleus of Cajal 80–1 nucleus of Meynert 243, 247–8 nucleus prepositus hypoglossi (NPH) 77 nucleus reticularis tegmenti pontis (NRTP) 79 numbness, lateral medullary infarct 534–5 nutrition for stroke patients 347, 349 nystagmus abduction 77 cerebellar hemorrhage 553 contralateral beating torsional 81 convergence retractory 515 dissociated vertical 515 downbeat 138 dysarthria 338 gaze-evoked 48, 82 internuclear ophthalmoplegia 76 lateral medullary infarcts 536, 668, 669 PICA infarcts 548, 673 pontine ischemia 677

733

734

Index

nystagmus (cont.) retractation 465 retractory 680 see-saw 81, 515 spontaneous 131 torsional 133 upbeat 138 obsessive–compulsive behaviours 290 occipital lobe xxiii hematoma with lobar hemorrhage 606–7, 608 occipitofrontal fibre infarcts 256–7 occipitofugal system 487 ocular abnormalities movement 523 pontine hemorrhage paramedian massive/large 528 small unilateral tegmental 529 ocular bobbing 82 paramedian massive/large pontine hemorrhage 528 pontine ischemia 676–7 ocular ischemic syndrome 115, 654 ocular lateropulsion 670 ocular motor apraxia, acquired 105 ocular tilt reaction 129 contralateral 138–9 incomplete contraversive 136 lateral medullary infarcts 669–70 tonic 515 top of the basilar syndrome 680 vertebral artery occlusion 132–5 ocular torsion binocular 133 lateral medullary infarcts 669 skew deviation 135, 138 oculomotor circuit 469, 470 oculomotor nuclei 79 oculomotor palsies 513–15 carotid dissection 657 oculomotor paralysis, ipsilateral 79 oculomotor rootlet lesions 79 omnipause neurons 77, 79 lesions 82 Ondine's curse 202, 356, 358, 359, 360, 672 one-and-a-half syndrome 77, 81 paramedian pontine infarcts 523 pontine ischemia 676 small unilateral tegmental pontine hemorrhages 529, 530 thalamic–subthalamic artery infarcts 465 top of the basilar syndrome 680 vertical 515 Opalski's syndrome 536 opercular cheiro-oral syndrome 416, 417 opercular syndrome 416, 431 ophthalmic artery central retinal artery occlusion 117 TIAs 11 ophthalmic artery occlusion 119 clinical signs 119 differential diagnosis 120 treatment 119–20

ophthalmopathy, ischemia EC–IC bypass surgery 579–80 low-flow infarcts 568–9, 571 salvage of eye 579 ophthalmoplegia painful 654–5, 656 see also internuclear ophthalmoplegia optic aphasia 303, 306–7, 318 optic ataxia 321 Balint's syndrome 104 disconnection 100 posterior cerebral artery bilateral infarcts 487 simultanagnosia 309 optic atrophy 90 optic disc, swollen 123, 124 optic nerve decompression for ischemic optic neuropathy 124 ischemia 13 optic neuropathy, ischemic 120, 121–4 anterior 122, 654 arteritic 123 clinical signs 123–4 non-arteritic 122–3 perioperative 122 optic nerve decompression 124 posterior 122 steroid therapy 124 treatment 124 optic radiations 87–8 anterior choroidal artery supply 452 infarction 90, 92 optic tract 87 anterior choroidal artery supply 452 partial lesions 90 optico-cerebral syndrome 502, 654 simultaneous infarcts in one hemisphere 505 oral contraceptives 63 cerebral venous thrombosis 630, 639, 645 cervico-cerebral artery dissection 664 headache 70 orbital infarction, complete 656 orbitofrontal artery 441, 442 territory infarct 411 orbitofrontal cortex lesions 238–9 inhibitory control of interference loss 228 oro-crural symptoms 38 orofacial apraxia 314, 316 oropharyngeal muscle paralysis 671 oscillopsia 138, 668–9 osteogenesis imperfecta type I 663–4 otoacoustic emissions 149 otoliths 133 neuron loss 134 outcome predictors 363–5 owl's eye sign 697, 702 Oxfordshire Community Stroke Project (OCSP) TIAs 9, 10–11, 13–15 pain asymbolia for 41 central post-stroke 35, 42–3

Index

facial 38–9 ruptured intracranial aneurysm 619 sensation lateral medullary infarct 536 superior cerebellar artery classic syndrome 543 palatal myoclonus pontine ischemia 675–6 superior cerebellar artery classic syndrome 543 palinopsia 96, 98 palpatory apraxia 314 panhemispheric infarcts 490–7 panic symptoms 14–15 pantomime agnosia 314, 316 Papez circuit 103, 243 papillitis, ischemic 123–4 paraballism 166 paracentral artery 441, 442 paragnosia, face 308 parakxia 484 paralinguistic agnosia 313 paralytic pontine exotropia 676 paramedian diencephalic syndrome 196 paramedian infarcts, unilateral 522–4 paramedian mesencephalic artery 479 paramedian pontine artery, vestibular syndromes 135, 137, 138 paramedian pontine reticular formation (PPRF) 76, 77, 78, 78 caudal syndrome 77, 78 lesions 78–9 pontine infarction 676 paramedian pontine tegmentum lesions 676 paramnesia, reduplicative 248, 259, 269 posterior cerebral artery right-hemisphere infarction 485 paranoid delusions, poststroke psychosis 291 paraparesis anterior cerebral artery infarction 446 subarachnoid hemorrhage 623 paraplegia, psychogenic 695–7 paratonia 194 paravermal zone of cerebellum 545 paresis, precentral territory infarct 414 paresthesia posterior cerebral artery stenosis 480–1 rostral basilar artery syndrome 544 parietal artery anterior territory infarct 416–17 see also inferior parietal artery; posterior parietal artery; superior parietal artery parietal cortex action patterns 315 working memory 243 parietal cortical sensory syndrome 41 parietal fibre infarcts 256–7 parietal lobe xxiii hematoma 605–6, 607 motor syndrome 170 parieto-insular vestibular cortex 139, 140, 141 parieto-occipital arteries 479 parieto-occipital border zone infarctions 576 Parinaud's syndrome 623 parkinsonian-ataxia 57 parkinsonism

arteriosclerosis 162 bilateral putaminal infarction 432 cerebrovascular disease 163 lower body 57, 162, 163, 164 pseudobulbar 163 small vessel disease 162–3 tremor 167 vascular 162, 163 Parkinson's disease 339 peduncular hallucinations 197, 682 see also hallucinosis, peduncular peduncular perforating arteries 479 penetrating arteries, basilar branch atheromatous disease 521–2 penetrating branch artery disease 473 auditory symptoms 150–1 perception hemineglect 264, 265 shape 267–8 see also visual perceptions perceptual characterization deficits 267–8 perforating arteries 377–8 periarteritis nodosa headache 71 vasospastic transient monocular blindness 116 pericallosal artery 441, 442 posterior 479 perilymph fistulas 129 perimesencephalic hemorrhage 66 periodic lateralizing epileptiform discharges (PLEDS) 187, 188 low-flow infarctions 569 perioral paresthesia 42 perioral sensory symptoms, bilateral 41–2 peripheral nerve compression 330–1 disease 323–4, 325, 326, 327, 328–32 peripheral resistance reduction 566 periventricular region circulation 612 periventricular white matter 252–3 peroneal nerve 331 persistent vegetative state (PVS) 201 personality change with orbitofrontal cortex lesions 238–9 Petren's gait 163, 164 pharyngeal paresis, lateral medullary infarct 536 phenylpropanolamine 602 phonagnosia 153, 313 phonation 334 physical therapy 368 physical training 367 Pick's disease 214 pituitary apoplexy 621 platelet aggregation 64 platelet antiaggregation 664 platelet-fibrin emboli 120, 121 platelets 63 plugs 113 plial artery occlusion 651 plial infarctions circle of Willis 652 internal carotid artery occlusion 652 middle cerebral artery 652 persistent trigeminal artery 652

735

736

Index

pneumonia, aspiration 343, 345, 349 pneumotaxic centre 354 polar artery 461, 462 infarcts 462–3, 466, 682–3 thalamus supply 479 polyarteritis nodosa 700 polycystic kidney disease 622 polycystic liver disease 622 polycythemia 115 polymyositis, acute 324 pons arterial supply 378–9 ataxic hemiparesis 56 base 52 multilocular brainstem ischemia 558 neurovascular anatomy 520 see also paramedian pontine reticular formation (PPRF) pontine artery, paramedian 135, 137, 138 pontine exotropia, paralytic 676 pontine hemorrhage 527–30 basal tegmental 528–9 bilateral tegmental 528–9 classification 527–30 clinical course 530 clinical features 527–30 drainage 531 large 527–8 massive 527–8 prognosis 530 stereotactic procedures 531 surgical management 531 treatment 530–1 unilateral small basal 530, 531 tegmental 529–30 pontine infarcts 520–5 basilar artery stenosis 525, 526 bilateral 525 imaging techniques 520–1 lacunar syndrome 520 lower 526 motor weakness 24–5 prognosis 525–6 skew torsion 137 stroke mechanisms 521–2 unilateral paramedian 522–4 tegmental 524–5 upper 526 pontine ischemia basilar artery disease 674–8 conjugate horizontal gaze 676 sixth nerve palsy 676 stroke mechanisms 678 vascular lesions 678, 680 treatment 526–7 pontine micturition centre 331 pontine nuclei afferent connections 50 see also dorsolateral pontine nuclei pontine stroke 55–6

hypersomnia 197 sensory dysfunction 37–9 pontine tegmentum, paramedian 676 pontomedullary infarctions ocular skew torsion 137 vestibular dysfunction 135, 138 positron emission tomography (PET) for carotid ischemic syndromes 651–2 postcentral gyrus 34, 35 posterior carotid artery infarction, occipital lobe 679, 681 posterior cerebral artery xxiii, xxiv, xxv, 668 anatomy 479, 480 brainstem supply 375, 376 branches 479, 480 cerebral hemisphere supply 381 headache 69 ischemia 90–1 bilateral 486–8 unilateral 479–86 optic aphasia 306 proximal disease 465 rami of interpeduncular arteries 380–1 stenosis 479–85, 486 stroke 224–5 syndrome 482 thalamus supply 461 TIAs 686–7 vestibular dysfunction 139, 141 posterior cerebral artery infarction 684–7 alexia pure 308 without agraphia 685 anomic aphasia 685 bilateral 486–8, 506 clinical signs 481 cortical blindness 686 Gerstmann's syndrome 685 hemiparesis 24 hemispheric 483–4 large 490 lateral thalamic ischemia 685 left-hemisphere 484–5 memory 685–6 loss 244–5 recovery 245 prosopagnosia 102, 307–8 right-hemisphere 485 simultaneous multiple 506–7 with single artery occlusion 505–6 stroke mechanism 686–7 unilateral 481, 485–6 mechanisms 485–6 visual agnosia 302, 303, 306 associative 686 posterior cerebral artery occlusion auditory symptoms 150 with hemiplegia 516 postcommunal ambient segment 482–3 proximal 481–2 posterior choroidal artery 244, 381, 461–2

Index

infarction 5, 465 lateral 479 occlusion 465 posterior circulation territory brainstem extended/multiple infarcts 557–60 cerebellar/brainstem combined infarcts 560–1 extended infarcts 557–2 ischemia 540 multiple infarcts 549–50 space-occupying cerebellar infarcts 561–2 strokes 224–6 posterior commissure lesion 81 posterior communicating artery 244 perforating branches 380 thalamus supply 461 posterior fossa hematoma 62 hemorrhage 68 veins 626–7 posterior inferior cerebellar artery (PICA) 52, 668 brainstem supply 375, 376 cerebellum supply 375, 377, 379 clinical features 547–8 dorsal lateral medullary syndrome 548 hemorrhage of vermis 134 lateral 548 medulla blood supply 534, 535 middle 548 occlusion 132–5 pseudotumoural pattern 548 posterior inferior cerebellar artery (PICA) infarction 54, 542–3, 546, 547–9 cause 549 cerebellar 506, 673, 674 pseudotumoural 552 course 549 medullary involvement 547, 548 multiple 507 cerebellar 507, 508 posterior circulation 549–50 partial territory 547 vermis 134 posterior internal frontal artery 441, 442 posterior operculum syndrome of Bruyn 416 posterior parietal artery territory infarct 418 posterior parietal cortex 82–3 posterior perforated substance 378 posterior pericallosal arteries 479 posterior spinal artery brainstem supply 375, 376 syndrome 697 posterior temporal artery 244 compression 479 posterior temporal lobe 482 posterior thalamo-subthalamic paramedian artery lesions 81 posterior trunk split signs 318–19 posteromedial portion of lateral nuclei vascularization 381 posteromedial thalamic hemorrhages 103 postural ataxia 48 posture, dystonic 43 presleep behaviour 196

precedence effect 151 precentral artery territory infarct 414–15 prefrontal artery territory infarct 411, 414 prefrontal cortex 233 depression 286 dorsolateral 235–6 left 243 right 243 stimulation for mood control 286 prefrontal syndrome of Luria 414 pregnancy, cerebral venous thrombosis 630, 639, 645 premotor cortex 234, 235 premotor structure afferences 79 premotor syndrome of Luria 414 preretinal hemorrhage 622 prerolandic territory infarct 414–15 pressure sore prophylaxis 365 proatlantal artery, persistent type I 652 progressive stroke 5 proprioceptive neuromuscular facilitation 367 prosody, dysarthria 334 prosopagnosia 16, 101–2, 268 apperceptive 307 associative agnosia 303, 307–8 prostaglandins, cerebral ischemia 14 protein C 366 deficiency 639 protein S deficiency 639 Proteus 638 protopathic sensory impairment 41 pseudoathetosis 43, 166 pseudobobbing, pretectal 515 pseudobulbar palsy 30–1, 355 pseudobulbar release phenomena 675 see also crying, pathological; laughter, pathological pseudodepression 289–90 pseudoneglect, bilateral crossed 448 pseudoparesis 43 pseudosixth phenomenon 680 pseudothalamic sensory syndrome 416–17 pseudotumour cerebri 630 pseudotumoural syndrome 684 pseudoxanthoma elasticum 622 psychiatric disorders, familial 286, 291 psychic akinesia 474 psychic blindness 294 psychic self-activation loss 290 psychosis, poststroke 291 ptosis anterior choroidal artery infarctions 455 internuclear ophthalmoplegia 515 pontine ischemia 677 puerperium, cerebral venous thrombosis 630, 638–9, 645 pulmonary edema, neurogenic 329–30 pulmonary embolism sinus thrombosis 640 stroke complication 360 pulsatility index, low-flow infarctions 565–6, 574 pulvinar nucleus hematoma 254 pupil afferent defect 123

737

738

Index

pupil (cont.) amaurotic 118 mydriasis 513, 514 pontine ischemia 677 uncal herniation syndrome 494 Wernicke's hemianopic 90 pupillary light reflex 87, 90 rostral brainstem lesions 680–1 pupillary reflex absence 360 putaminal hemorrhage 590–7 aphasia 592–3 classic 591–3 clinical features 590–1 fulminant 591 hematoma enlargement 595 non-dominant-hemisphere syndromes 593, 594 seizures 595 silent 596, 597 small 593–5 unilateral spatial neglect 591, 593 putaminal infarcts 432 caudate 472, 473 pyramidal syndrome 49 pyramidal tract 23 oculomotor rootlet lesions 79 QT interval 329 quadrantanopia 90 inferior 91, 94 middle cerebral artery inferior division territory infarct 411 striate 91 quadriplegia bilateral medullary infarct 538 paramedian massive/large pontine hemorrhage 528 quality of life 363 enhancement 367–8 radicular arteries 691, 693 compression 700 radiculomedullar arteries 691, 693 reading disorders 100 posterior cerebral artery left-hemisphere infarction 484 testing 101 see also alexia, pure recurrent artery of Heubner see Heubner's artery red cells altered viscosity 114–15 Tc-labelled scintigraphy 636–7 red eye, low-flow infarcts 567 red nucleus oculomotor rootlet lesions 79 upper pole 80 reduplicative paramnesia 102–3 reflex sympathetic dystrophy 331 region of Heschl 146 registration, memory 242 rehabilitation costs 363 physical training 367 REM sleep behaviour disorders 204

regulation 96 reperfusion, early 6 reperfusion injury of brain 491 respiration automatic 672 brainstem centres 353, 354 brainstem strokes 356, 357, 358–60 central organization 353–5, 358 dysarthria 334 hemispherical strokes 355 paramedian massive/large pontine hemorrhage 527–8 rostro-caudal organization 353 see also breathing; Ondine's curse respiratory apraxia 202 respiratory arrest 355 respiratory dysfunction 353, 355–6, 357, 358–61 lateral medullary infarct 536, 537, 672 retention, memory 242 reticular activating system lesions 96 rostral brainstem 681 sleep–wake cycle 682 reticular formation, respiration control 355 reticulo-thalamo-frontal afferents 199 retina damage with low-flow infarcts 569 pigmentary degeneration 14 TIAs 655 venous outflow blockage 622 retinal artery platelet plugs 113 pressure 13, 113 vasospasm 116 see also branch retinal artery occlusion; central retinal artery occlusion retinal emboli 111, 113 branch retinal vein occlusion 120–1 central retinal artery occlusion 118 retinal ganglion cells 87 retinal ischemia 11, 13 bilateral 13 visual loss in bright/white light 14 retinal vein rupture 622 retinopathy, venous stasis 14, 115 retinotopic pattern 87, 88 retrochiasmal defects 90 rheumatoid arthritis 328 right hemianopia 306–7 right hemisphere acquired deficit of emotional expression/comprehension 294 compensation 217, 218 hypometabolism 218 mania 285 right hemisphere lesions/syndromes 264–9 acute confusional state 269 anosognosia 269 body scheme alterations 269 constructional apraxia 316–17 depression 286 hemineglect 264–6 infarction of posterior cerebral artery 485

Index

mania 290 optic aphasia 306–7 paralinguistic agnosia 313 prosopagnosia 268 stroke and neglect 365 topographical disorientation 266 visual agnosias 266–8, 269, 302 right inferior temporal lobe 290 right prefrontal cortex 243 right temporal lobe infarcts 227, 228–9 rigidity, decerebrate 24 rolandic territory infarct 416 Romano–Ward syndrome 326 rostral basilar artery 668 delirium 225 disease 465 infarction 681–2, 684 syndrome 544–5 rotational vertebral artery occlusion 132 rubeosis iridis with low-flow infarcts 567, 569, 571 saccades 76 cerebral hemispheres 82–3 downward paralysis 80, 81 dysmetria 82 horizontal 78 premotor structure 77 triggering 82–3 upward paralysis 80, 81 vertical 79, 82 saccadic pursuit 131 sagittal sinus inferior 628 thrombosis 30, 70 see also superior sagittal sinus saline, hypertonic 496 sarcoidosis 700 sarcomeric proteins 324 schistosomiasis 700 scotoma 91 peripheral 91, 95 sectoranopia 90, 92 seizures clinical features of strokes 185–6 differential diagnosis 186–7 EEG after stroke 187, 188 epileptic 139 frequency 182, 183, 184 lobar hemorrhage 603 low-flow infarcts 567, 569 management 187 mimicking stroke 186 mimicking TIAs 187 morbidity/mortality 186 parietal hematoma 605–6 pathogenesis 186 poststroke 182, 183, 184–7, 188, 189 preceding stroke 187, 189 primary brain hemorrhage 595 putaminal hemorrhage 595 risk factors 185–6

stroke 185–6, 187, 189 subarachnoid hemorrhage 621 temporal hematoma 604 timing 182, 184 types 184–5 underlying pathology 185 see also epilepsy selective serotonin reuptake inhibitor (SSRI) 368 semicircular canal 133 senile gait disorders 162, 163–4 sensation disturbances 49 sensorimotor stroke 583, 585–6 ischemic lesion size 586 sensorimotor syndrome anterior choroidal artery infarctions 454 thalamic infarcts 462 sensory agnosia 294 sensory ataxia 43, 321 sensory deficit anterior choroidal artery infarctions 453 hemispheral infarction in posterior cerebral artery territory 484 loss with posterior cerebral artery occlusion 482 motor dysfunction 43 sensory dysfunction after stroke 35–40 bilateral 41–2 delayed-onset symptoms 43 discriminative 43 motor incoordination 43 pontine tegmental infarcts 524–5 poststroke sequelae 42–3 related motor dysfunction 43 thalamic infarcts 462 unilateral 16 sensory homunculus 34, 35 sensory stroke anterior choroidal artery infarctions 454 paramedian pontine infarcts 522 posterior cerebral artery stenosis 481 pure 583, 584 ischemic lesion size 586 pontine 525 small putaminal hemorrhage 595, 596 thalamic 525 sensory syndrome acral 40 cortical 418 pure 462 septal nuclei 247–8 medial 243 serotonin 62 cerebral ischemia 14 trigemino-vascular system 61 serotonin receptor upregulation 286 serotonin reuptake inhibitors 287 pathological laughing/crying 290 sexual changes 332 shaggy falx 633 shape agnosia 303, 306–7 perception 267–8

739

740

Index

sharp activity and frontal intermittent delta activity (FIRDA) 187 sickle cell disease 114–15, 621 sigmoid sinus 628 simultanagnosia 104, 307, 309–10 sinus venous thrombosis recanalization 640–1 sixth nerve palsy 623, 676 sixth nerve pseudopalsy 465 Sjögren's disease 700 skew deviation 515 ocular torsion 135, 138 pontine ischemia 677 skew torsion 137 sleep breathing disturbance 202, 203 EEG changes 204 enhanced mechanisms 195 increased production 195 leg movements 204 myoclonus 204 neurons 194 non-REM 194, 201, 204 REM 201 mentation release 202, 204 slow wave 194 spindles 194 see also dreaming; dreams sleep apnea 359–60 central 202 obstructive 202, 359–60 see also Ondine's curse sleep-disordered breathing 202, 203 sleep-promoting systems 194 sleepiness 195–8 sleep–wake cycle 194 dreaming and rostral basilar artery infarction 681–2 inversion 199, 201 reticular activating system 682 sleep–wake functions disturbances 192, 194–202, 203, 204 physiology 192–4 small artery disease, border zone cerebellar infarcts 351–2 small deep infarct (SDI) 583 small vessel disease 18 auditory symptoms 150–1 headache 71–2 multiple brain infarcts 501 pontine infarcts 521 smoking 63 bilateral carotid occlusion 656 caudate nucleus infarcts 473 smooth pursuit cerebellum 82 circuitry 83 double decussation 79 eye movement 76 paramedian pontine infarcts 523 impairment 83–4 inferior parietal/superior temporal lobe lesions 95 ipsilateral deficit 84 vertical 80 snake bite (owl's eye) sign 697, 702

Sneddon's disease 119, 502 sneeze 360 social behaviour changes, orbitofrontal cortex lesions 238–9 somatosensory areas 35 somatosensory evoked potentials, brainstem infarcts 559 somatosensory system functional anatomy 34–5 somatosensory–verbal disconnection 314 somatotopic body representation 35 somatotopic organization 23 somnolence 192, 195–8 bilateral/basal tegmental pontine hemorrhages 529 see also hypersomnia/hypersomnolence sorbitol 496 sound agnosia 312 lateralization in binaural tests 147 localization tests 147 spaces, recognition 266 spasms, tonic 169 spasticity with spinal vascular lesions 23–4 spatial disorders, visual 309–11 spatial disorientation 89, 266 spatial orientation 266 speech apraxia 316 deficit motor 252–3 superior cerebellar artery infarcts 684 discrimination 146, 148, 153 disorder with cerebellar lesions 337–8 disturbance caudate infarcts 474–5 TIAs 10–11, 16 dysfunction in hemiparesis 30 lateral premotor region stroke 234 spontaneous 214 stereotypies 169 superior mesial frontal cortex stroke 236 thalamic aphasia 254, 255 time-compressed recognition 148 see also dysarthria speed of onset of stroke 3–5 sphenoid air sinus infection 638, 646 sphincter dysfunction 446–7, 695 spinal apoplexia 695 spinal arterial plexus, connecting 693 spinal artery see anterior spinal artery; posterior spinal artery; spinal cord, arteries spinal claudication 697 spinal cord arteries 691, 692, 693–4 blood supply 691, 692, 693–4 chronic syndrome 701 compression 700 TIAs 694 transection and motor unit loss 330 vascular malformations 693, 701 veins 694 thrombosis 701 spinal cord infarction bilateral weakness 30

Index

MRI 696, 698, 701–2 transverse 695 spinal cord ischemia 326, 695–7, 698 angiography 702 anterior spinal artery syndrome 695–7 anticoagulants 703 antiplatelet therapy 703 aortic disease 699 arterial 699–701 causes 698–701 cervical 695 CT 702 electrophysiology 702 follow-up 702–3 iatrogenic complications 700–1 lumbar 695 mechanisms 698–701 myelography 702 prophylaxis 703 thoracic 695 treatment 703 ultrasonography 702 venous 701 spinal ischemic syndromes 693 spinal motoneurons 330 spinal nerves, swallowing 341 spinal shock 23, 695 urinary retention 331 spinal stroke syndromes 691, 694–703 angiography 702 clinical features 695–7, 698 CT 702 diagnostic evaluation 701–2 electrophysiology 702 follow-up 702–3 MRI 696, 698, 701–2 myelography 702 spinal cord ischemia mechanisms/causes 698–701 TIAs 694 treatment 703 ultrasonography 702 spinal vascular lesions, acute 23–4 spinothalamic system 34 central poststroke pain 43 sensation loss 36–7 spinothalamic tract 52 lateral medullary infarct 670–1 pontine ischemia 677 splenial split signs 317–18 split-brain syndromes 317 stapedius reflex measurements 149 Staphylococcus aureus 638 status epilepticus 184 cerebral venous thrombosis 644 lobar hemorrhage 603 stereotypies 169 paroxysmal complex dyskinesia 169 stimuli, competing/distorted 148 straight sinus thrombosis 635, 661 streptokinase 602 stress, abnormal fear reactions 293

striate cortex 88–9 infarction 90–1 vasculature 89 striato-pallido-thalamo-cortical loop 432 striatocapsular hemorrhage 476 striatocapsular infarction 428, 429–30, 432–5 lacunar syndromes 430 middle cerebral artery occlusion 256 pathogenesis 429 seizures 185 string sign 660, 661 stroke acute phase 366 care 365–6 disability 363 migraine induction 64 mimicking seizures 186 onset 3–5 prevention and poststroke dementia 276 recurrence 63 stroke recovery 363–9 complications 365–7 natural 363 therapeutic correlates 365–8 stupor 198–9 mortality 199 stuttering 447 subarachnoid hemorrhage agitation 230 aneurysmal 618, 619, 622, 623 antecedent events 620 caudate hemorrhage 476 cerebellar signs 623 cisternal blood volume 621 consciousness 620–1 examination 622–3 family history 621–2 headache 66, 68–9, 618–19 history 618–22 hypertension 622 medical history 621 memory loss 247–8 monoparesis 623 mycotic aneurysms 621, 623 neck stiffness 622 non-aneurysmal 621 paraparesis 623 Parinaud's syndrome 623 pulmonary edema 329 pyrexia 622 ruptured aneurysm 619 seizures 185, 621 sixth nerve palsy 623 subhyaloid hemorrhage 622 syndromes 618–23 third nerve palsy 622–3 thunderclap headache differential diagnosis 67–8 visual field defects 622 warning leaks 619–20 subcortical arteriosclerotic encephalopathy (SAE) 56–7 subcortical disequilibrium 164

741

742

Index

subcortical infarcts 654 subcortical-junction infarcts 502 subcortical lesions agraphia 256 apraxia 256–7 hemineglect 265 subcortical loops, hemineglect 265–6 subcortical region depression 286 subcortical stroke behavioural change 259–60 depression 259–60 dysarthria 336 neglect 257–8 neurobehavioural changes 252–61 pathological crying/laughter 260 sensory dysfunction 40–3 white matter lesions 56–7 subcortical structures, frontal lobe interconnections 233–4 subcortical vascular dementia 260–1 subcortical vascular disease 260 subdural hematoma 486 subependymal region circulation 612 subhyaloid hemorrhage 622 subinsular infarcts 432 subjective experience 291–3 subjective visual vertical (SVV) tilt 132 cortical artery infarcts 141 deviation 133 pathological 132–5 thalamic infarcts 138–9 substance P 62 substantia nigra Lewy bodies 163 pars reticulata lesions 96 reticular nucleus 469 subthalamic nucleus lesion 165 suicide risk 294 sulcocommissural arteries 693–4 sulcocommissural artery syndrome 696 sundowning 200 superficial sylvian vein 629 superior cerebellar artery (SCA) 52, 53, 668 aneurysm 622 brainstem supply 375, 376 territory 543 cerebellar arterial supply 380 cerebellar hemorrhage 553 cerebellum supply 375, 377 classic syndrome 541–3, 683 lateral syndrome 545 occlusion 524 superior cerebellar artery (SCA) infarcts 54, 541–6, 683–4 branch 683, 684 causes 545–6 cerebellar 506 multiple 507, 508 pseudotumoural 552 clinical features 542–5 course 545

lateral branches 683 medial branches 683, 684 multiple posterior circulation 549–50 partial territory 542 stroke mechanism 686 superior colliculus 79 lesion 79 saccade triggering 83 superior mesencephalic arteries 465 superior oblique palsy, isolated 513 superior olivary complex 145 superior parietal artery 441, 442 superior rectus muscle 79–80 superior sagittal sinus 627–9 thrombosis 630, 631 septic 638 superior sagittal sinus thrombosis angiography 635, 642 empty delta sign 631–2, 633 MRI 637 Tc-labelled red cell scintigraphy 637 supplementary motor area 446 supplementary motor cortex 214 damage 236 motor neglect 445–6 supranuclear lesions 336 supranuclear palsy 335 conjugate-vertical-gaze 515 disconjugate-vertical-gaze 515 facial 29 suprareticular structures 82 supratentorial infarctions dysarthria 335 multiple 504 prognosis 494 vestibular dysfunction 141 swallow reflex 343 swallowing anatomy 341–2 brainstem centres 341 function association with lesions 346 inability 356, 357 initiation 342 persistence of abnormalities 349–50 physiology 341–2 stages 341 tests 342, 343 thermal stimulation 347, 349 videofluoroscopy 342, 344 voluntary 355 sweating disorders 332 paramedian massive/large pontine hemorrhage 528 sympathomimetic drugs 602 syncope 199 syphilis cervical meningovascular 696 neurosyphilis 328 spinal cord ischemia 700 systemic lupus erythematosus (SLE) 328 cerebral venous thrombosis 639, 645

Index

CSF analysis 702 multiple brain infarcts 502 spinal cord ischemia 700 tachypnea 360 tactile agnosia 313–14 tactile anomia 314, 447, 448 tactile transfer loss 318–19 Takayasu's disease 71 taste sensation thalamic stroke 40 trigeminal neuralgia 38–9 tegmental infarcts, unilateral 524–5 tegmental mesencephalic stroke 197 temperature, body brain damage 366–7 progressive stroke 5 regulation 332 temperature sensation lateral medullary infarct 536 loss with superior cerebellar artery classic syndrome 543 temporal arteritis 71 temporal artery territory infarct 419 see also anterior temporal artery; posterior temporal artery temporal lobe xxiii posterior 482 right 227, 228–9 inferior 290 temporal lobe lesions auditory agnosia 156 cortical deafness 151 hematoma with lobar hemorrhage 604–5, 606 word deafness 155–6 temporopontine tract 51–2 tendon reflex 443 tentorial herniation 492 tentorium cerebelli 628 contrast enhancement 633 téphromalacie antérieure 696 Terson's syndrome 622 tetraparesis, anarthric 200 thalamic astasia 462 thalamic hemorrhage 461, 465–6 posteromedial 103 thalamic infarction 461, 462–3, 464, 465 abulia 259 amnesia 245–7, 259 ataxic hemiparesis 454 behavioural change 259–60 cortical metabolism 256 dementia 259 hemiparesis 30 lateral 462 memory loss 245–7, 259 parkinsonism associated with small vessel disease 163 vestibular syndrome 138–9, 140 thalamic lesions and hemineglect 265 thalamic peduncle, anterior 431 thalamic relay nuclei 194

thalamic stroke agitation 225 hypersomnia 196 sensory dysfunction 39–40 thalamic syndrome 462 thalamic–subthalamic arteries 244, 380–1, 461, 462, 479, 681 infarcts 463, 465, 682–3, 686 posterior paramedian 81 superior mesencephalic arteries 465 thalamic–subthalamic injury 321 thalamocortical neurons 194 thalamocortical pathway interruption 585 thalamocortico–thalamic networks 194 thalamogeniculate arteries 381, 461, 462 occlusion 465 pure sensory stroke 481 thalamomesencephalic artery 515 thalamoperforating arteries see thalamic–subthalamic arteries thalamus ataxic hemiparesis 56 blood supply 461–2, 463, 464 hematoma 465–6 hemiataxia 56 nuclei 461–2, 464 posterior cerebral artery 461 infarct 482 posterior communicating artery 461 stroke 55–6 vascularization 381 ventrolateral 482, 483 see also lateral thalamus thermic dysregulation 332 third nerve palsy isolated 513 plus abnormal movements 515 plus cerebellar signs 514–15 plus hemiplegia 514 subarachnoid hemorrhage 622–3 thalamic–subthalamic artery infarcts 465 top of the basilar syndrome 681 three-dimensional information use 266 thrombocythemia, essential 502, 503, 504 thrombocytopenic purpura 502 thrombocytosis 114–15 thromboembolism brain infarcts 564 see also embolism; venous sinus thrombosis; venous thrombosis thrombolysis intra-arterial 554 intraventricular hemorrhage 615, 616 thrombolytic agents in basilar artery thrombosis 526–7 tinnitus 146 brainstem strokes 149 carotid dissection 657 pontine ischemia 678 tissue plasminogen activator (tPA) 602 intraventricular hemorrhage 615 Todd's paresis 569 tone order recognition 148 tongue paralysis 672

743

744

Index

top of the basilar syndrome 96, 197 agitation 224 apperceptive agnosia 303 mechanisms 517–18 medial thalamus infarcts 683 rostral basilar artery occlusive disease 506, 508 rostral brainstem ischemia 679–83 wakefulness disturbances 198 topagnosia, cortical stroke 41 topographical agnosia 102, 310 topographical disorientation 266 torcular Herophili 628 torsade de pointes 329 tractus solitarius 672 transcortical aphasia, acute mixed 421–2, 655–6 transhemispheric diaschisis 194 transient ischemic attacks (TIAs) anxiety symptoms 14–15 aura differentiation 65 brainstem infarction 4 capsular warning syndrome 28 cardioembolic 18–19 carotid artery 111 carotid dissection 114 cerebral infarction frequency 6 cervico-cerebral artery dissection 663 clinical history 17 clinical types etiological relevance 16–19 neurovascular relevance 15–16 common carotid occlusion 656 consciousness loss 12, 15 cortical 17, 18 definition 8 diplopia 14 focal neurological dysfunction 8 focal neurological symptoms 8, 9 headache 14, 65 hemiphenomena 10, 16 hemodynamic 655 internal carotid occlusion 655 ischemia 8–9 lacunar 17–18 syndromes 587 low flow 18 infarctions 567–8 motor symptoms 9–10 movement disorders 10 neglect 11, 12 panic symptoms 14–15 posterior cerebral artery infarction 686–7 stenosis 479–80, 481 pure cortical sensory 42 recurrence 9 repetitive 6 retinal 655 seizures 185 mimicking 187 sensory symptoms 11, 12, 13–15, 42 somatosensory symptoms 11, 12

speech disturbance 10–11, 16 spinal cord dysfunction 694 swallowing difficulty 10 symptoms 8–11, 12, 13–15 types 8–11, 12, 13–15 unsteadiness 10 vertebrobasilar 16 vertigo 12, 14 vestibular symptoms 12, 14–15 visual symptoms 11, 12 watershed infarction 4 weakness both sides of body 10 lower limb 18 on one side of body 10, 16 transient monocular blindness 11, 13, 15–16, 111, 112, 113–17 anisocoria 113 carotid artery dissection 69, 657 carotid bruit 113 central retinal artery occlusion 118 cholesterol emboli 111, 113 clinical signs 111, 113, 115, 116–17 crescendo 111, 117 emboli sources 112 facial pulses 113 ischemic optic neuropathy 123 platelet plugs 113 retinal artery pressure 113 type I 111, 112, 113–15 type II 112, 115 type III 112, 115–16 type IV 112, 116–17 vasospastic 115–16, 117 transtentorial herniation 486 trapezoid body 145 infarcts and auditory symptoms 151, 152, 153 trauma, central retinal artery occlusion 118 trazodone 98, 287, 368 tremor 167–8, 169 acute 167 delayed 167–8 intention 683 limb 48 modification of previous by strokes 167, 170 parkinsonian 167 tricyclic antidepressants 290 trigeminal artery, persistent 652 trigeminal nerves 34 bilateral sensory involvement 41 sensory abnormalities 36, 37, 38–9 trigeminal reflex stimulation 62 trigemino-vascular system serotonin 61 vasodilation in headache 62 triptans 61, 72 trochlear nuclei 79 infarcts 513 truncal ataxia dysarthria 338 superior cerebellar artery infarct 545 truncal lateropulsion 673

Index

trunk apraxia 164 trunk dysesthesia 670–1 tuberothalamic artery see polar artery tuberothalamic infarction aphasia 255 memory impairment 247 tumours 455 cerebral 601, 604 seizures 185 see also pseudotumour cerebri; pseudotumoural syndrome two-dimensional information use 266 ulcerative colitis 639 ulnar nerve 330–1 ultrasonography cerebral venous thrombosis 637 spinal cord ischemia 702 uncal herniation syndrome 494 uncal syndrome 194 upper eyelid retraction 515, 680 upper limb weakness 10, 16 upper motor neuron lesions dysarthria 334–6, 337 ischemic 335 urinary bladder dysfunction with spinal cord ischemia 695 function 331 hypotonia 345 sphincter dysfunction 446–7, 695 vesicourethral dysfunction 697 urinary incontinence 331 anterior cerebral artery infarction 446–7 outcome prediction 363, 365 urinary retention in spinal shock 331 urokinase 644 intraventricular hemorrhage 615 utilization behaviour 238 uveitis, ischemic 115 valproic acid 72 mania 291 stroke prevention in migraine 72 Valsalva manoeuvre 360 varicella zoster 700 CSF analysis 702 vasa coronae 693, 694 vascular dementia 244, 273 bilateral paramedian thalamic infarcts 247 multiple infarcts 508–9 posterior cerebral artery infarction 245 subcortical 260–1 vascular embolisms 323–4 vascular malformations see arteriovenous malformations vascular occlusive lesion 4 vasculitis 326, 327, 328 classification 326, 327 cryoglobulinemic 327, 328 drug-induced 327, 328 eosinophilic 116 lobar hemorrhage 602–3 necrotizing 328

spinal cord ischemia 700 vasospasm in subarachnoid hemorrhage 66, 67 vegetative syndrome 201 vein of Labbé 629 venous anastomoses 629 venous infarcts 503 cerebral venous thrombosis 632–3 venous sinus thrombosis 503 venous thrombosis 70 cerebral 632–3 ventilation mechanical 360 support 365 ventral frontal syndromes 238–9 ventralis posterolateralis (VPL) nucleus 34 ventralis posteromedialis (VPM) nucleus 34 ventricular compression 591 ventricular drainage 553 ventroamygdalofugal pathway 259 ventroanterior nucleus 52 ventrolateral nucleus 52 ventrolateral thalamic infarction 482, 483 ventromedial pulvinar vascularization 381 ventroposterolateral nucleus 52 verapamil 72 verbal memory 246 verbal recall, polar artery infarcts 463 vermal nucleus lesions 134 vertebral artery xxvi, 691, 692 angiography 225 brainstem supply 375, 376 cervico-cerebral artery dissection 663, 664 compression with rotational head motion 132 disease in spinal cord ischemia 700 dissection 70, 326, 549, 620 incidence 660 sneezing 360 transmural 620 distal 534, 535 extracranial 674 atherosclerosis 667 multiple intracranial territory infarcts 687 occlusion 678 stroke mechanism 686 intracranial 668, 674 atherosclerosis 667 multiple intracranial territory infarcts 687 occlusion 678 stroke mechanism 686 lateral medullary infarcts 534, 535 vertebral artery occlusion bilateral 560 border zone cerebellar infarcts 551 lateral medullary infarcts 537 rotational 132 treatment 560 vestibular dysfunction 132–5 vertebrobasilar artery disease auditory symptoms 149–50 multiple lesions 506, 508 posterior cerebral artery infarction 485–6

745

746

Index

vertebrobasilar artery system collateral circulation 656 evaluation 525–6 vertebrobasilar blood flow 130 vertebrobasilar infarction 96, 516–17 mechanisms 517 multiple 506 vertebrobasilar ischemia 131 vertebrobasilar migraine 69 vertebrobasilar stroke 69 acute syndrome 560 vertebrobasilar territory TIAs 15, 16 vertigo 12, 14, 16, 129, 130 AICA infarcts 547 anterior inferior cerebellar artery infarcts 131 central ischemic syndromes 131 central vascular 129 cerebellar stroke 540 disabling positional 129 epileptic seizures 139 episodic 130 lateral rotational 133 PICA infarcts 547, 548, 673 rotary 131 severe positional 135 vestibular cortex 139 see also dizziness vesicourethral dysfunction 697, 703 vestibular cortex 139 vestibular dysfunction anterior cerebral artery 139, 141 pontomedullary infarctions 135, 138 posterior cerebral artery 139, 141 roll plane 132 supratentorial infarctions 141 vestibular ocular reflex 132 vestibular nuclei climbing fiber pathways 133–4 see also medial vestibular nucleus vestibular ocular reflex 76, 78, 79, 81 vestibular dysfunction 132 vestibular pathways 130–1 vestibular syndromes 129, 130 basilar artery 135, 137, 138 cortical infarction 139, 140, 141 mesencephalic artery 135, 137, 138 paramedian pontine artery 135, 137, 138 thalamic infarction 138–9, 140 vascular 130 vestibular vermis 133–5 vestibulo-ocular reflex 131, 668 vision binocular blurring 12, 13, 18 central 88 foveal 89 loss in bright/white light 13–14 in left/right half of visual field 13 monocular blurring 18 preattentive 264 spatial aspects 89

visual acuity ischemic optic neuropathy 123 low-flow infarcts 569 visual agnosia 89, 99–100, 266–8, 269, 302–3, 306–7 anatomical correlates 306 apperceptive 267, 274 associative 686 dorsal visual pathway preservation 307 models 268 posterior cerebral artery infarction 686 left-hemisphere 485 right hemisphere syndromes 266–8, 269 visual allesthesia 98 visual amnesia 103, 245 visual anomia 99–100 visual cortex 87–90 extra-striate 89 pathways 302 visual defects/visual field defects 90–2 angular artery territory infarct 418 anterior choroidal artery infarctions 453–4 common carotid occlusion 656 distortions 95–6, 98 hemifield 102 hemispheral infarction in posterior cerebral artery territory 483–4 homonymous 90 lateral medullary infarct 534 middle cerebral artery inferior division territory infarct 410–11 migraine 72 posterior cerebral artery infarction 684–5 stenosis 480 posterior choroidal artery infarcts 465 rostral basilar artery syndrome 544 spatial disorders 309–11 subarachnoid hemorrhage 622 see also cerebral visual dysfunction visual hallucinations 95–6 visual hemianomia, left 317–18 visual hypoemotionality 103 visual image persistence 96, 98 visual imagery defects 89 neglect 265 visual information processing 268, 269 visual memory polar artery infarcts 463 thalamic infarcts 246 visual neglect 92–4, 264–5 constructional apraxia 99 perception/imagery 265 temporal arteries territory infarct 419 testing 93–4 visuospatial 409 visual perceptions abnormal positive 95–6, 98 complex 98 internally represented knowledge 267 neglect 265 visual recognition deficits 267 visual spread, illusory 98 visual–spatial–perceptual dysfunction 11, 12

Index

visual–vertical axis deviation 669–70 visuomotor apraxia 257 visuospatial agnosia 307, 310, 311 visuospatial disorders 309–11 visuospatial impairment 408, 418 visuospatial processing 235–6 vitreous hemorrhage 622 vocal fold paralysis 346 voice dysarthria 336, 337, 339 lateral medullary infarct 535 vomiting cerebellar stroke 540 frontal hematoma 604 lateral medullary infarcts 672 lobar hemorrhage 603 PICA infarcts 673 rostral basilar artery syndrome 544 superior cerebellar artery infarct 545 wakefulness 192–3 decreased 195 disorders 192, 194–9 left hemispheric dominance 195 Wallenberg syndrome 70, 82, 129, 132–5, 534–37 AICA infarcts 546 medial vestibular nucleus lesions 78 ocular tilt reaction 132–5 PICA infarcts 548 roll 133 warfarin brainstem infarction 560 caudate infarcts 475 cerebellar infarcts 554 cervico-cerebral artery dissection 664 watershed area see cortical border zone watershed infarctions 422 bilateral 30, 421, 652 anterior 502, 503 giant internal 431, 432, 438 heart disease 653 hemianopia 653–4

hypotension 653 internal 431, 437 internal capsule 436 internal carotid artery occlusion 652–4 lacunar strokes 552 low-flow 575, 576 motor aphasia 653 posterior 653–4 subcortical 654 terminology 577–8 unilateral 652 Weber syndrome 30, 79, 514 Wegener's granulomatosis 327, 328 Wernekinck commissure syndrome 516 Wernicke's aphasia 212, 214–15 agitation 227 apraxia 315 middle cerebral artery inferior division territory infarct 411 neologistic jargon 215 pure word deafness 312 putaminal hemorrhage 593 temporal arteries territory infarct 419 temporal hematoma 604 Wernicke's hemianopic pupil 90 white blood cells 366 white-matter hyperintensity 260 lesions aphasia 212, 213 deep pathways 239 periventricular 252–3 poststroke dementia 275 subcortical changes in vascular dementia 260–1 word deafness 153 form 215 meaning 215 pure 212, 215, 312–13 temporal lobe lesions 155–6 writing 217 see also agraphia yawn 360

747

Axial sections of the cerebral hemispheres showing the territories of the anterior, middle, and posterior cerebral arteries and the anterior choroidal arteries. The section on the right is more dorsal and shows the high frontal and parietal lobes. The section on the left is more ventral and also includes the temporal and occipital lobes.

Sagittal section of the right cerebral hemisphere showing the anterior, middle, and posterior cerebral arteries and their territories.

Lateral, somewhat oblique, view of the convexal surface of the left cerebral hemisphere and the paramedian portion of the right cerebral hemisphere showing the anterior, middle, and posterior cerebral arteries and their territories.

Oblique view of the brainstem and cerebellum showing the vertebral and basilar arteries and their branches. VA ⫽ vertebral artery, ASA ⫽ anterior spinal artery, PICA ⫽ posterior inferior cerebellar artery, AICA ⫽ anterior inferior cerebellar artery, BA ⫽ basilar artery, SCA ⫽ superior cerebellar artery, PCA ⫽ posterior cerebral artery.