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.

iReferencesi Adams, R.D., Victor, M. & Ropper, A.H. (1997). Principles of Neurology, 6th edn, pp. 405–16. New York: McGraw-Hill. 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. Amyes, E.W. & Nielsen, J.M. (1955). Clincopathological study of the vascular lesions of the anterior cingulate region. Bulletin of the Los Angeles Neurological Society, 20, 112–30. APA (1987). Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised (DSM-III-R), pp. 100–3. Washington, DC: American Psychiatric Association. Arseni, C. & Danaila, L. (1977). Logorrhea syndrome with hyperkinesia. European Neurology, 15, 183–7. Awada, A., Poncet, M. & Signoret, J. (1984). Troubles de comportement soudains avec agitation chez un homme de 68 ans. Revue Neurologique, 140, 446–51. Bakchine, S., Lacomblez, L., Benoit, N., Parisot, D., Chain, F. & Lhermitte, F. (1989). Manic-like state after bilateral orbitofrontal and right temporoparietal injury: efficacy of clonidine. Neurology, 39, 777–81. Bedford, P.D. (1959).