Sudden Death in Epilepsy: Forensic and Clinical Issues

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Sudden Death in Epilepsy: Forensic and Clinical Issues

SUDDEN DEATH in EPILEPSY FORENSIC AND CLINICAL ISSUES SUDDEN DEATH in EPILEPSY FORENSIC AND CLINICAL ISSUES EDITED BY

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SUDDEN DEATH in EPILEPSY FORENSIC AND CLINICAL ISSUES

SUDDEN DEATH in EPILEPSY FORENSIC AND CLINICAL ISSUES EDITED BY

CLAIRE M. LATHERS PAUL L. SCHR AEDER MICHAEL W. BUNGO JAN E. LEESTMA

Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2011 by Taylor and Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-13: 978-1-4398-0223-6 (Ebook-PDF) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

To (DS) a 4-year old boy with a history of nocturnal seizures who found hidden Christmas presents, including the one he wanted most of all, a remote control car two weeks before Christmas. The next morning he was found dead in bed. He and other victims of SUDEP challenge all of us to find preventive measures as quickly as possible. (CML) To Carol and Richard Lathers and to Marcel J. Lajoy for their love, support, and words of wisdom while completing this endeavor. (CML) To two university students (MB) and (AG) who were victims of SUDEP and to their courageous families who helped to found Epilepsy Bereaved in the United Kingdom. (PLS) To my patient wife Barbara and daughters Maria and Ellen who dealt with my many hours of editorial distraction with forbearance, encouragement and love. (PLS) To my grandson, Lucas, who missed quality time, so that this endeavor could be completed. (MWB)

Table of Contents

Foreword by Samuels Foreword by Schachter Preface Acknowledgments Editors Contributors

xv xvii xxi xxv xxvii xxxi

Section I Forensics of Sudden Death

1

Neurocardiologic Mechanistic Risk Factors in Sudden Unexpected Death in Epilepsy

3

Claire M. Lathers, Paul L. Schraeder, and Michael W. Bungo

2

Forensic Considerations and Sudden Unexpected Death in Epilepsy

37

Jan E. Leestma

3

Omega-3 Fatty Acids in Sudden Unexpected Death in€Epilepsy: Guardian of the Brain–Heart Connection

57

Fulvio A. Scorza, Esper A. Cavalheiro, Ricardo M. Arida, Vera C. Terra, Carla A. Scorza, Eliza Y. F. Sonoda, and Roberta M. Cysneiros

4

Unanswered Questions: SUDEP Studies Needed

67

Claire M. Lathers, Paul L. Schraeder, and Michael W. Bungo

5

Medullary Serotonergic Abnormalities in Sudden Infant Death Syndrome: Implications in SUDEP David S. Paterson

vii

77

viii Table of Contents

6

Forensic Case Identification

95

Paul L. Schraeder, Elson L. So, and Claire M. Lathers

7

Sudden Unexpected Death in Epilepsy: Future Research Directions

109

Simona Parvulescu-Codrea

8

Forensic Postmortem Examination of Victims of Sudden Unexpected Death in Epilepsy

131

Claire M. Lathers, Paul L. Schraeder, Steven A. Koehler, and Cyril H. Wecht

9

One-Year Postmortem Forensic Analysis of Deaths in Persons with Epilepsy

145

Steven A. Koehler, Paul L. Schraeder, Claire M. Lathers, and Cyril H. Wecht

10

Drug Abuse and SUDEP

159

Steven B. Karch

11

Cocaine-Induced Seizures, Arrhythmias, and Sudden Death

169

Claire M. Lathers, Michelle M. Spino, Isha Agarwal, Laurie S. Y. Tyau, and Wallace B. Pickworth

12

Risk Factors for Sudden Death in Epilepsy

187

Thaddeus S. Walczak

13

EEG Findings in SUDEP

201

Maromi Nei and Nicole Simpkins

14

Severity of Seizures as a Forensic Risk and Case Reports

209

Edward H. Maa, Michael P. Earnest, Mark C. Spitz, and Jacquelyn Bainbridge

15

Intractable Epilepsy in the Setting of Malformations of Cortical Development as a Mechanism for SUDEP

221

Lara Jehi and Imad Najm

16

Neurogenic Cardiac Arrhythmias Howan Leung and Anne Y. Y. Chan

235

Table of Contents

17

Stress and SUDEP

ix

253

Claire M. Lathers and Paul L. Schraeder

18

Genetics of Sudden Death in Epilepsy

267

Neeti Ghali and Lina Nashef

19

Cardiac Channelopathies and Sudden Death

285

Benito Herreros

20

Sodium Channel Dysfunction: Common Physiopathologic Mechanism Associated with Sudden Death ECG Abnormalities in Brugada Syndrome and Some Types of€Epilepsy: Case Histories

303

Claire M. Lathers, Paul L. Schraeder, and Michael W. Bungo

21

Not Seizure but Syncope

311

Saumya Sharma, Trieu Ho, and Bharat K. Kantharia

22

Syncope, Seizures, and SUDEP: Case Histories

325

Claire M. Lathers, Paul L. Schraeder, and Michael W. Bungo

23

Sudden Death in Epilepsy: Relationship to the Sleep–Wake Circadian Cycle and Fractal Physiology

333

John D. Hughes and Susumu Sato

24

SUDEP: Medicolegal and Clinical Experiences

347

Braxton B. Wannamaker

Section II SUDEP Animal Models: MECHANISMS OF RISKS

25

Sudden Death: Animal Models to Study Nervous System Sites of Action for Disease and Pharmacological Intervention Claire M. Lathers

363

x Table of Contents

26

Synaptic Plasticity of Autonomic Ganglia: Role of Chronic Stress and Implication in Cardiovascular Diseases and Sudden Death

395

Karim A. Alkadhi and Karem H. Alzoubi

27

Animal Model for Sudden Cardiac Death: Autonomic Cardiac Sympathetic Nonuniform Neural Discharge

427

Claire M. Lathers

28

Animal Model for Sudden Unexpected Death in Persons with Epilepsy

437

Claire M. Lathers and Paul L. Schraeder

29

A Characterization of the Lockstep Phenomenon in Phenobarbital-Pretreated Cats

465

Jeffrey M. Dodd-O and Claire M. Lathers

30

Relationship of the Lockstep Phenomenon and Precipitous Changes in Blood Pressure

481

Amy Z. Stauffer, Jeffrey M. Dodd-O, and Claire M. Lathers

31

Interspike Interval Histogram Characterization of€Synchronized Cardiac Sympathetic Neural Discharge and€Epileptogenic Activity in the Electrocorticogram of€the€Cat

495

Daniel K. O’Rourke and Claire M. Lathers

32

Power Spectral Analysis: A Procedure for Assessing Autonomic Activity Related to€Risk Factors for Sudden and Unexplained Death in€Epilepsy

513

Animal Model for Sudden Cardiac Death: Sympathetic Innervation and Myocardial Beta-Receptor Densities

539

Stephen R. Quint, John A. Messenheimer, and Michael B. Tennison

33

Claire M. Lathers and Robert M. Levin

34

Antiepileptic Activity of Beta-Blocking Agents

551

Claire M. Lathers, Kam F. Jim, William H. Spivey, Claire Kahn, Kathleen Dolce, and William D. Matthews

Table of Contents

35

Arrhythmias Associated with Epileptogenic Activity Elicited by Penicillin

xi

567

Claire M. Lathers and Paul L. Schraeder

36

Role of Neuropeptides in the Production of Epileptogenic€Activity and Arrhythmias

577

Claire M. Lathers

37

Sudden Epileptic Death in Experimental Animal Models

591

Ombretta Mameli and Marcello Alessandro Caria

38

Sympathetic Nervous System Dysregulation of Cardiac Function and Myocyte Potassium Channel Remodeling in Rodent Seizure Models: Candidate Mechanisms for SUDEP 615 Steven L. Bealer, Cameron S. Metcalf, Jason G. Little, Matteo Vatta, Amy Brewster, and Anne E. Anderson

39

The Urethane/Kainate Seizure Model as a Tool to Explore€Physiology and Death Associated with Seizures

627

Mark Stewart

40

Acute Cardiovascular Response during Kindled Seizures

645

Jeffrey H. Goodman, Richard W. Homan, and IsAac L. Crawford

41

DBA Mice as Models of Sudden Unexpected Death in€Epilepsy

659

Carl L. Faingold, Srinivasan Tupal, Yashanad Mhaskar, and Victor V. Uteshev

Section III Clinical Issues of Sudden Death

42

Cardiac and Pulmonary Risk Factors and Pathomechanisms€of Sudden Unexplained Death in Epilepsy€Patients Josef Finsterer and Claudia Stöllberger

679

xii Table of Contents

43

Neurocardiac Interactions in Sudden Unexpected Death in€Epilepsy: Can Ambulatory Electrocardiogram-Based Assessment of Autonomic Function and T-Wave Alternans Help to Evaluate Risk?

693

Richard L. Verrier and Steven C. Schachter

44

Arrhythmogenic, Respiratory, and Psychological Risk Factors for Sudden Unexpected Death and Epilepsy: Case Histories

711

Claire M. Lathers

45

Sudden Arrhythmic Death Syndrome: Underlying Cardiac Etiologies, Their Implications, and the Overlap with SUDEP

721

Paramdeep S. Dhillon and Elijah R. Behr

46

Odds Ratios Study of Antiepileptic Drugs: A Possible Approach to SUDEP Prevention?

743

Claire M. Lathers, Paul L. Schraeder, and H. Gregg Claycamp

47

Antiepileptic Drugs Benefit/Risk Clinical Pharmacology: Possible Role in Cause and/or Prevention of SUDEP

755

Claire M. Lathers and Paul L. Schraeder

48

Clinical Pharmacology and SUDEP

789

Claire M. Lathers and Paul L. Schraeder

49

Experience-Based Teaching of Therapeutics and Clinical€Pharmacology of Antiepileptic Drugs: Sudden Unexplained Death in Epilepsy: Do Antiepileptic Drugs Have a Role?

801

Claire M. Lathers and Paul L. Schraeder

50

Clinical Pharmacology of Antiepileptic Drug Use: Clinical Pearls about the Perils of Patty

827

Paul L. Schraeder and Claire M. Lathers

51

Compliance with Antiepileptic Drug Treatment and the€Risk of Sudden Unexpected Death in Epilepsy Torbjörn Tomson

845

Table of Contents

52

SUDEP Clinical Case Histories: Typical and Atypical

xiii

853

Paul L. Schraeder

53

Cardiac Antiarrhythmic Agents: Pharmacological Basis for Their Antiarrhythmic and Proarrhythmic Effects

861

Saumya Sharma, Trieu Ho, and Bharat K. Kantharia

54

Could Beta–Blocker Antiarrhythmic and Antiseizure Activity Help Prevent SUDEP?

877

Claire M. Lathers

55

Decision Analysis and Risk Management

887

H. Gregg Claycamp

56

Epilepsy Surgery and the Prevention of SUDEP

905

Ryan S. Hays and Michael R. Sperling

57

Challenges in Overcoming Ethical, Legal, and Communication Barriers in SUDEP

915

Jane Hanna and Rosemary Panelli

58

Bereavement and Sudden Unexpected Death in Epilepsy

937

Lina Nashef and Lene Sahlholdt

59

SUDEP: A Clinical and Communicative Conundrum

943

Paul L. Schraeder and Claire M. Lathers

60

Epilepsy and SUDEP: Lessons Learned: Scientific and Clinical Experience

953

Claire M. Lathers and Paul L. Schraeder

61

SUDEP: A Mystery Yet to Be Solved

967

Claire M. Lathers and Paul L. Schraeder

62

Forensic Evidence and Expert Witnesses: Scientific Evidence: Getting It in and Keeping It Out

973

Thomas L. Bohan

Index

983

Foreword by Samuels

Epilepsy is one of the most prevalent neurological diseases in the world. Known for ages and clearly described in some of the oldest medical treatises, it was greatly feared in the ancient world because of the belief that it could cause sudden death. As reasonable treatments arose—ἀrst bromides, then phenobarbital, and, in the mid-twentieth century, phenytoin, the ἀrst modern antiepileptic drug—the mainstream of the medical community came to believe that epileptic seizures themselves were relatively harmless. During my own training in internal medicine in the 1970s, it was widely taught that the best treatment for a convulsion was to simply place the patient in a safe environment and let the seizure take its course. With the development of newer, safer treatments that include drugs and nonpharmacological approaches such as surgery and, more recently, vagal and deep brain stimulation, it became progressively more apparent that the ancients were, in fact, correct. Epilepsy, a state of recurrent unprovoked seizures, itself indeed carried with it an increased risk for sudden unexpected death and the term SUDEP (sudden unexpected death in epilepsy) was born. SUDEP now joins a long list of sudden death syndromes, including sudden death in middle aged men, sudden unexpected nocturnal death syndrome (SUNDS), sudden death from fright, sudden infant death syndrome (SIDS), sudden death in young athletes, sudden death associated with drug use, sudden death from heart disease, sudden death during sedative drug (including alcohol) withdrawal, sudden death during delirium, sudden death from stroke (including subarachnoid hemorrhage), and sudden death from head injury. With the advent of long-term monitoring of various physiological parameters, including the electrocardiogram, arterial oxygen saturation, and the electroencephalogram, it became apparent that some of these sudden death syndromes had in common a capacity to produce malignant cardiac arrhythmias, respiratory arrest, or both. In his landmark paper of 1942, “Voodoo” Death, the eminent physiologist Walter B. Cannon recounted stories of sudden death from the anthropological literature and posited an autonomic storm as the unifying hypothesis. In the past half-century, much has been learned about the capacity of the brain to damage the visceral organs, but many features of SUDEP remain an enigma. Despite all of the advances in the diagnosis and treatment of seizure disorders, the threat of sudden death still hovers over the epileptic patient, much as it did in ancient times. In Sudden Death in Epilepsy: Forensic and Clinical Issues, four of the most eminent experts in SUDEP, Claire Lathers, Paul Schraeder, Michael Bungo, and Jan Leestma, have put together an impressive tome representing the state of this art and science. The book’s three sections, Forensics of Sudden Death, SUDEP Animal Models: Mechanisms of Risk, and Clinical Issues in Sudden Death, are written by a veritable who’s who in the ἀeld. The interested reader can ἀnd chapters on the history, diagnosis, phenomenology, mechanisms, genetics, animal models, pathology, physiology, and even the social repercussions of this devastating phenomenon. Books written by so many authors inevitably create a challenge with regard to organization and thematic coherence, but the four editors, themselves xv

xvi

Foreword by Samuels

each major contributors to the literature on SUDEP, have done an admirable job pulling together the disparate array of experts into a volume that holds together and is readable. Sudden Death in Epilepsy: Forensic and Clinical Issues should be of great interest to neurologists, psychiatrists, neurosurgeons, internists, cardiologists, neuroscientists, and cardiovascular specialists. Epileptologists and their trainees will ἀnd the content invaluable in their day-to-day lives of counseling and treating people with epilepsy. Taken as a whole, the content acts as a roadmap to those who hope to someday fully understand and prevent this dramatic and tragic event. Martin A. Samuels, MD, FAAN, MACP, DSc (hon) Chairman, Department of Neurology Brigham and Women’s Hospital and Professor of Neurology Harvard Medical School Boston, Massachusetts

Foreword by Schachter

If sudden death in epilepsy is the most feared and serious consequence of epilepsy, why is it seldom discussed and woefully under-researched? The editors point to many reasons for this in the Preface—inadequate animal models and basic understanding, lack of clinical recognition from treating physicians and medical examiners, inability to eliminate the possibility of sudden death in the nearly one in three patients with epilepsy whose seizures are drug-resistant, and continuing reluctance among physicians to discuss sudden death with patients and their families. Compounding these issues is the silo-style infrastructure of academic medicine, which creates intrinsic barriers to establishing clinical and research collaborations across relevant disciplines, such as epidemiology, neurology, cardiology and pulmonology, as well as between physicians and applied scientists, including electrical, mechanical, and computer engineers. Despite these and other problems, there are reasons to be optimistic that research will begin to solve the mysteries posed by Drs. Lathers and Schraeder at the end of this book. First, creative and passionate researchers are dedicated to eradicating sudden death in epilepsy, perhaps most of all the editors of this volume, who have put together the most comprehensive and current treatise on the topic. The like-minded authors span numerous disciplines and their chapters challenge current paradigms and suggest new ways of thinking about sudden death in epilepsy. Second, the National Institute of Neurological Disorders and Stroke (NINDS) is actively engaged. Curing Epilepsy 2007: Translating Discoveries into Therapies, organized by the NINDS, and attended by more than 400 researchers, health care professionals, patients, and family members, affirmed sudden death in epilepsy as a major target for research, with the development and validation of at least one prevention strategy to decrease its occurrence as a short-term goal, and identiἀcation of the responsible mechanisms, including effects of seizures on autonomic functioning, particularly cardiac and respiratory, as a longer-term goal. The NINDS also sponsored a workshop on sudden death in epilepsy, held in November, 2008, which brought together researchers, clinicians, and patient advocacy groups to discuss strategies and to make plans for research and outreach. Third, professional epilepsy societies have recently established committees and taskforces with patient advocacy organizations, and have committed resources to work together to educate epilepsy professionals, doctors in training, and patients and families about sudden unexpected death in epilepsy (SUDEP), and to chart research agendas. The recommendations of one such task force include “convening a multidisciplinary workshop to reἀne current lines of investigation and to identify additional areas of research for mechanisms underlying SUDEP; performing a survey of patients and their families and caregivers to identify effective means of education that will enhance participation in SUDEP research; conducting a campaign aimed at patients, families, caregivers, coroners, and medical examiners that emphasizes the need for complete autopsy examinations for patients with suspected SUDEP; and securing infrastructure grants to fund a consortium xvii

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Foreword by Schachter

of centers that will conduct prospective clinical and basic research studies to identify preventable risk factors and mechanisms underlying SUDEP” [1]. Fourth, numerous patient advocacy groups and family survivors are talking openly and urgently about sudden death in epilepsy at conferences and on Web sites. In addition, these groups are aggressively funding research projects with the hope of uncovering answers that will move the ἀeld forward. Indeed, these and other developments will likely enable critically important progress to be made in the understanding of sudden death in epilepsy and its prevention. These answers cannot come soon enough. And yet answers alone are not sufficient. If lack of seizure control is a signiἀcant risk factor for sudden death in epilepsy, then we must also urgently address the treatment gap in epilepsy, both by making treatments available to the tens of millions of persons with epilepsy in developing countries who currently have no access to anticonvulsants, and by ensuring that all patients everywhere with epilepsy have access to state-of-the-art care, including the full range of pharmacological and nonpharmacological treatment options. Even if researchers identify the underlying mechanism(s) of sudden death in epilepsy and patients have full access to comprehensive care, there will still remain one major barrier—lack of effective communication between physicians and their patients. Here are the agonizing reflections of a physician about whether to inform patients about sudden death€[2]: As a doctor and an epileptologist, I experience the deepest frustration when I am notiἀed of the sudden and unexpected death of one of my patients. Often these patients have been found dead in bed, lying dead on the floor of their apartment, or drowned in the bathtub. They are invariably young and are often at the beginning of their lives. I never forget them, and I feel that I have truly and ultimately failed them. . . . one of my young patients, a 25-year-old man, died last year while in bed. His parents had encouraged him to live alone so that his life would be as normal as possible. They had visited him that evening and had eaten dinner with him. He had a girlfriend, but she had not been there that night. The next morning he was found lying face down on his bed, fully dressed. No one was sure whether or not he had experienced a seizure. When his parents called me, we talked about the problem of sudden death and epilepsy. They wondered why his other doctors and I had not told them or their son that this could occur. I asked them if they thought he would have lived any differently if he had known. If we told every patient with epilepsy about this possibility, some might not dare live independent lives or might be burdened by anxiety, knowing that they might not awake in the morning. To this day, I do not know if my answer was appropriate.

This challenge must be addressed and solved before the discoveries of research can be translated to patient care if we are ever to end the scourge of sudden death. As physicians caring for patients with epilepsy, we should not wait for all the answers. We must accept the imperfect state of knowledge and inform our patients and, where appropriate, their families in a meaningful and compassionate way about sudden death, and work with them as much as possible to reduce the risk factors, especially by completely controlling generalized convulsive seizures. The editors and authors of Sudden Death in Epilepsy: Forensic and Clinical Issues have produced a landmark book that holds extraordinary promise for meaningful progress, bringing us closer to the day when sudden death will be fully preventable. Until then, my

Foreword by Schachter

xix

hope is that this book will inspire researchers, and give some measure of comfort to the bereaved and hope to those living with epilepsy and to their loved ones. Steven C. Schachter, M.D. Departments of Neurology Beth Israel Deaconess Medical Center Harvard Medical School Chief Academic Officer Center for Integration of Medicine and Innovative Technology Boston, Massachusetts

References 1. So EL, Bainbridge J, Buchhalter JR, et al. Report of the American Epilepsy Society and the Epilepsy Foundation Joint Task Force on sudden unexplained death in epilepsy. Epilepsia 2009;50: 917–922. 2. Schachter SC, ed. Epilepsy in our experience: Accounts of health care professionals. Oxford: Oxford University Press; 2008, pp. 7–8.

Preface

This book should be considered a sequel to, rather than a substitute for, the 1990 book Epilepsy and Sudden Death, edited by Lathers and Schraeder. Much of the material in the 1990 book, especially the discussion of animal research data, is still timely, as little additional animal-based work is extant. In addition, the epidemiological, behavioral, and drug-abuse-related data is also currently relevant. This current volume is an expansion rather than an updated sequel to the previous book on sudden unexpected death in epilepsy (SUDEP). These statements are based on our extensive review of the literature for this current book, which indicates that most of the research questions regarding evaluation of mechanisms and prevention of SUDEP have, to date, not been adequately addressed. When the previous book was published, the phenomenon of sudden unexpected/unexplained death in persons with epilepsy was considered to be a controversial topic or a very rare phenomenon by clinicians and pathologists alike. The public had little or no knowledge of the phenomenon. However, one positive consequence of the work done in SUDEP over the ensuing years is that now the phenomenon is widely referred to as SUDEP and it is accepted as a complication of epilepsy worldwide. SUDEP is one of the most common causes of death in young adults with a history of epilepsy, and presents a spectrum of dilemmas to forensic experts, clinicians, and researchers. At a most basic level, as determined in a national survey of coroners and medical examiners and discussed in this book, even in self-evident cases, SUDEP is infrequently used on death certiἀcates as a ἀnal diagnosis or medical cause of death. Ironically, this survey found that the majority of those same coroners and medical examiners who did not routinely use SUDEP on death certiἀcates, nonetheless acknowledged its validity as a diagnosis in a theoretical case in which no cause of death in a person with epilepsy could be found on postmortem examination. This disconnect between intellectual acknowledgment of its existence, and actual use of SUDEP as a death certiἀcate diagnosis, in all likelihood, results in signiἀcant underreporting of the prevalence of this tragic phenomenon. It is hoped that this book will prove to be an important resource to improve the knowledge of coroners and medical examiners about the use of the term SUDEP in appropriate cases. Since a portion of this new book addresses forensic issues, it is intended to be a resource for forensic pathologists, attorneys, coroners, and medical examiners as they struggle to determine the cause of death in persons with epilepsy. Because most other clinical and research aspects of SUDEP are also addressed, neurologists, experts in epilepsy, cardiologists, clinical pharmacologists, pharmacists, nurses, students, and persons with epilepsy or with a family member so diagnosed should all ἀnd sections of interests. Over the past two decades, many more basic and clinical scientists doing research in the ἀeld of epilepsy are focusing on the problem of SUDEP, as it is one of the most common causes of death associated with having epilepsy. However, to date, most research has focused on clinical and epidemiological data, with relatively few investigators using xxi

xxii

Preface

animal models. In addition, there has been little effort to determine whether there are common links between the risk of SUDEP and sudden cardiac deaths. While cardiologists are focusing increasingly on genetic risk factors for potentially life-threatening arrhythmias in young persons without coronary artery disease, there has been little effort to establish collaboration between neuroscience investigators interested in SUDEP and cardiology researchers interested in unraveling the genetically determined risk factors for potentially fatal arrhythmias. This book will be of help in directing neurological and cardiologic investigators to common areas of interest, especially as relates to the unanswered question of why some persons with epilepsy seem to be at risk for neurogenically induced fatal cardiac events. The basic science of epilepsy as relates to SUDEP is updated and expanded in this book. The role of alcohol and other drugs as seizure enhancing or producing conditions are discussed. The role of medication, compliance with prescribed antiepileptic drugs, or lack thereof, is an even more important problem today and is addressed in several chapters. The relevance of epidemiological studies of SUDEP is also presented. Sudden death in the pediatric population is also reviewed. The neurocardiological aspects of SUDEP are addressed in some detail. While SUDEP remains a major unsolved problem, thanks to the efforts of those who have conducted animal and epidemiological studies, what was once denied and called a myth is an acknowledged reality that has to be dealt with as a multidisciplinary issue. To solve the mystery of SUDEP, a global focus is required. Persons at risk must be identiἀed and preventive treatment regimens developed to decrease the occurrence of SUDEP. Clinical chapters emphasize that sophisticated simultaneous ambulatory EKG and EEG telemetry and respiratory function monitoring of patients at risk for sudden death will help identify cardiac, respiratory, and epileptogenic interactions in order to decrease the risk of SUDEP. Basic scientiἀc research programs and clinical and epidemiology studies are needed. Multidisciplinary teams working in clinical settings and with laboratories must address the global issues of SUDEP. Forensic chapters in this book discuss the fact that if the correct term “SUDEP” is used on autopsy reports, and if postmortem verbal autopsies are conducted when needed, the true incidence of SUDEP well may be determined to be much higher than previously thought. Drug development can justify the need for new antiepileptics and drugs in other pharmacological classes that address the reduction of the risk of SUDEP. Animal model chapters discuss new data gleaned by building on the previously utilized models and the lessons learned during the last quarter century. The use of animal models continues to be one of the most useful approaches to better understanding SUDEP. Discussion in various chapters may be summarized by stating that it is important to “think out of the box” when evaluating an established animal model that has the potential, with modiἀcation(s), to investigate possible mechanisms of SUDEP. Various authors of the animal model chapters presented in this book emphasize that multiple models are needed to investigate the pathophysiology of SUDEP, to hypothesize about effective treatments, to develop pilot studies in persons with epilepsy, and to conduct conἀrmatory large-scale clinical trials. The ἀelds of pharmacology, clinical pharmacology, and cardiology have much to offer as we work to improve compliance, develop new antiepileptic drugs, and apply different categories of drugs that hopefully attenuate the chances of occurrence of SUDEP. Authors address the possible overlapping mechanisms that may apply to the risk of sudden

Preface

xxiii

unexpected death occurring in epilepsy and in cardiac disease. Several chapters explore the interaction between the central and peripheral autonomic nervous systems and the cardiopulmonary systems. Included is a discussion of the potential interactive role of genetically determined subtle cardiac risk factors for arrhythmias, with a predisposition for seizurerelated cardiac arrhythmias. The possible mechanisms that are operant in producing both epileptogenic and cardiogenic arrhythmias are addressed. Several chapters examine proposed mechanistic factors in SUDEP, listing risk categories of arrhythmogenic, respiratory, and hypoxia, and psychological factors and discussing mechanisms for risks associated with each category. Several chapters discuss patients with Brugada syndrome and an interesting, interpretive presentation of a hypothesis to explain a common pathophysiologic mechanism associated with sodium channel dysfunction that may be common to clinical electrophysiological abnormalities and some types of epilepsy. Clariἀcation of risk factors and establishment of the mechanism of SUDEP are important to establish preventative measures for SUDEP and emphasize the need to strive for full seizure control. Several chapters discuss the importance of encouraging patients with epilepsy to receive nonmedical, common sense, lifestyle-modifying interventions that have generally accepted public health beneἀts, even though there is as yet no consensus that they may or may not prevent sudden death. Cardiac patients, psychiatric patients, and certain ethnic groups experiencing acute stressful circumstances are at risk for unexpected sudden death. The impact of adverse emotional states on the autonomic control of cardiac rhythm is an established factor leading to cardiac dysrhythmias in humans and other species. Although stress is associated with changes in autonomic neural function, its role as a potential risk factor for SUDEP has not been investigated. The association of epilepsy with depression and anxiety indicates that emotional stress should be evaluated as a potential risk factor for SUDEP. The interactions between emotional factors and the arrythmogenic potential of epileptiform discharges, and the possibility of beneἀt from stress management intervention need investigation. Prospective studies of patients are needed to determine how we can identify which persons with epilepsy are at risk for SUDEP. In a number of chapters, the authors speculate about common potential preventive measures to minimize the risk of both sudden unexpected death in epilepsy and sudden cardiac death. Several chapters address the issue of clinicians who treat persons with epilepsy, manifesting reluctance to discuss the possibility of SUDEP with their patients. This reluctance seems to be the result of concern that even introducing the topic to the patient and family would be stressful for them. However, for the most part, families of SUDEP victims express disappointment that they had not known of this possibility and call for widespread acknowledgment of the potential for occurrence of sudden death in association with epilepsy. Epilepsy Bereaved in the United Kingdom, an organization founded by families of SUDEP victims, has been particularly successful in raising the level of awareness of SUDEP in persons with epilepsy and their families, and within the medical profession and the general public. This kind of advocacy and dissemination of information will serve to increase the availability of resources used to solve the tragic mystery of SUDEP. A primary purpose of this book is to provide clinicians with the knowledge necessary to improve their comfort level in discussing SUDEP with patients and families and thereby to allow for freer dissemination of information about minimizing the known risk factors for SUDEP (e.g., erratic compliance in taking prescribed antiepileptic drugs). Committed investigators in research must solve the mystery of SUDEP using a leadership philosophy foundation that provides innovative vision and approaches for SUDEP

xxiv

Preface

research and teaching programs. The interaction of teaching and research is essential. While a student is learning how to conduct research, that person must simultaneously learn to become a teacher. Academic fellowships and competitions and grant funding for medical students, postdoctoral fellows, residents, and faculty will attract medical and graduate trainees to work on SUDEP and move the SUDEP knowledge base forward. As self-learning exercises, we have incorporated a variety of case studies of sudden death within chapters and as standalone chapters as practical teaching exercises. Clinical and basic science investigators must provide vision and a fertile environment to teach students to become tomorrow’s leaders in the struggle to solve the mystery of SUDEP. Claire M. Lathers Paul L. Schraeder Michael W. Bungo Jan E. Leestma

Acknowledgments

I wish to acknowledge the dedication and hard work of co-editor Claire Lathers. (JEL) We would not have been able to complete this book in a timely manner without the diligent secretarial assistance of Marie Faiola. (CML, PLS, MWB, JEL).

xxv

Editors

Claire M. Lathers, PhD, FCP, has been credentialed as a Senior Biomedical Research Scientist by the U.S. Food and Drug Administration (FDA) for international recognition of her work in the two areas of cardiovascular autonomic dysfunction associated with sudden death in persons with epilepsy and with space flight. The primary focus of her international cardiovascular pharmacology research career has centered on autonomic peripheral and central mechanisms involved in the control and regulation of blood pressure, heart rate and rhythm, and the electroencephalogram. Dr. Lathers and Dr. Schraeder have collaborated and published numerous studies and two books focusing on epilepsy and sudden unexplained death. Dr. Lathers served the FDA for a total of 11 years, including four years as the Senior Advisor for Science to the director in the Center for Veterinary Medicine and director of the Office of New Animal Drug Evaluation and ἀve years in the Center for Drug Evaluation and Research as a pharmacology reviewer. Claire also served as a special government expert for 2 years. Dr. Lathers spent 14 years working as a visiting scientist at NASA/ USRA, collecting data from subjects in ground-based studies and from astronauts and cosmonauts before, during and after space flight. Dr. Lathers earned a BS in pharmacy from Albany College of Pharmacy, Union University and her PhD in pharmacology from the State University of New York at Buffalo School of Medicine. She completed an NIH funded two-year postdoctoral fellowship at the Medical College of Pennsylvania. Her academic faculty experience includes working at the Medical College of Pennsylvania (15 years), Albany College of Pharmacy (two years as president, dean, and tenured professor); Uniformed Services University of the Health Sciences (three years part time); and Gwynedd Mercy College (11 years part time). Dr. Lathers is currently collaborating with a number of academicians on scientiἀc issues of the nexus between human and veterinary medicine clinical pharmacology, antimicrobial resistance, food safety, and biodefense measures. In addition to her academic and government service, Dr. Lathers has worked in the pharmaceutical industry. She served as chief scientiἀc officer of Barr Pharmaceuticals for three years and worked part time with four other pharmaceutical companies during a 15-year period. Dr. Lathers has authored or co-authored over 300 publications and abstracts, has edited three books, and has presented data at over 140 international meetings. She is an emeritus fellow, an honorary member of the Board of Regents, and a past president of the American College of Clinical Pharmacology, having served as regent, treasurer, and president. Dr. Lathers also served as the section editor of the educational series entitled: “Innovative Teaching Methods in Clinical Pharmacology” for the Journal of Clinical Pharmacology for 17 years. Claire served as a member of the Board of the Annapolis Center, charged to evaluate risk assessments, and worked on the epidemiology, toxicology, and food safety workshops and accords. In recognition of her work, Dr. Lathers has been the recipient of numerous awards and honors. xxvii

xxviii Editors

Paul L. Schraeder, MD, FAAN, is professor emeritus of neurology at Drexel University College of Medicine, former chief of neurology at the Medical College of Pennsylvania Hospital, Philadelphia, Pennsylvania and former professor of medicine and neurology at the Robert Wood Johnson School of Medicine in Camden, New Jersey; head of the Division of Neurology at Cooper Hospital/University Medical Center, Camden, New Jersey; and former associate professor of neurology at the Medical College of Pennsylvania. He is a member of the Philadelphia Neurological Society, the American Epilepsy Society, and a fellow of the American Academy of Neurology. He has served on the professional advisory board of the Epilepsy Foundation of Southeastern Pennsylvania and the Epilepsy Foundation of America and as medical advisor to Epilepsy Bereaved, a support organization for surviving friends and family of victims of sudden unexplained death in epileptic persons (SUDEP) in the United Kingdom. Dr. Lathers and Dr. Schraeder co-edited the ἀrst book addressing the topic of Epilepsy and Sudden Death (Marcel Dekker, 1990). Dr. Lathers and he have collaborated for over three decades studying and investigating the mystery of SUDEP and developed the ἀrst experimental animal models of this fatal phenomenon. Dr. Schraeder organized a collaborative nationwide survey of how coroners and medical examiners evaluate the deaths of persons with a history of epilepsy. Dr. Schraeder received the AB€ degree from Bucknell University, Lewisburg, Pennsylvania and the MD degree from€Jefferson Medical€College, Philadelphia, Pennsylvania. He completed his residency in neurology and fellowship in electroencephalography and experimental epilepsy at the University of Wisconsin. Michael W. Bungo, MD, FACC, FACP, has agreed to serve as the third co-editor of this new book. After residency and fellowship training in cardiology at Harvard Medical School programs in Boston, Dr. Bungo worked full time for NASA as director of the Space Biomedical Research Institute at the Johnson Space Center. During his time at NASA, Dr. Bungo ἀrst cataloged arrhythmias occurring in spaceflight crews and hypothesized that the unique physiological and psychological environments of space flight may be arrhythmogenic. The Aerospace Medical Association awarded him the Louis H. Bauer Founders Award and NASA awarded him the NASA Medal for Exceptional Scientiἀc Achievement for his pioneering research work concerning the heart’s adaptation to zero gravity. While at NASA, Dr. Bungo served on the Joint U.S.–U.S.S.R. Working Group that developed the now combined space station science program for these prior competitors. He left NASA to assume the positions of director of the Heart Station, Division of Cardiology and vice chair for Inpatient Affairs, Department of Internal Medicine at the University of Texas Medical Branch in Galveston. Dr. Bungo subsequently moved to the University of Texas Medical School in Houston and served as chief of staff at the LBJ General Hospital, CEO of UT-Physicians, and vice dean for Clinical Affairs. He is currently a professor of medicine in the Division of Cardiology at that same institution. Dr. Bungo’s current research project funded by NASA is entitled “Cardiac Atrophy and Diastolic Dysfunction during and after Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capacity, and Risk of Cardiac Arrhythmias.” In addition to numerous publications and presentations, Dr. Bungo and Dr. Lathers have collaborated since 1989 and have co-authored seven published papers. In 2008, Dr. Bungo has co-authored three papers and one book chapter with Drs. Lathers and Schraeder on the mystery of SUDEP. Dr.€Bungo has delivered scientiἀc presentations at three international symposiums organized by Dr.€Lathers.

Editors

xxix

Jan E. Leestma, MD, MM, is the lead author of the second edition of Forensic Neuropathology. He received the MD degree from the University of Michigan School of Medicine in 1964, and a Masters of Management (MM) degree from the J.L. Kellogg Graduate School of Management of Northwestern University, Evanston, Illinois in 1986. He completed residency training in anatomic pathology and neuropathology at the University of Colorado Medical Center, Denver, Colorado and a neuropathology fellowship at the€Albert Einstein College of Medicine, Bronx, New York. He is certiἀed in both anatomic pathology and neuropathology by the American Board of Pathology (1970). He served in the United States Air Force Medical Corps at the Armed Forces Institute of Pathology, Washington, D.C. (1968–1971) and was honorably discharged with the rank of major, USAF MC. He was an assistant and associate professor of pathology and neurology at Northwestern University School of Medicine (1971–1986) and served as chief of neuropathology at both Northwestern Memorial Hospital and the Children’s Memorial Hospitals, Chicago, Illinois. He was professor of pathology and neurology, and dean of students for the Division of the Biological Sciences and the Pritzker School of Medicine at the University of Chicago, Chicago, Illinois (1986–1987). He was an assistant medical examiner and neuropathology consultant to the Office of the Medical Examiner, Cook County, Illinois (1977–1987). He was a guest researcher at the Karolinska Institutet, Huddinge University Hospital, Pathology Institute, Stockholm, Sweden (1981–1982). He was associate medical director and chief of neuropathology at the Chicago Institute of Neurosurgery and Neuroresearch in Chicago (1987–2003). He has had a private consulting practice in forensic neuropathology since the early 1970s which continues to the present time. He has given expert testimony in more than 30 U.S. states, Canada, and the United Kingdom. He is the author of more than 100 professional publications including numerous book chapters in texts. He was the author of Forensic Neuropathology (ἀrst edition), Raven Press, New York, 1988. He is a member of the American Association of Neuropathologists, and of the American Academy of Forensic Sciences. Dr. Leestma wrote some chapters in Epilepsy and Sudden Death, edited by Drs. Lathers and Schraeder. Thus it is a natural extension of this collaboration for these three editors to work with co-editor Dr. Bungo and CRC Press is to expand the focus of forensics and clinical issues. The diverse scientiἀc expertise and endeavors of each of the four editors, working in the different ἀelds of forensics, neurology, cardiology, and clinical pharmacology, have united in this edition to produce a book with a special emphasis on the forensics and clinical issues associated with neurocardiology, epilepsy, arrhythmias, and sudden death.

Contributors

Isha Agarwal

Medical College of Pennsylvania Philadelphia, Pennsylvania

Karim A. Alkadhi, PhD

Department of Pharmacological and Pharmaceutical Sciences University of Houston Houston, Texas

Karem H. Alzoubi

Department of Clinical Pharmacy Jordan University of Science and Technology Irbid, Jordan

Anne E. Anderson, MD

Departments of Pediatrics, Neurology, Neuroscience Baylor College of Medicine Houston, Texas

Ricardo M. Arida

Departamento de Fisiologia Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM) São Paulo, Brasil

Jacquelyn Bainbridge, PharmD, FCCP School of Pharmacy University of Colorado Health Sciences Center Denver, Colorado

Steven L. Bealer, PhD

Department of Pharmacology and Toxicology University of Utah Salt Lake City, Utah

Elijah R. Behr, MD

Cardiac and Vascular Division St. George’s University of London London, United Kingdom

Amy Brewster

Department of Pediatrics Baylor College of Medicine Houston, Texas

Michael W. Bungo, MD, FACC, FACP,€CPE

Division of Cardiology University of Texas Medical School at Houston Houston, Texas

Esper A. Calvalheiro

Disciplina de Neurologia Experimental Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM) São Paulo, Brasil

Marcello Alessandro Caria

Department of Biomedical Sciences Human Physiology Division Sassari, Italy

Anne Y. Y. Chan

Department of Medicine and Therapeutics Chinese University of Hong Kong and Prince of Wales Hospital Hong Kong SAR, China

H. Gregg Claycamp, PhD

Center for Drug Evaluation and Research Office of Compliance U.S. Food and Drug Administration Silver Spring, Maryland

Isaac L. Crawford

Department of Neurology Southwestern Regional Epilepsy Center Veterans Administration Medical Center University of Texas Southwestern Medical Center Dallas, Texas

Thomas L. Bohan, PhD, JD, F-AAFS, D-IBFES MTC Forensics Peaks Island, Maine

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Roberta M. Cysneiros

Programa de Pós-Graduação em Distúrbios do Desenvolvimento do Centro de Ciências Biológicas e da Saúde da Universidade Presbiteriana€Mackenzie São Paulo, Brasil

Paramdeep S. Dhillon

Cardiac and Vascular Sciences St. George’s University of London London, United Kingdom

Contributors

Benito Herreros, MD, PhD

Cardiology Department Hospital Universitario Rio Hortega Valladolid, Spain

Trieu Ho, MD

Division of Cardiology University of Texas Medical School at Houston Houston, Texas

Richard W. Homan, MD

Department of Physiology Johns Hopkins University Baltimore, Maryland

Department of Neurology University of Texas Southwestern Medical Center Southwestern Regional Epilepsy Center Veterans Administration Medical Center Dallas, Texas

Kathleen Dolce

John D. Hughes, MD

Jeffrey M. Dodd-O, MD

Department of Drug Metabolism Smith Kline & French Laboratories King of Prussia, Pennsylvania

Michael P. Earnest, MD Department of Neurology Denver Health and Hospitals Denver, Colorado

Carl L. Faingold, PhD

Department of Pharmacology Southern Illinois University School of Medicine Springἀeld, Illinois

Josef Finsterer

Krankenanstalt Rudolfstiftung Vienna, Austria

Neeti Ghali

Department of Clinical Genetics Guy’s Hospital London, United Kingdom

Jeffrey H. Goodman, PhD

Department of Physiology and Pharmacology State University of New York Brooklyn, New York

Jane Hanna, OBE, MA, BCL Epilepsy Bereaved Wantage, United Kingdom

Ryan S. Hays

Department of Neurology Thomas Jefferson University Philadelphia, Pennsylvania

National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland

Richard Hughes

Department of Neurology Denver Health and Hospitals Denver, Colorado

Lara Jehi, MD

Department of Neurology Cleveland Clinic Neurological Institute Cleveland, Ohio

Kam F. Jim, PhD

Clinical Documentation Sanoἀ-Aventis Great Valley, Pennsylvania

Claire Kahn, PhD

Department of Drug Metabolism Smith Kline & French Laboratories King of Prussia, Pennsylvania

Bharat K. Kantharia, MD

Division of Cardiology University of Texas Medical School at Houston Houston, Texas

Steven B. Karch, MD, FFFLM, FFDov Berkeley, California

Steven A. Koehler

Office of the Coroner of Allegheny County Pittsburgh, Pennsylvania

Contributors

Claire M. Lathers, PhD, Emeritus FCP Albany, New York

xxxiii

Lina Nashef, MBChB, MD, FRCP

Chicago, Illinois

Departments of Neurology and Clinical Neurosciences King’s College Hospital London, United Kingdom

Howan Leung

Maromi Nei, MD

Robert M. Levin

Daniel K. O’Rourke, MD

Albany College of Pharmacy Albany, New York

Medical College of Pennsylvania Philadelphia, Pennsylvania

Jason G. Little

Rosemary Panelli, PhD

Jan E. Leestma, MD

Department of Medicine and Therapeutics Chinese University of Hong Kong Hong Kong SAR, China

Department of Neurology Jefferson Comprehensive Epilepsy Center Philadelphia, Pennsylvania

Department of Pharmacology and Toxicology University of Utah Salt Lake City, Utah

Joint Epilepsy Council of Australia Seymour, Australia

Edward H. Maa, MD

Graduate School of Nursing University of Virginia Newport News, Virginia

Neurology Denver Health and Hospitals Denver, Colorado

Ombretta Mameli, MD

Department of Biomedical Sciences Human Physiology Division Sassari, Italy

William D. Matthews, PhD

Department of Drug Metabolism Smith Kline & French Laboratories King of Prussia, Pennsylvania

John A. Messenheimer, MD

Department of Neurology University of North Carolina School of Medicine Chapel Hill, North Carolina

Cameron S. Metcalf

Department of Pharmacology and Toxicology University of Utah Salt Lake City, Utah

Yashanad Mhaskar

Department of Pharmacology Southern Illinois University School of Medicine Springἀeld, Illinois

Imad Najm, MD

Department of Neurology Cleveland Clinic Neurological Institute Cleveland, Ohio

Simona Parvulescu-Codrea, MD, PhD

David S. Paterson, PhD Department of Pathology Children’s Hospital Boston Boston, Massachusetts

Wallace B. Pickworth, PhD Addiction Research Center National Institute on Drug Abuse Baltimore, Maryland

Stephen R. Quint, PhD

Department of Neurology University of North Carolina Chapel Hill, North Carolina

Lene Sahlholdt

Danish Epilepsy Centre Dianalund, Denmark

Martin Allen Samuels, MD Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts

Susumu Sato, MD

Office of Clinical Director National Institute of Neurological Disorders and Stroke Bethesda, Maryland

xxxiv

Steven C. Schachter, MD

Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts

Paul L. Schraeder, MD, FAAN

Department of Neurology (emeritus) Drexel University College of Medicine Philadelphia, Pennsylvania

Carla A. Scorza

Disciplina de Neurologia Experimental Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM) São Paulo, Brasil

Fulvio Alexandre Scorza

Disciplina de Neurologia Experimental Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM) São Paulo, Brasil

Saumya Sharma, MD

Division of Cardiology University of Texas Medical School at Houston Houston, Texas

Nicole Simpkins

Jefferson Comprehensive Epilepsy Center Thomas Jefferson University Philadelphia, Pennsylvania

Elson L. So, MD

Section of Electroencephalography Mayo Clinic College of Medicine Rochester, Minnesota

Eliza Y. F. Sonoda

Disciplina de Neurologia Experimental Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM) São Paulo, Brasil

Michael R. Sperling, MD

Jefferson Comprehensive Epilepsy Center Thomas Jefferson University Philadelphia, Pennsylvania

Michele M. Spino

Medical College of Pennsylvania Philadelphia, Pennsylvania

Mark C. Spitz, MD Health Science Center University of Colorado Aurora, Colorado

Contributors

William H. Spivey, MD (deceased) Medical College of Pennsylvania Philadelphia, Pennsylvania

Amy Z. Stauffer, MD

Medical College of Pennsylvania Philadelphia, Pennsylvania

Mark Stewart, MD, PhD

Department of Physiology/Pharmacology and Neurology State University of New York Brooklyn, New York

Claudia Stöllberger

Second Medical Department Krankenanstalt Rudolfstiftung Vienna, Austria

Michael B. Tennison

School of Medicine University of North Carolina Chapel Hill, North Carolina

Vera C. Terra

Departamento de Neurologia, Psiquiatria e Psicologia Médica Universidade de São Paulo. Ribeirão Preto São Paulo, Brasil

Torbjörn Tomson

Department of Neurology Karolinska University Hospital Stockholm, Sweden

Srinivasan Tupal

Department of Pharmacology Southern Illinois University School of Medicine Springἀeld, Illinois

Laurie S. Y. Tyau, MD

Medical College of Pennsylvania Philadelphia, Pennsylvania

Victor V. Uteshev

Department of Pharmacology Southern Illinois University School of Medicine Springἀeld, Illinois

Matteo Vatta

Department of Pediatrics Baylor College of Medicine Houston, Texas

Contributors

Richard L. Verrier, PhD, FACC Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts

ἀ addeus S. Walczak, MD MINCEP Epilepsy Care Minneapolis, Minnesota

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Braxton B. Wannamaker, MD Epilepsy Services and Research, Inc. Orangeburg, South Carolina

Cyril H. Wecht, MD, JD

Office of the Coroner of Allegheny County Pittsburgh, Pennsylvania

Forensics of Sudden Death

I

Neurocardiologic Mechanistic Risk Factors in Sudden Unexpected Death in Epilepsy

1

Claire M. Lathers Paul L. Schraeder Michael W. Bungo

Contents 1.1 Introduction 1.2 Risk Factors for SUDEP 1.3 SUDEP Animal Models 1.3.1 Therapies as Factors 1.4 Case of SUDEP with a Premorbid Diagnosis of Nonepileptic Seizures 1.5 Discussion 1.5.1 Future Steps References

3 3 15 24 24 26 26 26

1.1â•…Introduction There are at least three categories of factors that may be operative in the mechanisms for sudden unexpected death in epilepsy (SUDEP) (Lathers et al. 2008a): arrhythmogenic, including changes in autonomic neural and cardiac function, respiratory and hypoxia, and psychological. Each of these main risk factor categories, in all likelihood, includes many subcategories. For example, the arrhythmogenic category includes pharmacological drug effects, genetic ion channelopathies, and acquired heart disease. The psychological factors include stress, anxiety, and depression states. This list of three primary areas of mechanism for SUDEP was expanded to include eight topics (Lathers et al. 2008b, 2008c).

1.2â•…Risk Factors for SUDEP The risk factors for SUDEP are as follows:

1. Pathophysiological mechanisms: cardio/autonomic 2. Respiratory/autonomic factors and hypoxia 3. Syncope 4. Genetic/structural mechanistic factors 5. Risk factors for SUDEP 6. Therapies: increased or decreased risk 7. Psychological factors 8. Unusual factors possibly modifying risk 3

4 Sudden Death in Epilepsy: Forensic and Clinical Issues

The pathophysiological mechanisms of SUDEP are not extant (see Table 1.1). From a cardiac standpoint, there is no question that the sympathetic component of cardiac innervation is involved in the production of potentially fatal tachyarrhythmias. It has also been established that postganglionic cardiac sympathetic innervation is altered in association with temporal lobe epilepsy and may be a pathophysiological risk factor for SUDEP (Druschky et al. 2001). These clinical data correlate with animal studies that found epiÂ� leptiform discharge–related postganglionic cardiac sympathetic abnormalities that were associated with cardiac conduction disturbances and arrhythmias (Lathers and Schraeder 1982, 1987, 1990a; Schraeder and Lathers 1983, 1989; Lathers 2010a, 2010b; Lathers et€al. Table 1.1â•… Pathophysiological Mechanisms Model, Symptoms, and/or Changes Nonuniform autonomic cardiac postganglionic neural discharge associated with coronary occlusion of left anterior descending coronary artery and/or ouabain toxicity in cats.

Arrhythmia monitoring of pacemaker patients. Cardiac beta receptor distribution: Beta receptor density right atria signiἀcantly lower than left atria; right ventricle signiἀcantly lower than left ventricle; density in ventricles higher than atria; beta receptor density of distal distribution of left anterior descending coronary artery signiἀcantly higher than proximal distribution. These regional density differences are related to the cardiac contractile strength of different areas of heart. Regional differences in beta adrenoreceptor densities reflect differences in postganglionic cardiac sympathetic innervation of the myocardium (Randall et al. 1977, 1978, 1984). Regulation of cardiac neural discharge is a new paradigm in the management of sudden cardiac death.

Mechanisms of Sudden Death Nonuniform (increases, decreases, and/or no change) autonomic neural postganglionic cardiac sympathetic discharge traveling through the stellate ganglia causes cardiac€arrhythmias, ventricular ἀbrillation, and/or SUD in the manner described by Han and Moe (i.e., nonuniform recovery of excitability in ventricular muscle). Suggested neural discharge site for drugs to modify occurrence of arrhythmia and death (Lathers et al. 1974a, 1974b, 1977a, 1977b, 1978, 1981, 1988; Lathers 1980, 1981, 1982; Lathers and Roberts 1980, 1985; Spivey and Lathers 1985; Han and Moe 1964). Revealed tachycardias, most likely ventricular tachycardia, related to SUD, give insight into terminal event mechanisms (Wichter et al. 2005; Nagele et al. 2007). A correlation with the release of norepinephrine at sympathetic nerve terminals in the heart in a manner to produce arrhythmia. Innervation density is high in subepicardium and central conduction system. Nonuniform postganglionic cardiac sympathetic cardiac innervation is related to nonuniform beta sympathetic receptor locations in the heart and affects cardiac contractility and development of arrhythmias and/or death. In diseased hearts, cardiac innervation density varies and may lead to sudden cardiac death (Lathers et al. 1986, 1986b, 1988, 1990, 2010a, 2010b, 2010c). These data were conἀrmed by Druschky et al. (2007), Ieda et al. (2006, 2007, 2008), and Kimura et al. (2007). These site differences will vary release of norepinephrine in various sites of the heart. This modiἀes cardiac contractile function and may trigger development of arrhythmias and/or sudden death. Site difference, in part, is one component of the mechanism(s) involved in sudden cardiac death. The heart is extensively innervated and its performance is regulated by the balance of discharges within and between the autonomic nervous system divisions (Ieda et al. 2008; Lathers et al. 1977a, 1977b, 1978; Lathers 1980, 1981). (continued)

Neurocardiologic Mechanistic Risk Factors in SUDEP

5

Table 1.1â•… Pathophysiological Mechanisms (Continued) Model, Symptoms, and/or Changes Nonuniform autonomic cardiac postganglionic neural discharge associated with pentylenetetrazol-induced interictal epileptogenic activity in cats. Lockstep phenomenon (LSP): Cardiac postganglionic sympathetic and vagal discharges were synchronized one for one with both ictal and interictal discharges and premature ventricular contractions, ST/T changes, and conduction blocks, and precipitous changes in blood pressure occurring concurrent with interictal spikes.

Blockading GABAergic and glycinergic receptors in medulla slices of newborn rats evoked intermittent seizure-like ἀring of cardiac parasympathetic neurons, suggesting the seizure-like pattern of ἀring during an epileptic attack may cause neurogenic ictal bradyarrhythmias, cardiac asystole, or even sudden death in persons with epilepsy (Wang et al. 2006). Cardiac postganglionic denervation in patients with epilepsy examined to evaluate ictal asystole because tachyarrhythmias are common during epileptic seizures, while bradyarrhythmias or asystoles occur less frequently (Kerling et al. 2009).

Chaos science: Simple systems that manifest periodic activity are easily perturbed, and are less able to return to the preperturbed state.

Mechanisms of Sudden Death Nonuniform autonomic neural discharge, autonomic neural imbalance of postganglionic cardiac sympathetic, and vagal discharge causes cardiac arrhythmias, ventricular ἀbrillation, and/or asystole and/or SUDEP (Lathers and Schraeder 1982, 1987; Schraeder and Lathers 1983, 1988; Lathers et al. 1984, 1990, 1993; Carnel et al. 1985; Tumer et al. 1985). Lockstep phenomenon is considered to be one potential mechanism for SUDEP (Lathers et al. 1987; Lathers and Schraeder 1990a, 1990b; Stauffer et al. 1989, 1990; Dodd-O and Lathers 1990; O’Rourke and Lathers 1990). 1. Spatial and temporal summation of neuronal discharges in a subcortical center producing a stimulus strong enough to overcome the cortical and ganglionic threshold (Dodd-O and Lathers 1990). 2. Increased synaptic recruitment, resulting in ampliἀcation of subcortical stimuli along their path, so when reaching the cortex and sympathetic ganglion, they are capable of causing susceptible neurons in these regions to discharge. 3. Increased irritability of all neurons so that subcortical impulses could stimulate cortical and ganglionic neurons (Dodd-O and Lathers 1990). Provides supporting data for the lockstep phenomenon ἀnding of Lathers et al. (1987) and colleagues. It is to be determined if the predisposition of central PNS ἀring correlates with electrical remodeling of myocardium, possibly secondary to epileptogenic activity related cardiac neural discharges (LSP).

Single-photon emission computed tomography examined I-(123)-meta-iodobenzylguanidine as a marker of postganglionic cardiac norepinephrine uptake. Pronounced reduction in cardiac single-photon emission computed tomography uptake in asystolic patients indicated postganglionic cardiac catecholamine disturbance. Impaired sympathetic cardiac innervation limits adjustment and modulation of heart rate and may increase the risk of asystolic events and, eventually, SUDEP (Kerling et al. 2009). Data of Kerling et al. support the ἀndings of Lathers et al. (1986a, 1986b, 1987, 1990), Lathers and Levin (2010), and those of Han and Moe (1964). A periodic rhythm in the brain, where normally rich complexity exists, implies a susceptibility to failure that may result in death (Gleick 1987). (continued)

6 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 1.1â•… Pathophysiological Mechanisms (Continued) Model, Symptoms, and/or Changes Mode locking: Epileptic focus and medullary cardiac center may be locked one to one during state of LSP in the manner suggested by Gleick (1987).

Power spectral analysis (Quint et al. 1990).

Sympathetic innervation is critical for effective cardiac function (Saffitz 2008). Developmental and regulatory mechanisms determining density and pattern of cardiac sympathetic innervation are unclear, as is role of innervation in arrhythmogenesis. Sema3a establishes cardiac sympathetic innervation patterning. Sema3a is abundantly expressed in the trabecular layer in early-stage embryos but is restricted to Purkinje ἀbers after birth, forming an epicardial-to-endocardial transmural sympathetic innervation pattern. Sema3a(−/−) mice lacked a cardiac sympathetic innervation gradient and exhibited stellate ganglia malformation, leading to marked sinus bradycardia due to sympathetic dysfunction. Sympathetic dysfunction: altered postganglionic cardiac sympathetic innervation found postmortem in patients with chronic temporal lobe epilepsy (Druschky et al. 2001).

Mechanisms of Sudden Death Occurrence of a very regular oscillator in the brain is theoretically dangerous, regardless of mechanism. Fractal processes are ubiquitous in biological systems, include brain electrical depolarizations, and are systems that convey different information. Complexity of a fractal process may at times depreciate into a simple periodic process representing decay of the system and dramatic change (Goldberger et al. 1985; Winfree 1987). Causes of death include failure of the brain and heart. If the brain sends a message to the heart triggering a fatal arrhythmia, or if the heart enters an arrhythmia via its own initiative, sudden death will occur. Perturbations of cardiac electrical depolarization may have several mechanisms, any or several of which may be operations (O’Rourke and Lathers 1990). Time-frequency domain analyses of heart rate variability in patients with epilepsy and time-frequency mapping of R–R intervals during partial seizure may provide procedures to assess autonomic activity related to risk factors for SUDEP (Novak et al. 1999; Everengul et al. 2005; Persson et al. 2007). Cardiac-speciἀc overexpression of Sema3a in transgenic mice (SemaTG) associated with reduced sympathetic innervation and attenuation of the epicardial-to-endocardial innervation gradient. SemaTG mice demonstrated sudden death and susceptibility to ventricular tachycardia, due to catecholamine supersensitivity and prolongation of the action potential duration. Concluded appropriate cardiac Sema3a expression is needed for sympathetic innervation patterning and is critical for heart rate control (Ieda et al. 2007).

Altered postganglionic cardiac sympathetic innervation may increase risk of cardiac abnormalities and/or SUDEP (Lathers et al. 1990, Chapter 22).

(continued)

Neurocardiologic Mechanistic Risk Factors in SUDEP

7

Table 1.1â•… Pathophysiological Mechanisms (Continued) Model, Symptoms, and/or Changes Amygdaloid kindled seizure effect on cardiovascular system was examined in rats. An abrupt 50% increase in mean arterial pressure (BP) lasting 20–30 s after initiation of seizure occurred with profound bradycardia, characterized by a rate about half of that recorded before stimulation. Changes in heart rate and BP observed during amygdaloid kindled seizures are similar to those observed during secondary spontaneous seizures. Effects apparently are independent of kindling stimulus because stimulusinduced cardiovascular changes were not present at the beginning of kindling. Use of electrical stimulation as a therapy for epilepsy is currently being studied in experimental animals and in patients with epilepsy. This study examined the effect of preemptive, low-frequency, 1-Hz sine wave stimulation (LFS) on incidence of amygdala kindled seizures in rats. Amygdaloid kindled seizures in unanesthetized rats induced abrupt elevation of blood pressure accompanied by a signiἀcant decrease in heart rate.

Mechanisms of Sudden Death Results suggest the kindling seizure model is useful to study underlying mechanisms of seizure-induced cardiac arrhythmias and possibly the clinical phenomenon of SUDEP (Vindrola et al. 1984; Goodman et al. 2005).

Dramatic decrease in incidence of stage 5 seizures in fully kindled animals after preemptive LFS suggests low-frequency stimulation may be an effective therapy for prevention of seizures in patients with epilepsy (Gary-Bobo and Bonvalette 1977). Muscarinic receptor blockade with atropine (1 mg/kg, i.v. abolished seizure-induced bradycardia. Seizure-induced hypertension was unaffected by beta-adrenergic blockade with timolol (1 mg/kg, i.v.), but reduced by phentolamine (5€mg/kg, s.c., an alpha-adrenergic receptor antagonist). Chemical sympathectomy was induced with 6-hydroxydopamine (100 mg/kg, i.v.), an agent that does not cross the blood–brain barrier, eliminated the pressor response but did not completely block seizure-induced bradycardia. Effectiveness of 6-hydroxydopamine was tested with tyramine (0.5 mg/kg, i.v.), an agent that releases endogenous catecholamines. Results indicate amygdaloid kindled seizures activate both branches of the autonomic nervous system. Bradycardia was mediated by the parasympathetic system; the pressor response was caused by an increase in peripheral resistance due to alpha-adrenergic receptor activation. Findings show kindling is a useful seizure model for future studies on the effect of seizures on cardiovascular function and possible mechanisms of seizure-related sudden unexplained death (Goodman et al. 1989, 1990).

Source: Lathers, C. M., P. L. Schraeder, M. W. Bungo, in Psychological Factors and Cardiovascular Disorders, ed. L. Sher, Nova Science Publishers, Inc., Hauppauge, NY, 2008. With permission.

8 Sudden Death in Epilepsy: Forensic and Clinical Issues

1986a, 1986b, 1986c, 1987, 1993, 2008a, 2008b, 2008c). In addition to the risk of neurogenically induced arrhythmias, neurogenic apnea could be associated with SUDEP. Table 1.2 summarizes the SUDEP risk factors of respiratory/autonomic changes and hypoxia. Rare clinical case reports describe incidences of apnea associated with epileptiform activity (So et al. 2000). Additionally, a well-known sheep model of epilepsy (Simon et al. 1982; Table 1.2â•…Respiratory Factors and Hypoxia Model, Symptoms, and/or Change Postmortem found multiple areas of pulmonary punctuate hemorrhages and large areas of gross hemorrhage and edema in animals dying after induced epileptogenic activity, asystole, or ventricular ἀbrillation (Lathers and Schraeder 1982; Lathers et al. 1984; Carnel et al. 1985; Schraeder and Lathers 1983). In addition to the general and neurological risk factors, there is increasing evidence that cardiac (Aurlien et al. 2009; Kerling et al. 2009; Pezzella et al. 2009; Strzelczyk et al. 2008) and pulmonary (Scorza et al. 2007; Tavee and Morris 2008) changes additionally predispose a person to SUDEP. As with neurological risk factors, cardiac and pulmonary risk factors have neither been investigated by prospective observational follow-up studies nor by intervention studies. The pathomechanisms are still not established (Johnston and Smith 2007). Finsterer and Stöllberger (2010, this book) discuss recent ἀndings and practical implications concerning potential cardiac and pulmonary risk factors and pathomechanisms of SUDEP.

Changes in cardiac function alter cerebral blood flow, which, in turn, produces central hypoxia resulting in epileptogenic activity.

Mechanisms of Sudden Death Tissue hypoxia, hypercarbia, and alterations in acid–base balance may have contributed to the results in our model of experimental epilepsy. Acid–base balance was maintained only within physiological range before the initiation of epileptogenic activity.

So far, there is minimal evidence that any primary pulmonary disease could be a deἀnite risk factor for SUDEP (Finsterer and Stöllberger, 2010, this book). It is also unknown if patients with muscular respiratory insufficiency are at increased risk not to survive a tonic–clonic seizure. These patients appear particularly endangered because they often also have epilepsy and their epilepsy is often difficult to treat. Despite this uncertainty about pulmonary risk factors, there are frequent reports about patients who develop severe pulmonary problems during or after seizures, such as ictal hypoxemia or hypercapnia (Bateman et al. 2008), apnea (Bell and Sander 2006; Jehi and Najm 2008; Ryvlin et al. 2009), acute neurogenic pulmonary edema (Jehi and Najm 2008), or postictal laryngospasm (Tavee and Morris 2008). In a prospective autopsy series on 52 SUDEP patients, 80% had pulmonary congestion and edema (Leestma et al. 1989). It is uncertain if these abnormalities are due to primary pulmonary, cardiac, or laryngeal mechanisms. It is also unclear if only patients with previous lung disease, as opposed to previously healthy subjects, develop such problems. There is little information available about the effects of generalized tonic–clonic seizures on the respiratory system in general. Do generalized seizures induce bronchospasm or loss of tone of the muscles involved in respiration? Recent investigations have shown that at least the vital capacity, forced vital capacity, and forced expiratory volume within the ἀrst second (FEV1 etc.), are not signiἀcantly different between healthy subjects and epilepsy patients (Scorza et al. 2007) (Finsterer and Stöllberger 2010, this book). Some patients exhibit changes in cardiovascular status preceding the onset of convulsions (Schott et al. 1977; Schraeder et al. 1983). (continued)

Neurocardiologic Mechanistic Risk Factors in SUDEP

9

Table 1.2â•…Respiratory Factors and Hypoxia (Continued) Model, Symptoms, and/or Change The pulmonary edema model of status epilepticus in unanesthetized, chronically instrumented sheep in which sudden death and pulmonary edema occur.

Audiogenic seizures: respiratory arrest. Central alveolar hypoventilation syndrome (Ondine’s curse). Failure of automatic involuntary respiration with preservation of voluntary respiratory drive (Ondine’s curse) is rare, reported following a variety of morphologic lesions near respiratory centers in the lower brainstem. Risk factors include uncontrolled convulsive seizures, as well as respiratory and cardiac factors relating to treatment and supervision.

Epilepsy-related hypoxia. Ictal apnea. Postictal central apnea appears to be one potential mechanism for SUDEP. A 55-s convulsive seizure occurred in a 20-year-old female as she underwent video-EEG monitoring (So et al. 2000). Persistent apnea then developed. Electrocardiogram monitoring rhythm was not altered for the

Mechanisms of Sudden Death Catecholamine levels and seizure type and duration did not differ between animals dying suddenly or those surviving. Benign arrhythmias were generated in all animals; in no case did an arrhythmia account for death of an animal. Striking hypoventilation demonstrated in sudden death group but not in surviving animals. Differences in peak left atrial and pulmonary artery pressures, and in extravascular lung water; pulmonary edema did not account for the demise of sudden death animals. Thus, this model of epileptic sudden death supports a role of central hypoventilation in etiology of sudden unexpected death and shows an association, albeit not fatal, with pulmonary edema. The importance of arrhythmia in its pathogenesis is not conἀrmed (Simon et al. 1982; Johnston et al. 1995, 1997). Respiratory arrest mechanisms, modulated in part by serotonin, may cause SUDEP (Tupal and Faingold 2006a, 2006b). Central alveolar hypoventilation syndrome causes sudden death in a 39-year-old woman with heterotopia of the inferior olive (Matschke and Laas 2007). Neuropathologic examination disclosed preexisting malformation of the lower brain stem and acute local subarachnoid bleeding. Both respiratory and cardiac mechanisms are important. The apparent protective effect of lay supervision supports a role for respiratory factors, in part amenable to intervention by simple measures. Malignant tachyarrhythmias are rare during seizures and sinus bradycardia/arrest, although infrequent, occurs. Both types of cardiac arrhythmias can have a genetic basis as a contributory factor. Authors explore the potential of coexisting liability to cardiac arrhythmias as a contributory factor, but acknowledge that bridging evidence between inherited cardiac gene determinants and SUDEP is lacking (Terrence et al. 1981; Coulter 1984; Schraeder 1987; Nashef et al. 2007). Central apnea with seizures (Schraeder 1987) and neurogenic pulmonary edema and adult distress syndrome (Terrence et al. 1981). (Penἀeld and Jasper 1954; Bobo and Bonvallet 1975) So et al. (2000) note that although epileptic seizures may be associated with arrhythmogenic actions at the heart, in this patient the mechanism of marked central suppression of respiratory activity after seizures was clearly involved and almost resulted in sudden death. This case and Dr. Schraeder’s (1983) case highlight that both respiratory and cardiac changes do occur in persons with epilepsy. The (continued)

10 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 1.2â•…Respiratory Factors and Hypoxia (Continued) Model, Symptoms, and/or Change ἀrst 10 s, then it gradually and progressively slowed and stopped 57 s later. Cardiorespiratory resuscitation was successful. No evidence of airway obstruction or pulmonary edema was noted. One previous cardiorespiratory arrest after a complex partial seizure without secondary generalization had been reported for this patient. Postictal respiratory arrest was induced by serotonin receptor inhibition and prevented by selective serotonin reuptake inhibitor drugs (Tupal and Faingold 2006a, 2006b). Audiogenic seizure in mice. Obstructive sleep-apnea–induced cardiovascular complications.

Likely processes of the sudden infant death syndrome (SIDS) are identiἀed (apnea, failed arousal, failed autoresuscitation, etc.). The way in which epidemiological risk factors, genetics, neurotransmitter receptor defects, and neonatal cardiorespiratory reflex responses interact to lead to sudden death during sleep is unclear. 5-HT SIDS: Role of medullary 5-HT abnormalities in pathogenesis of SIDS, putative in utero origin of these abnormalities, and environmental and genetic factors interact to ultimately result in sudden death of the infant (Patterson 2010, this book).

Mechanisms of Sudden Death timing of events such as seizures, respiratory and/or laryngospasm, and cardiac EKG changes do vary in different patients.

The role of serotonin in SUDEP must be examined in future animal studies, including the DBA mice model of SUDEP (Faingold et al. 2010, this book). Suggested for use to study postictal respiratory arrest (So 2008). Implicated in pathogenesis of various cardiovascular diseases, including systemic hypertension, coronary artery disease, congestive heart failure, pulmonary hypertension, stroke, and cardiac arrhythmias. Mechanisms by which obstructive sleep apnea affects the cardiovascular system may involve mechanical effects on intrathoracic pressure, increased sympathetic activation, intermittent hypoxia, and endothelial dysfunction (Malow et al. 2000; Jain 2007). It is hypothesized that the neurophysiological basis of SIDS resides in a persistence of fetal reflex responses into the neonatal period, such as ampliἀcation of inhibitory cardiorespiratory reflex responses and reduced excitatory cardiorespiratory reflex responses. Explores ways in which multiple subtle abnormalities interact to lead to sudden death and emphasizes difficulty of ante-mortem identiἀcation of infants at risk for SIDS (Leiter and Böhm 2007). Underlying vulnerability involves a developmental defect in brainstem serotonergic (5-HT) systems that results in failure of protective cardiorespiratory responses to potentially life-threatening, but normally occurring events (e.g., hypoxia, hypercapnia), in the infant during sleep (Patterson 2010, Chapter 5, this book).

Source: Lathers C. M., P. L. Schraeder, M. W. Bungo, in Psychological Factors and Cardiovascular Disorders, ed. L. Sher, Nova Science Publishers, Inc., Hauppauge, NY, 2008. With permission.

Johnston et al. 1995, 1997) found that although neurogenic pulmonary edema was commonly observed, the mechanism of death in the animals was central neurogenic hypoventilation. Likewise, syncope is a factor for sudden death (Table 1.3). It is evident that, in all likelihood, there are multiple contributing risk factors that, in unfortuitous combinations (including environmental circumstances) in individuals with epilepsy, may result in unexpected death (Nashef et al. 1998). This chapter consists of summary tables highlighting possible risk categories and mechanisms for risks. The reader is encouraged to use the table

Neurocardiologic Mechanistic Risk Factors in SUDEP

11

Table 1.3â•… Syncope Symptoms and/or Changes Syncope is a transient loss of consciousness and postural tone. Usually due to temporary, self-terminating global cerebral hypoperfusion. Important to differentiate from other nonsyncopal transient loss of consciousness attacks (Chen et al. 2008).

Although arising suddenly from prolonged recumbency or returning from weightlessness to earth’s gravity can result in syncope from orthostatic or vasovagal effects, there are many other possible causes. Cardiac causes are more likely to occur in the elderly; noncardiac causes are more common in the younger population. Cases described illustrate often unexpected mechanisms of syncope in otherwise healthy individuals. Cases of sudden collapse. At times, there are obvious cardiac etiologies or central nervous system etiologies; at other times, there are interactive cause and effects with cardiac disorders leading to central nervous system effects or visa versa. However, all too often there are subtle interplays with genetic predispositions, environmental interaction, therapeutic interventions, or unknown organic disease. As consequences are extreme, a thorough investigation and understanding of the mechanisms leading to syncope are of paramount importance. Psychogenic syncope and psychogenic seizures are common disorders but are difficult to identify. Headupright, tilt-table testing evaluates vasovagally mediated syncope and convulsive syncope. In eight patients with syncope and/or tonic–clonic motor activity, without changes in blood pressure and heart rate, transcranial Doppler cerebral blood flow velocity, and EEG monitoring revealed they were, in all instances, psychogenic or malingering. Combined long term ECG and EEG monitoring. Isolated cardiac rhythm abnormalities were noted in 21 patients, but none were symptomatic and no deἀnitive arrhythmias occurred. Isolated EEG abnormalities were noted in 11 patients, 5 of whom had EEG abnormalities consistent with seizure disorders. Simultaneous EEG and ECG abnormalities were seen in four patients. In two, a previously unsuspected etiology for syncope was found: seizures in one patient with heart disease and sinus pauses in another thought to have a seizure disorder.

Mechanisms of Sudden Death The most important screening tool in identifying mechanism(s) of syncope is a detailed history emphasizing a search for underlying disease, speciἀc associated circumstances, and pre- and post-event symptoms. The type of diagnostic studies (i.e., cardiac or neurologic) undertaken should be based on historical data. Seizures must be considered as a possible mechanism of otherwise unexplained loss of consciousness in nonelderly persons, including air crew members (Schraeder et al. 1994; Williams and Frenneaux 2007). Review recent research relevant to managing syncope in adults: syncope evaluation in the emergency department, effectiveness of a structured and standardized approach to syncope, role of the implantable loop recorder, and efficacy of nonpharmacological physical treatments (Chen et al. 2008; Bungo et al. 2010, this book). Clinical cases briefly explore the interactions of disordered electrical potentials in the brain and disordered electrical potentials in the heart (Lathers et al. 2010b, Chapter 22, this book).

It was concluded that patients who pass out or convulse during head-upright tilt without any change in physiologic parameters can be presumed psychogenic in origin and may be referred for psychiatric evaluation without further expensive diagnostic studies (Grubb et al. 1992). Combined ambulatory EEG/ECG monitoring may prove useful in evaluation of some patients with syncope (Beauregard et al. 1991).

(continued)

12 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 1.3â•… Syncope (Continued) Symptoms and/or Changes Vasovagal syncope. Much of the natural history is unknown. Study determined whether patients presenting for care had a recent increase in worsened syncope frequency. Insufficient cerebral perfusion is a common cause leading to a loss of consciousness with a critical reduction of blood flow to the reticular activating system. In neurally mediated syncope, a paradoxical reflex can occur that induces an increase in cerebrovascular resistance and contributes to the critical reduction of cerebral blood flow.

Mechanisms of Sudden Death Many syncope patients present for care after a recent worsening of their frequency of syncope (Franco 2007; Sheldon et al. 2007). Outlined anatomic structures involved in cerebral autoregulation, its mechanisms in normal and pathologic conditions, and noninvasive neuroimaging techniques used to study cerebral circulation and autoregulation. Emphasis placed on description of autoregulation pathophysiology in orthostatic and neurally mediated syncope (Franco 2007).

Source: Modiἀed and updated from Lathers C. M., P. L. Schraeder, M. W. Bungo, in Psychological Factors and Cardiovascular Disorders, ed. L. Sher, Nova Science Publishers, Inc., Hauppauge, NY, 2008. With permission.

of contents of this book to identify which chapters are pertinent to a given topic within each table. The reader is referred especially to chapters in this book discussing risks for SUDEP by Walczak (2010), arrhythmias (Lathers and Schraeder 1982, 1987; Lathers et al. 1987), LSP (Schraeder and Lathers 1983, 1989), respiratory issues (Scorza et al. 2007; Finsterer and Stöllberger 2010; Lathers and Schraeder 1982; Carnel et al. 1985), syncope (Sharma et al. 2010, Chapter 21, this book; Lathers et al. 2010b, Chapter 22, this book), genetics (Herreros 2010), stress (Lathers and Schraeder 2006), therapies (Lathers and Schraeder 2002, 2010; Lathers et al. 2003a, 2003b, 2003c; Tompson 2008, 2010; Ryvlin et al. 2009), and unusual factors that may modify SUDEP risk (Scorza et al. 2008a, 2008b, 2010a, 2010b; Calderazzo et al. 2009; Terra-Bustamante et al. 2009). All are encouraged to read Brodie and Holmes (2008) and the chapter presenting how to educate persons with epilepsy about their risk factors and how to help families and survivors of SUDEP deal with the unexpected loss of a person with epilepsy (Hanna and Panelli, 2010, Chapter 57). There is general agreement that central nervous and autonomic nervous system/cardiorespiratory interactions include arrhythmias and apnea (Tables 1.1 and 1.2). Complicating the nervous system/cardiac relationship are relatively recent discoveries of genetically determined predispositions to arrhythmias that may result in seizure-like events at the time of the acute cardiac dysfunction (Table 1.4). How these genetic cardiac predispositions interact with the central and autonomic nervous systems is not understood. It is generally accepted that certain associated clinical circumstances [e.g., male gender (Table 1.5), poorly controlled generalized tonic clonic seizures, use of multiple antiepileptic drugs, changing doses or drugs, withdrawal of antiepileptic drugs, and poor compliance with antiepileptic drug use] are associated with an increased risk of SUDEP (Table 1.6). That psychogenic factors associated with life stresses are risk factors for cardiac arrhythmias and sudden death is well recognized by cardiologists (Lathers and Schraeder 2006). Also, certain ethnic groups have an increased incidence for stress-related sudden deaths [e.g., bangungut in healthy Filipino men (Table 1.7)]. There has been almost no organized effort to determine the role of stress as a risk factor for SUDEP. The stress response involves acute or chronic increases in sympathetic neural activity. Furthermore, Scorza and colleagues have identiἀed unusual factors that may modify the risk for SUDEP such as ambient temperature, the lunar phases of the moon,

Neurocardiologic Mechanistic Risk Factors in SUDEP

13

Table 1.4â•… Genetic/Structural Mechanistic Factors Associated Changes Four main inherited arrhythmia syndromes that are thought to be responsible for sudden death. Two clinical cases exhibit both Brugada syndrome and epilepsy produced by sodium channel dysfunction (Lathers et al. 2010b, this book). Brugada syndrome is produced by a mutation in gene SCN5A, which encodes the alpha subunit of the cardiac sodium channel (Antzelevitch et al. 2005a, 2005b; Aurlien et al. 2009. Herreros (2010, Chapter 19) note that some epileptic syndromes (Graves 2006) are due to different mutations in genes encoding alpha subunits of neuronal sodium channels (SCN1A, SCN2A) or in the beta subunit (SCN1B), common for both cardiac and neuronal isoforms (Lehmann-Horn and Jurkat-Rott 1999). The long QT syndrome: A genetically transmitted cardiac arrhythmia due to ion channel protein abnormalities, affecting the transport of potassium and sodium ions across the cell membrane. Patients may present with syncope, seizures, or aborted cardiac arrest. Long QT syndrome is an important cause of unexplained sudden cardiac death in the young.

Cardiac hypertrophy: An independent predictor of cardiovascular morbidity and mortality, predisposition to heart failure, QT interval prolongation, and ventricular arrhythmias.

Mechanisms of Sudden Death Four syndromes: long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia reviewed by Herreros (2010, Chapter 19, this book). Additional clinical, electrocardiographic, and genetic studies are needed to improve individual risk stratiἀcation and to determine any relationship among sodium channel dysfunction, Brugada ECG, and idiopathic epilepsy. Two patients presented in the cases appear to support the possibility that a common pathophysiologic mechanism associated with sodium channel dysfunction may be common to ECG abnormalities of Brugada syndrome and some types of epilepsy. Many patients must be screened to conἀrm. Risks factors for sudden death must be deἀned and linked with mechanisms for death (Kornick et al. 2003; Lathers et al. 2008a, 2008b, 2008c; Herreros, 2010, Chapter 19; Lathers et al. 2010a, Chapter 20).

Diagnosis of long QT syndrome depends on an ECG showing a prolonged QT interval (Kiehne and Kauferstein 2007). Establishment of a registry and discovery of genetic mutations causing the syndrome contribute greatly to understanding this condition and impetus to understanding other inherited cardiac arrhythmias. Genotype-phenotype correlation studies allow risk stratiἀcation of long QT syndrome patients. Lifestyle modiἀcation to avoid triggers for malignant cardiac arrhythmias, and use of beta blockers, pacemakers, and implantable deἀbrillators may reduce mortality in these patients (Vohra 2007). Mutations of cardiac ion channel genes affecting repolarization cause the majority of congenital cases. Despite detailed molecular characterizations of mutated ion channels, understanding how individual mutations may lead to arrhythmias and sudden death requires study of intact heart and modulation by autonomic nervous system. Studies of molecularly engineered mice with mutations in genes known to cause long QT syndrome in humans and speciἀc to cardiac repolarization in mice are reviewed (Salama and London 2007). Cardiac angiotensin II overproduction leads to long QT syndrome, resulting from IK1 potassium-dependent prolongation of action potential duration via modulation of channel subunit expression (Domenighetti et al. 2007). (continued)

14 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 1.4â•… Genetic/Structural Mechanistic Factors (Continued) Associated Changes Inherited arrhythmia syndromes, channelopathies.

Short QT syndrome: ECGs show a shortened QT interval and tall and narrow T waves. The cause is mutation of the potassium channel genes. Cardiac hypertrophy: associated with a dramatic change in gene expression proἀle of cardiac myocytes. Many genes important during development of the fetal heart but repressed in adult tissue are reexpressed, resulting in gross physiological changes and arrhythmias, cardiac failure, and sudden death. One transcription factor possibly important in repressing expression of fetal genes in the adult heart is REST (repressor element 1-silencing transcription factor).

Genetic factors in SUDEP: Likely to reflect underlying heterogeneous mechanisms common to the brain and heart, as has been shown to be the case with sudden cardiac death and sudden infant death syndrome (Ghali and Nashef 2010, this book).

Mechanisms of Sudden Death Long QT syndrome (Kiehne and Kauferstein 2007), short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and overlapping phenotypes; established connections between these syndromes and idiopathic ventricular ἀbrillation (Sarkozy and Brugada 2005). Persons with short QT syndrome have increased familial risk of sudden cardiac death (Gaita et al. 2003, 2004). REST expression prevents increased BNP (Nppb) and ANP (Nppa) gene, encoding brain and atrial natriuretic peptides. Adult rat ventricular myocytes response to endothelin-1 and inhibition of REST results in increased expression of these genes in H9c2 cells. Increased expression of Nppb and Nppa correlates with increased histone H4 acetylation and histone H3 lysine 4 methylation of promoter-proximal regions of these genes. Deletions of individual REST repression domains combined activities of two domains of REST required to efficiently repress transcription of Nppb gene. A single repression domain is sufficient to repress Nppa gene. Data provide insight into molecular mechanisms for changes in gene expression proἀle cardiac hypertrophy (Bingham et al. 2006, 2007). Overlapping mechanisms. The increasing number of mongenically associated epilepsy syndromes raises the question of how epilepsy and arrythmogenic genetic disturbances may be concurrent. The association of uncontrolled epilepsy with risk of SUDEP leads to speculation that in some cases of idiopathic epilepsy, a genetic mutation may also cause a predisposition to fatal cardiac arrhythmias. The recent association of long QT syndrome with epilepsy suggests that ion channel gene mutations may be inherited susceptibility factors for neurogenic cardiac arrhythmia in some persons with epilepsy. Further investigation into overlap of epileptogenic and arrhythmogenic epidemiological and genetic factors is warranted.

and other factors (Table 1.8). As is evident from the listings in the above-mentioned tables, there is a likelihood that common risk factors for SUDEP and arrhythmogenic cardiac disease are related to centrally initiated peripheral autonomic dysfunction in association with epileptiform discharges and stress. Issues that need resolution include a better understanding of the individual risks, the mechanisms of cardiac arrhythmia and arrest in persons without a previously identiἀed structural heart disease, a deἀnition of abnormal interactions between the central nervous system (CNS) and the heart, the role of neurogenic pulmonary edema and central apnea in combination with cardiac autonomic neural and subtle anatomic and genetic factors as risk for SUDEP, and development of primary and secondary preventive measures along with educational programs to disseminate essential information to physicians, patients, and families.

Neurocardiologic Mechanistic Risk Factors in SUDEP

15

Table 1.5â•…Risk Factors for SUDEP SUDEP Risk Factors in a Swedish Population (Nilsson et al. 2001)

Retrospective Study of Risk Factors, United States Reviewed association between several clinical variables and SUDEP to elucidate risk factors. Characteristics of 67 cases correlated with published previous studies. Education of physicians about existence of SUDEP and risk factors is imperative to improving patient education and reduction in mortality (Lear-Kaul et al. 2005). Behavioral Risk Factor Surveillance System Data from South Carolina Compared health insurance coverage, health care visits, health-related behaviors among persons with epilepsy vs. general population (Ferguson et al. 2008).

Position of Patients at Night (Kinney et al. 2009; Monter et al. 2007; McGregor and Wheless 2006).

1. Higher number of seizures per year (relative risk of 10.16 in patients with more than 50 seizures/year compared to no more than 2 years) 2. Increased number of antiepileptic drugs (9.89 for three drugs vs. monotherapy) 3. Early vs. late onset epilepsy (7.72) 4. Frequent changes in antiepileptic drug dosage vs. unchanged dosage (6.08) 5. Risk and early onset and SUDEP risk and seizure frequency was weaker for females 6. Frequent dosage changes had a stronger association in females 7. Early age of onset and male sex 1. Long history of seizure disorder 2. Under medication or poorly controlled seizure activity 3. Male gender 4. Age younger than 40 years 5. Mental or physical stress

Persons with epilepsy: 1. Are more likely to smoke. 2. Have less physical activity. 3. Need better access to health care. 4. Need interventions focused on smoking cessation and increase in physical activity. 5. Lack money to visit a doctor. One-third of respondents with active epilepsy reported in past 12 months needed to see a doctor but could not because of cost. Note: Authors do not relate these behavior risk factors to increased likelihood of SUDEP per se, but one could also consider them to be risk factors for SUDEP. 1. Especially important in persons with uncontrolled epilepsy in institutional settings. 2. Avoid prone position and soft pillows when sleeping. 3. Use respiration monitors during sleep. 4. Train caregivers to be vigilant and to intervene to prevent respiratory compromise for institutionalized and at-home patients.

1.3â•… SUDEP Animal Models The importance of using many different animal models to study SUDEP in order to glean insights into the various mechanisms of risks and their contribution to the initiation of the death event is discussed by Lathers (2010a, Chapter 25) (Table 1.1). So (2008) emphasizes the signiἀcance of using audiogenic seizure mice to study postictal respiratory arrest. Postictal respiratory arrest was induced by serotonin receptor inhibition and prevented by

16 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 1.6â•… Therapies: Increased or Decreased Risk Symptoms and/or Changes

Mechanisms of Sudden Death

Increased risk SUDEP The putative advantage of new drugs is a smaller spectrum of Antiepileptic drugs—New antiepileptic possible adverse events, such as sedation and some may drugs, e.g., topiramate and lamotrigine, minimize noncompliance by reducing side effects of developed for chronic focal and secondarily lethargy and cognitive impairment. Many new antiepileptic generalized epileptic seizures. Therapeutic drugs do have less frequent interactions, leading to efficacy of these drugs does not seem to be improved tolerability with comedication (Lathers et al. superior to traditional anticonvulsants such 2003a, 2003b, 2003c; Walczak 2003). However, difficulty in as phenobarbital. achieving therapeutic dosage with some of the newer antiepileptic drugs because of side effects makes one question whether some newer agents are better than the older antiepileptic drugs. Suggests SUDEP rates reflect population rates and not a Risk of SUDEP rates in patients on speciἀc drug effect. FDA requires warning labels on the risk lamotrigine, gabapentin, topiramate, of SUDEP in association with use of each of the mentioned tigabine, and zonisamide are similar to drugs (Lathers and Schraeder 2002). those on standard antiepileptic drugs. Compliance with antiepileptic drugs In a coroner’s office review of forensic cases in Allegheny important in prevention of SUDEP. County for the year 2001, Lathers et al. (2003a, 2003b) found low, or no, levels of antiepileptic drugs postmortem in persons with epilepsy who died of SUDEP. Hughes (2009) deemed the most important SUDEP risk Noninterventional, single-arm study (Martin factor to be noncompliance with antiepileptic medication. et al. 2009). Explored the effectiveness and Ryvlin et al. (2009) found the risk of SUDEP is increased in behavioral outcomes in intellectually patients who have poor compliance and exhibit nocturnal disabled patients with topiramate for seizures and generalized tonic–clonic seizures. However, epilepsy. compliance is not the only therapeutic question to ask about victims of SUDEP. Others include: Is the correct dose of the antiepileptic drug being used? Was more than one drug prescribed and were there recent dose drug changes? All agree that maintenance of a stable therapeutic drug levels is crucial to avoid SUDEP. Some improvement in nearly all behavioral aspects was observed under concomitant topiramate therapy. In addition, seizure frequency decreased. Two unexpected deaths in patients taking the antiepileptic drug topiramate were attributed to SUDEP (Martin et al. 2009). A prolonged QT interval leads to increased risk for QT-prolonging drugs and risk of SUD. development of ventricular tachyarrhythmias, particularly Torsades de pointes is associated with early polymorphic ventricular tachycardia (torsades de pointes). cardiac depolarization. Drugs that prolong Polymorphic arrhythmia may rapidly develop into QT interval: class III antiarrhythmic agents, ventricular ἀbrillation and cause sudden death antimicrobial agents (fluoroquinolone and (Reingardiene and Vilcinskaite 2007). macrolide antibiotics), antipsychotic and antidepressant drugs, agents used in general anesthesia, and antimycotics (Reingardiene and Vilcinskaite 2007). Adverse cardiovascular effects of antipsychotic treatment: Cardiovascular Effects of Antipsychotics tachycardia, orthostatic hypotension, and rarely, SUD, Older antipsychotic literature was primarily muscarinic cholinergic antagonism, alpha(1)-adrenergic concerned with physiological consequences antagonism, or receptors associated with cardiac of muscarinic cholinergic antagonism, (continued)

Neurocardiologic Mechanistic Risk Factors in SUDEP

17

Table 1.6â•… Therapies: Increased or Decreased Risk (Continued) Symptoms and/or Changes

Mechanisms of Sudden Death

Alpha(1)-adrenergic antagonism, or receptors associated with cardiac conduction, but current literature recognizes that, for most antipsychoticexposed patients, the more signiἀcant cardiovascular burden of treatment is mediated by metabolic adverse effects such as weight gain, dyslipidemia, and diabetes mellitus.

conduction, metabolic adverse effects of weight gain, dyslipidemia, and diabetes mellitus (Michelsen and Meyer 2007). High-dose methadone can induce QT prolongation by hERG inhibition, resulting in QT prolongation, but new evidence shows that QT prolongation can occur at much lower doses, even when the drug is not given IV.

Methadone produces QT prolongation, arrhythmias, and sudden death (Karch 2010, this book, Chapter 10).

May be acting directly on myocardial conduction to produce arrhythmia and death (Lathers and Lipka 1986, 1987; Lathers et al. 1986a; Lipka and Lathers 1987; Lipka et al. 1988).

Chlorpromazine or thioridazine do not appear to produce arrhythmia or death via a central locus in an experimental cat model. Decreased risk SUDEP The question must be asked if persons thought to be at risk for SUDEP should be placed on a beta blocker, in addition to the prescribed anticonvulsant(s). Beta blockers are also used to reduce stress and persons with epilepsy generally are stressed by the disease and associated problems (Lathers and Schraeder 2006). Beta blockers produce anticonvulsant activity whether administered via the intraosseous route or intravenously (Jim et al. 1988, 1989; Spivey et al. 1987a, 1987b; Lathers et al. 1989, 1990, 2008). Note the intraosseous and endotracheal routes of administration of antiepileptic drugs may be used when IV access is not available in status epilepticus. These routes are appropriate for emergency room pediatric seizures or cardiac arrest when unable to establish a traditional IV line (Rusli et al. 1987; Jim et al. 1988, 1989; Spivey et al. 1987a, 1987b; Lathers et al. 1989, 1990, 2008). Postmortem found no serious pathology in the tibia bone after intraosseous administration, other than the expected needle track (Lathers et al. 1989). Selective serotonin reuptake inhibitor drugs. Postictal respiratory arrest was induced by serotonin receptor May be protective in some persons at risk inhibition and prevented by selective serotonin reuptake for SUDEP with a component of apnea. inhibitor drugs. The role of serotonin in SUDEP must be examined in future animal studies (Tupal and Faingold 2006). Vagal nerve stimulation may decrease risk of SUDEP by 50% Vagal nerve stimulation may decrease (Annegars et al. 2000). susceptibility to ventricular tachycardias (Verrier et al. 2009; Verrier and Schachter 2010). Beta blockers exhibited anticonvulsant activity.

Source: Lathers C. M., P. L. Schraeder, M. W. Bungo, in Psychological Factors and Cardiovascular Disorders, ed. L. Sher, Nova Science Publishers, Inc., Hauppauge, NY, 2008. With permission.

18 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 1.7â•… Psychological Factors Symptoms and/or Changes Scared to death. A 21-year-old student had generalized tonic–clonic seizures induced by mental image of human pain. One ictal event occurred while listening to a description of suffering, as read from Fox’s Book of Martyrs. While again listening to the offending passage during EEG and ECG monitoring, had 25 s of asystole terminating in electrocerebral silence and a generalized tonic, tonic–clonic seizure. A 24-hour ambulatory monitor recorded episodes of progressive sinus bradycardia concomitant with P–R interval prolongation and Wenckebach atrioventricular block. Sinoatrial conduction times and sinus node recovery times were normal on atrial pacing (Schraeder et al. 1983). Emotional trauma and psychological stress. Stress response is associated with increased sympathetic activity and catecholamine levels that may be associated with increased risk of cardiac arrhythmias, especially in context of epileptiform cerebral discharges (Pickworth et al. 1990). Stress is associated with changes in autonomic neural function. Its role as a potential risk factor for SUDEP is not known. Association of epilepsy with cardiac abnormalities, such as neurogenic arrhythmias and microscopic perivascular and interstitial ἀbrosis, and with depression and anxiety indicates emotional stress with related increases in catecholamines should be evaluated as a potential risk factor for SUDEP. Stress and anger. Compare morphology and initiation pattern between ventricular arrhythmias that are triggered by anger and those that are not. At the time of shock, patients with implantable cardioverter-deἀbrillators recorded levels of deἀned mood states preceding the shock in a diary. Stress risk factors and triggers of sudden death. An autopsy proven case-control study (Owada et al. 1999).

Mechanisms of Sudden Death Since implantation of a permanent pacemaker, has been asymptomatic. Patient demonstrates advantages of reproducing the circumstances associated with an unexplained loss of consciousness while monitoring EEG and ECG (Schraeder et al. 1983).

Arrhythmogenic effects of efferent sympathetic drive precipitate cardiac arrhythmia and sudden death. Patients with preexisting heart disease are particularly at risk. Generation of proarrhythmic activity patterns within cerebral autonomic centers may be ampliἀed by afferent feedback from a dysfunctional myocardium (Gray et al. 2007). Impact of adverse emotional states on autonomic control of cardiac rhythm is a known important factor leading to cardiac dysrhythmias in humans and other species. Interaction between emotional factors and arrythmogenic potential of epileptiform discharges and possibility of beneἀt from stress management intervention need to be investigated (Lathers and Schraeder 2006). Ventricular arrhythmias occurring in setting of anger are more likely pause dependent and polymorphic. Suggests that in predisposed populations anger may create an arrhythmogenic substrate susceptible to more disorganized rhythms, a possible mechanism linking emotion and sudden death (Stopper et al. 2006). Identiἀed risk factors and triggers of sudden death in cases where causes of death were deἀnitely proven by autopsy in Japan. Legal and medical records for 4 years were investigated. Of 271 cases, 176 patients, 20 to 59 yrs-old were cases of sudden death in working generations. Of these, 91 cases, 52% could be analyzed by telephone interviews from close family members. One examiner undertook all phone interviews with the case subjects. As control subjects, 1167 employed persons who consulted for a health check. Of sudden death cases, ἀnal diagnosis in 29 cases was coronary artery disease (31.9%), 18 acute cardiac dysfunction (continued)

Neurocardiologic Mechanistic Risk Factors in SUDEP

19

Table 1.7â•… Psychological Factors (Continued) Symptoms and/or Changes

Retrospective study. Reviewed association between several clinical variables and SUDEP to elucidate risk factors. Characteristics of 67 cases correlated with published ἀndings in previous studies (Lear-Kaul et al. 2005).

Mechanisms of Sudden Death (19.8%), 6 other cardiac diseases (6.6%), 4 acute aortic dissection (4.4%), 4 cerebrovascular disease (4.4%), and 30 other diseases (32.9%). Through conditional logistic analysis, the following risk factors emerged as candidates: Long-term stress, history of heart disease, hypertension, chest symptoms, autonomic disturbance, short-term stress, and a smoking habit. Short-term stress, autonomic disturbance and a smoking habit increased the risk of sudden death due to coronary artery disease. Long-term stress was associated with an increased risk of sudden death due to acute cardiac dysfunction. Demonstrated that autonomic disturbance and stress were closely related to occurrence of sudden death (Owada et al. 1999). Attributes that deἀne an at-risk group of epileptics include: less than 40 years old, male, long history of seizure disorder, under medication or poorly controlled seizure activity, and mental or physical stress. Education of physicians about the existence of SUDEP and risk factors is imperative in improving patient education and reduction in mortality (Lear-Kaul et al. 2005).

Source: Lathers C. M., P. L. Schraeder, M. W. Bungo, in Psychological Factors and Cardiovascular Disorders, ed. L. Sher, Nova Science Publishers, Inc., Hauppauge, NY, 2008. With permission.

selective serotonin reuptake inhibitor drugs. The possible role of serotonin in SUDEP must be examined in future animal studies (Faingold et al. 2010, Chapter 41). The ἀring pattern of cardiac parasympathetic neurons, as well as cardiac sympathetic postganglionic nerves, during an epileptic attack has been shown to change and has been termed the lockstep phenomenon (Lathers et al. 1987; Stauffer et al. 1989, 1990; Dodd-O and Lathers 1990; O’Rourke and Lathers 1990). The observation of autonomic neural discharges time-locked to cortical epileptiform is evidence that epileptogenic activation of the cardiac parasympathetic nerves, revealed by ictal bradyarrhythmias or cardiac asystole, may be one contributing cause of sudden death of patients with epilepsy. Likewise, epileptogenic activation of the cardiac sympathetic nerves may be another contributing cause of SUDEP. An imbalance between the two systems’ (i.e., the cardiac parasympathetic and the cardiac sympathetic) neural discharge patterns may contribute to SUDEP (Lathers and Schraeder 1982, 1986; Schraeder and Lathers 1983, 1989). Wang et al. (2006) provided supporting data for the LSP ἀnding. They examined blockade of inhibitory neurotransmission evoked seizure-like ἀring of cardiac parasympathetic neurons in brainstem slices of newborn rats. Speciἀcally, blockade of GABAergic and glycinergic receptors in medulla slices evoked intermittent seizure-like ἀring of cardiac parasympathetic neurons, suggesting the seizure-like pattern of ἀring during an epileptic attack may cause neurogenic ictal bradyarrhythmias, cardiac asystole, or even sudden death in persons with epilepsy. Nonuniform autonomic cardiac postganglionic neural discharges are associated with coronary occlusion of the left anterior descending coronary artery and/or ouabain toxicity in cats (Lathers et al. 1974a, 1974b, 1977a, 1977b, 1978; Lathers 1980, 1981). Nonuniform

20 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 1.8â•…Unusual Risk Factors Modify SUDEP Factor Unusual potential risk factors for SUDEP were examined by Scorza and colleagues (2008a, 2008b, 2010a, 2010b), Calderazzo et al. (2009), and Terra-Bustaman et al. (2008).

Physical activity (Scorza et al. 2008a).

SUDEP seems to occur more commonly during sleep (Asadi-Pooya and Sperling 2009). Chronobiology of acute pulmonary edema (Bilora et al. 1998).

Mechanism of Sudden Death Studies are needed to examine the role of unusual factors that are listed below to determine if they are applicable to SUDEP. These include life style modifying interventions with accepted public health beneἀts, but as yet with no consensus that they may or may not prevent sudden death. Animal studies and clinical studies are needed (Lathers et al. 2008b, reply; 2010c, Unanswered question). May modify the role of autonomic effects and cardiorespiratory disturbances. Beneἀts of physical activity may be related to reductions in sympathetic activity. Morbidity and mortality in cardiovascular disease are often associated with elevations in sympathetic activity (Scorza et al. 2008a; Schraeder et al. 1983). Increased physical action does have a beneἀcial cardiovascular effect. The question is, will increased physical activity be of beneἀt if one assumes cardiovascular sympathetic dysfunction or insufficiency in persons with epilepsy? In general, regular exercise does not have a downside, if the patient is cardiovascularly ἀt. The role of regular exercise in prevention of SUDEP is not established (Lathers et al. 2008b reply; 2010c, this book). Autonomic cardiorespiratory disturbances. Alterations in clinical parameters including ECG changes, blood pressure, respiration, and vasomotor tone (Hirsch and Martin 1971; Lathers and Schraeder 1982; Schraeder and Lathers 1983; Wannamaker 1985). ECG changes in experimental epilepsy include heart rate changes, arrhythmias, conduction blocks, altered ECG morphology, and QT interval). See discussion of Bilora et al. (1998) below and Chapter 23 by Hughes and Sato (2010, this book). Found pulmonary edema incidence higher during the night. No signiἀcant weekly or circannual rhythms detected. Examine possible relations with decreased heart output, increased sympathetic tone, or partial baroceptor desensitization occurring at night (Bilora et al. 1998). Evaluation of some cases of SUDEP and ners-SUDEP during long-term electroencephalography monitoring suggest that autonomic instability ending in cardiorespiratory arrest may be triggered by postictal suppression rather than by ictal activation of the autonomic nervous system. More epidemiologic studies on high-risk populations of persons with epilepsy are needed (Schuele 2009). The increase sympathetic tone or desensitization of baroceptors may contribute to occurrence of cardiac autonomic arrhythmias. See discussions of interictal activity and cardiac arrhythmias (continued)

Neurocardiologic Mechanistic Risk Factors in SUDEP

21

Table 1.8â•…Unusual Risk Factors Modify SUDEP (Continued) Factor

Seizure activity and neurogenesis (Scorza et al. 2008b). Omega-3 fatty acid nutritional deἀciency (Scorza et al. 2008a).

Low temperature (Scorza et al. 2008a).

Winter temperatures may lead to cardiac abnormalities and, hence, to sudden death. Are they a risk factor for SUDEP? (Colugnati et al. 2008).

Role of heart rate in rats with epilepsy during low temperature exposure (Sonoda et al. 2008). Minimum external temperature, mean external temperature (Bell et al. 2009). Climate fluctuations (Calderazzo et al. 2009). Sunlight may be a beneἀt in that vitamin D deἀciency may increase risk of SUDEP (Scorza et al. 2010a).

Mechanism of Sudden Death and baroreceptor changes by Lathers (2010a, 2010b) and cardiac and pulmonary risk factors and pathomechanisms of SUDEP by Finisterer and Stollberger (2010, Chapter€42). Aberrant dentate granule cell neurogenesis may influence negatively the cardiovascular system of a patient with epilepsy and lead to cardiac abnormalities and risk of SUDEP. Beneἀcial effect of nutritional aspects of omega-3 fatty acid may decrease cardiac arrhythmias and sudden death (SUD) in patients at risk for cardiac disease. No established answer at this time. See comments by Lathers et al. (2008b). Questions have been raised (Lathers et al. 2008a, 2008b, 2008c, 2010c) that need to be addressed: 1. Exactly how does one deἀne a low temperature? 2. What is the degree range used to deἀne a low temperature? 3. What is the duration at this low degree range? 4. Is there a dose response so that there is an increased risk of sudden death related to the lowest temperature? Mammals hibernate as a strategy to survive cold conditions. Hibernating mammals inherit a stable cardiovascular function. They show resistance to hypothermia at a cellular level, the membrane potential and excitability are more stable in their cardiac cells. Aortic smooth muscle cells maintain ionic gradients upon prolonged exposure to low temperature, cardiac myocytes from the mammals maintain constant levels of intracellular free calcium and forceful contractility at 10°C or lower. Postulate hibernating mammals have cardiovascular particularities that confer heart protection. The relevance to persons with epilepsy is to be determined. Low temperature increased the heart rate of patients with epilepsy. Authors suggest exposure to low temperatures could be a risk factors for cardiovascular abnormalities and, thus, for SUDEP. Found no evidence of association between either mean temperature group or minimum temperature group and SUDEP but there was a slight excess of SUDEP in the coldest (mean temperature) groups. May have an effect on SUDEP occurrence. Some clinical studies suggest low vitamin D levels may be associated with death from heart failure and sudden cardiac death. There also appears to be an association between low vitamin D and seizure occurrence. Scorza et al. suggest vitamin D may exhibit anticonvulsant action. More data are needed. (continued)

22 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 1.8â•…Unusual Risk Factors Modify SUDEP (Continued) Factor The lunar phase (Terra-Bustamante et al. 2009).

Lunar phase, month, season: no association found between these factors and SUDEP (Bell et al. 2009).

Mechanism of Sudden Death An epilepsy unit performed an 8-year analysis, examining possible associations between the phase of the moon and SUDEP. Incidence of SUDEP was highest at full moon (70%), followed by waxing moon (20%), and new moon (10%). No SUDEPs occurred during the waning cycle. Preliminary ἀndings suggest the full moon correlates with occurrence of SUDEP. Dataset of National Sentinel Clinical Audit of EpilepsyRelated Deaths examined all death certiἀcates of those who died in England and Wales between 9/1999 and 8/2000 to see if epilepsy was mentioned. Of 2412 deaths, 409 were identiἀed as probable SUDEP.

(increases, decreases, and/or no change) autonomic neural postganglionic cardiac sympathetic discharge traveling through the stellate ganglia, causes cardiac arrhythmias, ventricular ἀbrillation, and/or sudden cardiac death in the manner described by Han and Moe (1964), i.e., nonuniform recovery of excitability in ventricular muscle. It was suggested that the modiἀcation of neural discharge is a way for drugs to modify the occurrence of arrhythmia and death (Lathers et al. 1974a, 1974b, 1977a, 1977b, 1978; Lathers 1980, 1981; Han and Moe 1964). Nonuniform autonomic cardiac postganglionic neural discharge was also found to be associated with pentylenetetrazol-induced interictal epileptogenic activity in cats. Nonuniform autonomic neural discharge and autonomic neural imbalance of postganglionic cardiac sympathetic and vagal discharge cause cardiac arrhythmias, ventricular ἀbrillation, asystole, and/or SUDEP. Regional differences in the beta adrenoceptor densities reflects differences in postganglionic cardiac sympathetic innervation of the myocardium (Randall 1977, 1984; Randall et al. 1984). These site differences will vary the release of norepinephrine in various sympathetic nerve terminals and sites in the heart to modify cardiac contractile function and may trigger development of arrhythmias and/or sudden death. Innervation density of beta adrenoceptor densities is high in the subepicardium and central conduction system. Nonuniform postganglionic cardiac-sympathetic cardiac innervation is related to the nonuniform beta-sympathetic receptor locations in the heart and affects cardiac contractility and development of arrhythmias and/or death. In diseased hearts, cardiac innervation density varies and may lead to sudden cardiac death (Lathers et al. 1985, 1986a, 1986b, 1988, 1990, 2010; Lathers and Levin 2010, Chapter 33, this book). Seizures exert effects on cardiac function (Schuele, 2009). Since tachyarrhythmias are common during epileptic seizures, whereas bradyarrhythmias or asystoles occur less frequently, Kerling et al. (2009) evaluated cardiac postganglionic denervation in patients with epilepsy to determine if this was responsible for ictal asystole. I-(123)-metaiodobenzylguanidine was used as a marker of postganglionic cardiac norepinephrine uptake, using single-photon emission computed tomography. They concluded that a pronounced reduction in cardiac single-photon emission computed tomography uptake of asystole patients indicates postganglionic cardiac catecholamine disturbance. Impaired sympathetic cardiac innervation limits adjustment and heart-rate modulation and may increase the risk of asystole and, eventually, sudden unexpected death in persons with epilepsy. These data support the ἀnding of Lathers and colleagues described above. The

Neurocardiologic Mechanistic Risk Factors in SUDEP

23

reader is also referred to the chapter by Lathers and Levin (2010) that examines nonuniform sympathetic innervation and beta-sympathetic receptor locations and discusses how these factors affect cardiac contractility and the development of cardiac arrhythmias and/ or sudden death. Cerebral ischemia is associated with neuron degeneration. Accumulation of excess excitatory amino acids in the synaptic clef, activation of excitatory amino acid receptors, and influx of calcium into neurons are involved in the development of ischemia-induced neuronal death. Schwartz et al. (1995) hypothesized that neuroprotection may occur if inhibitory transmission via gamma-aminobutyric acid (GABA) is enhanced to offset excitation. Diazepam, a drug known to increase GABA-induced chloride channel opening, was studied in rats after hippocampal GABA levels had returned to post-transient global ischemia basal levels. The authors concluded that delayed enhancement of GABAergic neurotransmission directly at the site of vulnerability after an ischemic event does protect the vulnerable neurons from death. This model should be adapted to an animal model of seizure activity to study the effect of diazepam on GABA-mediated effects that may prevent ischemia-induced neuronal death, prevent the worsening of central neuronal communication due to epileptogenic activity, and eventually contribute a protective CNS effect that lessens individual at risk for SUDEP. Table 1.2 discusses postmortem multiple areas of punctuate hemorrhages and large areas of gross hemorrhage and edema in animals dying after inducing epileptogenic activity, asystole, or ventricular ἀbrillation (Lathers and Schraeder 1982; Schraeder and Lathers 1983; Lathers et al. 1984; Carnel et al. 1985). Tissue hypoxia, hypercarbia, and alterations in the acid–base balance may have contributed to the results in our model of experimental epilepsy. Acid–base balance was maintained only within physiological range before the initiation of epileptogenic activity (Lathers and Schraeder 1982, 1987; Schraeder and Lathers 1983, 1989; Carnel et al. 1985; Stauffer et al. 1989, 1990). Changes in cardiac function alter cerebral blood flow, which, in turn, produces central hypoxia that results in epileptogenic activity. Some patients exhibit changes in cardiovascular status preceding the onset of convulsions (Schott et al. 1977; Schraeder et al. 1983). So (2008) has emphasized risk factors of postictal apnea and hypoxia, with or without pulmonary congestion, in combination with generalized tonic–clonic seizures and, to a lesser degree, with complex partial seizures and respiratory arrest as a mechanistic cause of SUDEP. So et al. (2000) also noted that, although epileptic seizures may be associated with arrhythmogenic actions of the heart, in their patient, the mechanism of marked central suppression of respiratory activity after seizures was clearly involved and almost always resulted in sudden death. This case, and the case of Schraeder et al. (1983), highlight that both respiratory and cardiac changes do occur in persons with epilepsy. The timing of events such as seizures, respiratory and/or laryngospasm, and cardiac EKG changes does vary in different patients. Ryvlin et al. (2009) note that the pathophysiology of SUDEP is not clear, but postictal central or obstructive apnea is one likely mechanism. However, as noted by Lathers (2010b, Chapter 44, this book): Caution must be exerted when concluding respiratory changes alone are the primary mechanism of death. At the ἀrst onset of the clinical problem cardiac arrhythmias may be felt by the patient but may not be visually detected by a witness. ‘Invisible’ cardiac arrhythmias may be initiated and then followed by ‘visible’ respiratory distress. Therefore, in addition to repositioning of the patient to ensure ease of respiration and/or stimulation of respiration, it is important, if possible, also to simultaneously monitor and medically support cardiac rate and rhythm.

24 Sudden Death in Epilepsy: Forensic and Clinical Issues

The reader is referred to additional discussion of actual case histories focused on arrhythmogenic, respiratory, and psychological risk factors in Chapter 44 of this book (Lathers 2010b). Most likely, different mechanisms and/or a different combination of mechanisms are responsible for death in different persons with epilepsy. 1.3.1â•… Therapies as Factors Data suggest that beta blockers exert a protective effect against seizure induction and/ or the development of cardiac arrhythmias with interictal and ictal activity (Spivey et al. 1987b; Jim et al. 1988, 1989; Lathers et al. 1989a, 1989b, 1990, 2008a) (Table 1.6). The question must be asked whether persons thought to be at risk for SUDEP should be placed on a beta blocker, in addition to the prescribed anticonvulsant(s). Celiker et al. (2008) reported clinical experiences of patients with catecholaminergic polymorphic ventricular tachycardia and concluded that medical treatment with propranolol and verapamil may decrease the incidence of arrhythmia. If patients are still refractory, implantation of intracardiac deἀbrillators should be considered. Obviously, a delay in diagnosis or inadequate treatment can result in sudden cardiac death. The same is true for persons at risk for SUDEP. See the case history of SUDEP by Schraeder (2010). Hughes (2009) addressed the issue of how to predict patients at risk for SUDEP by reviewing published reports of such deaths. With a mean incidence of SUDEP at 1.8/1000, a mean standardized mortality ratio of 6.8, and a mean percentage of SUDEP cases among deaths from epilepsy at 16.6%, the problem of SUDEP and risk factors is an important issue to be resolved. Hughes identiἀed 17 risk factors and concluded, just as Lathers et al. (2008a, 2008b, 2008c) stated, that a cardiac or pulmonary problem may be a primary risk factor in different patients. He deemed the most important risk factor to be noncompliance with antiepileptic medication. Maintenance of therapeutic drug levels is crucial to avoid SUDEP. Ryvlin et al. (2009) also found that the risk of SUDEP is increased in patients who have poor compliance, nocturnal seizures, and generalized tonic–clonic seizures. However, compliance is not the only risk factor to be addressed if a person is a victim of SUDEP. There are several postmortem questions to be asked (Lathers and Schraeder 2009) about a patient on an antiepileptic drug that still becomes a SUDEP victim. One must inquire whether the correct dose of the antiepileptic drug was being used to control seizures. Another clinical pharmacology question that must be asked is whether the patient was on the correct antiepileptic drug to control the particular type or mixture of seizures experienced. When evaluating the role of drugs as protectors of life, clinical pharmacologists (Lathers and Schraeder 2002) caution us to remember that the use of all drugs is a risk/beneἀt ratio evaluation (Lathers et al. 2003a, 2003b, 2003c). Thus, the use of antiepileptic drugs may not provide 100% protection to the patient against sudden death.

1.4â•…Case of SUDEP with a Premorbid Diagnosis of Nonepileptic Seizures Table 1.8 discusses unusual risk factors examined by the laboratory of Scorza to determine if they are risk factors for SUDEP and/or have been speculated to be risk factors. This includes asking whether the lunar phase has an effect on SUDEP (Terra-Bustamante et al. 2009). A retrospective examination of the incidence of SUDEP in an epilepsy unit over an

Neurocardiologic Mechanistic Risk Factors in SUDEP

25

A 35-year-old woman was found dead in bed by her parents. She had a longstanding psychiatric history with the occurrence of seizure-like events. On one occasion,€she had a nonepileptic seizure in her neurologist’s office consisting of sliding to the floor with bizarre asynchronous bilateral motor activity without loss of consciousness. This event occurred consequent to an emotionally tense situation at her home. Past observation of another type of event consisting of some automatisms and postÂ� ictal confusion complicated the history. Multiple routine EEGs over the years were unremarkable, save for one that showed unequivocal isolated left temporal interictal discharges. The patient was placed on carbamazepine and found to have consistent therapeutic levels. The patient recognized that the complex partial events were no longer occurring, but that others continued. After the retirement of her neurologist, the patient was seen at another center and subjected to several days of inpatient EEG monitoring, during which multiple clinical events were observed without any epileptiform activity being documented on any of the EEG recordings. As a result, the patient was informed that her seizures were nonepileptic and was advised to taper her antiepileptic medications. Several weeks later her parents notiἀed her former neurologist of her demise. Co mment s by L at hers, Schraeder, and Bung o Persons with only nonepileptic seizures would, by deἀnition, not be at risk for SUDEP. However, the unfortunate reality is that from 10% to 30% of persons who appear to have long-established nonepileptic seizures also have epilepsy (Betts 1997). Thus, although the majority of persons with nonepileptic seizures do not have concurrent epilepsy, in those who also have a bona-ἀde seizure disorder, as demonstrated in this case, there is a risk of SUDEP associated with withdrawal of antiepileptic drugs based on the observation of only nonepileptic events. The physician must consider all aspects of the history and all prior EEG data before having conἀdence that the antiepileptic medication can be safely withdrawn. One should also keep in mind that rapid discontinuation of medication that was at a therapeutic serum level could induce a withdrawal seizure even in a person without epilepsy, further clouding the issue of diagnosis. From Betts, T. 1997. Psychiatric aspects of nonepileptic seizures. In Epilepsy: A Comprehensive Textbook, ed. J. Engel and T. A. Pedley. Philadelphia, PA: LippincottRaven Publishers.

8-year period was reviewed to look for a possible association. The review found the number of SUDEP cases was highest at the time of a full moon (70%), followed by a waxing moon (20%), and a new moon (10%). There were no SUDEP cases during the waning cycle. The authors concluded that a full moon appears to correlate with SUDEP. This same laboratory has examined other factors that may be involved in SUDEP, from regular imbibing of sardines and salmon to the influence of climate fluctuations (Calderazzo et al. 2009). Scorza et al. (2008b) have raised the question of whether seizure activity also influences dentate granule cell neurogenesis, since neurogenesis persists throughout life in adult mammalian dentate gyrus and is regulated by environmental, physiological, and

26 Sudden Death in Epilepsy: Forensic and Clinical Issues

molecular factors. The presence of hilar ectopic dentate granule cells was studied after status-�epilepticus was induced experimentally and it was determined that these cells migrate aberrantly, are abnormally integrated, and that the resulting hyperexcitability may contribute to seizure generation and/or propagation. Since high seizure frequency is a potential risk factor for SUDEP, the authors hypothesize that cardiac arrhythmias during and between seizures or transmission of epileptic activity to the heart via the autonomic nervous system may play a role. Thus, the aberrant neurogenesis may negatively influence the cardiovascular system of the patient with epilepsy and lead to cardiac abnormalities and then to the unwanted event of SUDEP. Studies are needed to examine the role in SUDEP played by these unusual factors to determine if they are risk factors.

1.5â•…Discussion 1.5.1â•… Future Steps The American Epilepsy Society and the Epilepsy Foundation Joint Task Force on SUDEP (So et al. 2008) assessed knowledge about SUDEP and recommended the following steps: 1. Hold a multidisciplinary workshop to reἀne current lines of investigation and identify additional areas of research for mechanism underlying SUDEP. 2. Conduct a survey of patients, families, and caregivers to identify effective means of education to enhance participation in SUDEP research. 3. Campaign for emphasis of the need for complete autopsy examinations for patients with suspected SUDEP. 4. Secure infrastructure grants to fund a consortium of centers to conduct prospective clinical and basic research studies to identify preventable risk factors and mechanisms underlying SUDEP. During the interim before these steps have been achieved, it is most important to provide prompt and optimal control of seizures, especially generalized convulsive seizures, to prevent SUDEP. A global focus is needed to resolve the risk factors for and mechanisms of epilepsy and sudden death (Lathers 2009).

References Annegers, J. F., S. P. Coan, W. A. Hauser, and J. Leestma. J. 2000. Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality, and sudden, unexpected, unexplained death. Epilepsia 41: 549–553. Antzelevitch, C. 2005a. Cardiac repolarization. The long and short of it. Eurpace 7 (Suppl 2): 3–9. Antzelevitch, C. 2005b. Modulation of transmural repolarization. Ann N Y Acad Sci 1047: 314–323. Asadi-Pooya, A. A., and M. R. Sperling. 2009. Clinical features of sudden unexpected death in epilepsy. J Clin Neurophysiol Aug 24. [Epub ahead of print]. Aurelien, D., T. P. Leren, E. Taubøll, and L. Gjerstad. 2009. New SCN5A mutation in a SUDEP victim with idiopathic epilepsy. Seizure 18: 158–160. Bateman, L. M., C. S. Li, and M. Seyal. 2008. Ictal hypoxemia in localization-related epilepsy: Analysis of incidence, severity and risk factors. Brain 131: 3239–3245.

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Quint, S. R., J. A. Messenheimer, and M. B. Tennison. 1990. Power spectral analysis: a procedure for assessing autonomic activity related to risk factors for sudden and unexplained death in epilepsy. In Epilepsy and Sudden Death, ed. C. M. Lathers and P. L. Schraeder, Chapter 16, 261–291. New York, NY: Marcel Dekker. Randall, W. C. 1977. Neural Regulation of the Heart, 1–440. New York, NY: Oxford University Press. Randall, W. C. 1984. Nervous Control of Cardiovascular Function, 1–476. New York, NY: Oxford University Press. Randall, W. C., J. X. Thomas, D. E. Euler, and G. J. Rozanski. 1978. Cardiac dysrhythmias associated with autonomic nervous system imbalance in the conscious dog. In Perspectives in Cardiovascular Research, Vol. 2, Neural Mechanisms in Cardiac Arrhythmias, ed. P. J. Schwartz, A. M. Brown, A. Malliani, and A. Zanchetti, 123–138. New York, NY: Raven Press. Reingardiene, D., and J. Vilcinskaite. 2007. QTc-prolonging drugs and the risk of sudden death. Medicina (Kaunas) 43: 347–353. Rusli, M., W. H. Spivey, H. Bonner, R. M. McNamara, C. K. Aaron, and C. M. Lathers. 1987. Pathological effects of endotracheal diazepam in cats. Ann Emerg Med 16: 314–318. Ryvlin, P., T. Tomson, and A. Montavont. 2009. Excess mortality and sudden unexpected death in epilepsy. Press Med 38 (6): 905–910. Saffitz, J. E. 2008. Sympathetic neural activity and the pathogenesis of sudden cardiac death. Heart Rhythm 5: 140–141. Salama, G., and B. London. 2007. Mouse models of long QT syndrome. J Physiol 578 (Pt 1): 43–53. Sarkozy, A., and P. Brugada. 2005. Sudden cardiac death: What is inside our genes? Can J Cardiol 21: 1099–1110. Schott, G. D., A. A. McLeod, and D. E. Jewitt. 1977. Cardiac arrhythmias that masquerade as epilepsy. Br Med J 1: 1454–1457. Schraeder, P. L. 1987. Adult respiratory distress syndrome (ARDS) associated with nonconvulsive status epilepticus. Epilepsia 28: 605. Schraeder, P. L. 2010. SUDEP case histories: Typical and atypical. In Sudden Death in Epilepsy: Forensic and Clinical Issues, ed. C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leestma, Chapter 52. Boca Raton, FL: CRC Press. Schraeder, P. L., and C. M. Lathers. 1983. Cardiac neural discharge and epileptogenic activity in the cat: An animal model for unexplained death. Life Sci 32: 1371–1382. Schraeder, P. L., and C. M. Lathers. 1989. Paroxysmal autonomic dysfunction, epileptogenic activity and sudden death. Epilepsy Res 3: 55–62. Schraeder, P. L., C. M. Lathers, and J. B. Charles. 1994. The spectrum of syncope. J Clin Pharmacol 34: 454–459. Schraeder, P. L., R. Pontzer, and T. R. Engel. 1983. A case of being scared to death. Arch Intern Med 143: 1793–1794. Schuele, S. U. 2009. Effects of seizures on cardiac function. J Clin Neurophysiol. Sep 11. [Epub ahead of print]. Schwartz, R. D., X. Yu, M. R. Katzman, D. M. Hayden-Hixson, and J. M. Perry. 1995. Diazepam, given postischemia, protects selectively vulnerable neurons in the rat hippocampus and striatum. J Neurosci 15 (1 Pt 2): 529–539. Scorza, F. A., A. M. Abreu, M. Albuquerque et al. 2007. Quantiἀcation of respiratory parameters in patients with temporal lobe epilepsy. Arq Neuropsiquiatr 65: 450–453. Scorza, F. A., M. Albuquerque, R. M. Arida, V. C. Terra, H. R. Machado, and E. A. Cavalheiro. 2010a. Beneἀts of sunlight: Vitamin D deἀciency might increase the risk of sudden unexpected death in epilepsy. Med Hypotheses 74: 158–161. Scorza, F. A., E. A. Cavalheiro, R. M. Arida et al. 2010b. Omega-3 fatty acids in SUDEP: Guardian of the brain-heart connection. In Sudden Death in Epilepsy: Forensic and Clinical Issues, ed. C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leestma. Chapter 3. In Sudden Death in Epilepsy: Forensic and Clinical Issues, ed. C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leestma, Chapter 22. Boca Raton, FL: CRC Press.

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Tomson, T., L. Nashef, and P. Ryvlin. 2008. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 7: 1021–1031. Tupal, S., and C. L. Faingold. 2006. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia 47: 21–26. Tupal, S., and C. L. Faingold. 2006. Respiratory arrest mechanisms, modulated in part by serotonin, may cause SUDEP. Epilepsia 47: 21–26. Tumer, N., P. L. Schraeder, and C. M. Lathers. 1985. The effect of phenobarbital upon autonomic function and epileptogenic activity induced by the hippocampal injection of penicillin in cats. Epilepsia 26: 520. Verrier, R. L., K. Kumar, and B. D. Nearing. 2009. Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective. Heart Rhythm 6 (3): 416–422. Verrier, R. L., and S. C. Schachter. 2010. Neurocardiac interactions in sudden unexpected death in epilepsy: Can ambulatory electrocardiogram-based assessment of autonomic function and T-wave alternans help to evaluate risk? In Sudden Death in Epilepsy: Forensic and Clinical Issues, ed. C. M. Lathers, P. L. Schraeder, M. W. Bungo and J. E. Leestma, Chapters 43 and 22. Boca Raton, FL: CRC Press. Vindrola, O., M. Asai, M. Zubieta, E. Talavera, E. Rodriguez, and G. Linares. 1984. Pentylenetetrazol kindling produces a long-lasting elevation of IR-Met-enkephalin but not IR-Leu-enkephalin in rat brain. Brain Res 297: 121–125. Vohra, J. 2007. The Long QT Syndrome. Heart Lung Circ 16 (Suppl 3): S5–S12. Walczak, T. 2003. Do antiepileptic drugs play a role in sudden unexpected death in epilepsy? Drug Saf 26: 673–683. Walczak, T. 2010. Risk factors for SUDEP. In Sudden Death in Epilepsy: Forensic and Clinical Issues, ed. C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leestma, Chapter 12. Boca Raton, FL: CRC Press. Wang, J., Y. Chen, K. Li, and L. Hou. 2006. Blockade of inhibitory neurotransmission evoked seizurelike ἀring of cardiac parasympathetic neurons in brainstem slices of newborn rats: Implications for sudden deaths in patients of epilepsy. Epilepsy Res 70: 172–183. Wannamaker, B. 1985. Autonomic nervous system and epilepsy. Epilepsia 26 (Suppl 1): S31–S39. Wichter, T., T. M. Paul, and L. Eckardt et al. 2005. Arrhythmogenic right ventricular cardiomyopathy. Antiarrhythmic drugs, catheter ablation, or ICD? Herz 30: 91–101. Williams, L., and M. Frenneaux. 2007. Syncope in hypertropic cardiomyopathy mechanism and consequences for treatment. Europace 9 (9): 817–822. Winfree, A. T. 1987. When Time Breaks Down: The Three-Dimensional Dynamics of Electrochemical Waves and Cardiac Arrhythmias. Princeton, NJ: Princeton University Press.

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Jan E. Leestma

Contents 2.1 Background of Sudden or Unexpected Deaths 2.2 Forensic Issues Regarding Epilepsy and SUDEP Deaths 2.2.1 Classifying Deaths as SUDEP 2.3 Drowning 2.4 SUDEP Deaths in the Home or Workplace 2.5 SUDEP Deaths Outdoors 2.6 Role of SUDEP in Traffic Deaths 2.7 SUDEP and Deaths in Agitated Delirium or Restraint 2.8 SUDEP in Criminal Cases 2.9 SUDEP and Anticonvulsant Medication References

37 39 39 41 41 42 42 44 48 50 52

2.1â•… Background of Sudden or Unexpected Deaths Sudden and unexpected deaths generally occur outside hospitals, although victims may be brought to an emergency room. In most locales in the United States, and likely in other developed countries, such deaths are usually not attended by a physician and are without detailed historical or medical information. They will usually be brought to the attention of a medical examiner or coroner, who is responsible for determining the cause and manner of death and for generating a death certiἀcate before the remains may be interred or otherwise disposed of. These responsibilities are statutory in most jurisdictions, but how they are discharged varies widely (DiMaio and DiMaio 2001). When a coroner is the responsible party, this individual may be elected or appointed, and may or may not be a medical doctor. A local pathologist (forensically trained or not) will usually be employed to conduct an autopsy or other examination of the body to make the determination of cause and manner of death. When a medical examiner is involved, that individual is almost always a trained forensic pathologist or will employ a staff of forensic pathologists to perform the required examinations to determine the medical cause of the death and its manner, which by convention may be labeled as a homicide (death at the hands of another), suicide (death by one’s own hand), accident, natural (natural disease processes), or “undetermined.” The coroner or medical examiner may direct that an autopsy be performed and that other studies that may include toxicological examinations of tissues or body fluids be undertaken (DiMaio and DiMaio 2001; Knight 1996). 37

38 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 2.1â•… Manner of Death Statistics Manner of Death

Percentage of Death Certiἀcates (%)

Natural diseases Homicide Suicide Accidents Undetermined

64–66 10–11 4–5 20–22 4–5

Sources: Office of the Medical Examiner, Cook County, IL, Annual Report, 1977– 1979, Office of the Medical Examiner, Chicago, IL, 1979; Leestma, J. E., and E. W. Sharp, in Forensic Neuropathology, CRC Press, Boca Raton, FL, 2009. With permission.

So-called sudden deaths may or may not be truly sudden, with many deἀnitions that surround such deaths (Davis and Wright 1980; de la Grandmaison and Durigon 2002; Kuller 1966; Kuller et al. 1966; Luke and Helpern 1968; Moritz 1954). When one refers to sudden deaths, more often than not, one is really referring to the fact that the victim actually died unexpectedly and, perhaps, also suddenly. When such deaths are witnessed, death may be described as having occurred in minutes rather than hours or longer. When a death is not witnessed, but the victim is found in circumstances that indicate death occurred in the course of normal activities and does not suggest a protracted agonal period, the unexpected and sudden quality of the death can be presumed (Haerem 1978). Such circumstances often involve ἀnding the victim dead in bed, in the bathroom (not bathing), or in a den or living room (in a chair or on the floor). When the victim is found in the bath (submerged or not), swimming pool, sauna or Jacuzzi, near electrical equipment or machinery, or in a vehicle (not involved in a crash), interpretations regarding the exitus may become complicated. When death occurs in the context of an apparent accident, with or without trauma, many facts and factors will have to be considered in reaching a proper determination of cause and manner of death (Leestma 1990a) (see Table 2.1). Owing to the variability in coroners’ and medical examiners’ statistics, it is generally recognized that 10–15% of their cases occurred suddenly and/or unexpectedly (see Table 2.2). Not unexpectedly, the majority of these deaths are due to some form of heart attack. Often this cannot be proven anatomically, although it can be inferred (Haerem 1978; Fineschi et al. 2006; Greenberg and Dwyer 1982; Schwartz and Gerrity 1975). Most central nervous system diseases do not kill suddenly, even though they present suddenly

Table 2.2â•… Medical Causes of Death in Sudden and/or Unexpected Deaths Disease Process Heart and great vessels Respiratory system Brain or meninges Digestive or urogenital systems Miscellaneous

Percentage (%) 56.1 (±7.4%) 14.5 (±6.4%) 15.8 (±2.4%) 8 (±1.7%) 9.5 (±8.9%)

Sources: Kuller, L., J Chronic Dis, 19 (11), 1165–1192, 1966; Kuller, L., A. Lilienfeld, and R. Fisher, Circulation, 34 (6), 1056–1068, 1966; Leestma, J. E., in Forensic NeuroÂ� pathology, CRC Press, Boca Raton, FL, 2009. With permission.

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and unexpectedly as in strokes (Leestma 2009a). The largest group of CNS-related sudden deaths appear to occur in the context of epilepsy [sudden death in epilepsy (SUDEP)] (Leestma 2009a, 1990b; Lhatoo and Sander 2002). A number of chapters in this volume deal with population statistics for SUDEP and these data will not be repeated here. Suffice it to say that deaths classiἀed as SUDEP—not a cause of death, but a category of death for which no anatomically evident cause is found, much like the label sudden infant death syndrome (SIDS)—forms an important and nonrare problem for forensic pathologists. As noted before in previous publications (Leestma 1990a, 1990b; Leestma et al. 1989, 1997), the apparent incidence of SUDEP cases at a large metropolitan medical examiner’s facility (Chicago-Cook County, IL) is 60–80 cases per year (Leestma et al. 1989). A casual survey of other large metropolitan offices by the author indicates similar numbers of cases in all of them (Los Angeles, Denver, and Miami). Collecting precise and accurate statistics on SUDEP incidence is problematic because there is wide variation in practices among the forensic community on how such cases are labeled on death certiἀcates as Schraeder et al. (2006) have reported. This is a function of the awareness or lack of awareness of the phenomenon and/or philosophical positions on how, presumably, epilepsy-related deaths should be classiἀed or labeled by forensic pathologists. As alluded to earlier, it is the task and responsibility of the forensic pathologist to determine the medical cause and the manner of death if possible. If this is not possible, then, after all the evidence is gathered, the medical cause of death and, sometimes, the manner of death, must remain undeclared (undetermined). This circumstance is certainly intellectually disappointing and frustrating and may lead to unwarranted speculations on the part of family, friends, attorneys, the media, and colleagues. Such cases, whether assigned the SUDEP designation or not, may ἀnd their way into the legal system as civil cases (torts) or even as criminal cases. The following discussion will explore some of these possibilities and, when possible, provide case examples of the issues involved.

2.2â•…Forensic Issues Regarding Epilepsy and SUDEP Deaths 2.2.1â•…Classifying Deaths as SUDEP Which cases are labeled with the designation SUDEP can be difficult and sometimes controversial. An attempt to provide some guidelines was arrived at in conjunction with data collected during the development of lamotrigine (Lamictal) at the behest of the then Burroughs-Wellcome pharmaceutical company, now Glaxo-SmithKline, Inc. In the clinical trial databases that drew upon studies in many countries with 4700 patients (5747 patient years of exposure) over several years, 45 sudden and/or unexpected deaths were discovered in all arms of the study. It was important to evaluate, if possible, if there was a different incidence of SUDEP deaths between the treated and control groups. To this end, a study group of professionals that included epidemiologists, epileptologists, and pathologists was impaneled to review the data and to determine what criteria might be applied to the cases in order to stratify them for analysis (Leestma et al. 1997; Tennis et al. 1995). As might be expected, the quality and quantity of individual case data varied widely. It was not possible to obtain further data beyond that reported. Cases were stratiἀed according to the following classiἀcation (Leestma et al. 1997):

40 Sudden Death in Epilepsy: Forensic and Clinical Issues

• SUDEP (definite or highly probable) The victim suffered from epilepsy as deἀned by Gastaut (1969) and Gastaut and Zifkin (1985) and had been treated with one or more anticonvulsive agents, usually for many years, and died unexpectedly in a reasonable state of health. The fatal attack occurred suddenly, but death might not have occurred for several hours, when it was usually associated with cardiorespiratory arrest, resuscitative efforts, and their complications. The attack occurred during normal activities in benign circumstances. An obvious medical cause of death was not found after autopsy. Cardiac arrhythmia may have been observed after the attack. If the victim was found in the bath but did not show evidence of drowning, the death may be assignable as SUDEP. If status epilepticus or acute neurotrauma occurred during seizure, the case was excluded. • Possible SUDEP These cases met most or all of the SUDEP criteria, but data suggested more than one possible cause of death associated with seizures, such as death while bathing, swimming, or due to aspiration, with or without an observed seizure. • Other non-SUDEP These cases could not be assigned to either of the ἀrst two categories and an obvious or likely cause of death had been established. • Insufficient data These cases could not be interpreted because of lack of information or ambiguous data concerning the circumstances of death or concurrent medical conditions in the victim. There are and were inevitable issues with the above classiἀcations, owing to all the informational problems that are inherent to any patient-based study. A particularly thorny one was the role of possible drowning in some of the victims, which is discussed later. Other confounding variables include the role of concurrent diseases in the victim, especially heart disease in the older victim, as well as conditions related to alcohol and drug abuse. There are a host of issues in infants and children that include possible SIDS-type deaths. Highly important to any death investigation of an individual who apparently dies suddenly and/or unexpectedly is the death scene investigation (DiMaio and DiMaio 2001; Knight 1996; Leestma 2009b). The physical death scene environment must be documented and carefully inspected. It is important to note if the body is in a position or location that would be consistent with normal activity that was interrupted by the fatal attack. The presence of bruises on the face, head, and extremities does not necessarily mean that the victim was assaulted; rather that if a seizure occurred, the victim may have fallen and been injured or become injured during the clonic phase of a seizure. Context and common sense in evaluating the scene is vital. Furthermore, the investigator should search for and collect any pill bottles that are present and any materials that suggest illicit drug use. The pill bottles may indicate the use of anticonvulsant medications and can provide the names of the pharmacies that dispensed the drug and the physician who prescribed it, who may be contacted later for additional information. If the pill bottles have pills in them and the date of prescription is on the label, or if the bottle is empty, one can make a judgment regarding medication compliance by the victim. If other medications are present, this can also give a

Forensic Considerations and Sudden Unexpected Death in Epilepsy

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clue as to other medical problems the victim may have had and can provide some guidance as to which toxicological examinations may need to be made. If any witnesses to the attack are present, a detailed description of what was seen is vital. If the attack was not witnessed, it may be possible to determine the timeframe of the attack by inference (when the individual was last seen and found). If friends or relatives are available, they may have knowledge about the health status of the decedent and, speciἀcally, if the victim was epileptic. To aid investigators in collecting this vital information, the author has previously described a “check sheet” that can serve as a template for investigators at death scenes where the victim was epileptic and sudden or unexpected death has occurred (Leestma et al. 1989; Leestma 1990b, 2009b).

2.3â•…Drowning Epileptic individuals are frequently found dead in bathtubs, swimming pools, hot tubs, and natural bodies of water in conjunction with swimming. It is a common instruction to epileptic persons not to bathe upon arising or immediately before going to bed, rather to bathe at another time of the day to avoid the increased likelihood of seizures that occur proximate to sleep (Laidlaw and Richens 1982; Engel and Pedley 2008). The postmortem diagnosis of drowning is imprecise and subject to many evidentiary problems that are well-known to any forensic pathologist such as the so-called “wet” and “dry” forms of drowning (DiMaio and DiMaio 2001; Knight 1996); thus, it cannot be known with complete assurance that a victim who was found submerged in the bathtub or swimming pool, and whose lungs did not show evidence of water aspiration, did not drown (laryngospasm), but rather died from the supposed mechanism(s) typical of SUDEP and simply sank into the water after the attack, when the victim was lifeless. If the potential drowning occurred in a natural body of water, such as a stream, lake, or ocean, it may be possible to recover diatoms and other small particles from the water in the lower respiratory passages, which may indicate aspiration. The forensics of this process and its reliability is controversial (Piette and De Letter 2006; Modell et al. 1999; Pachar and Cameron 1993). If the victim is found in the bathtub but the head is not immersed, this does not necessarily mean that drowning did not occur. The onset of rigor mortis may have shifted the position of the body after death, causing the head to rise out of the bath water. A careful examination of the oral cavity at autopsy may reveals bites of the tongue, lips, or buccal mucosa, which is presumptive evidence that a recent seizure occurred but still does not necessarily mean that drowning did not occur (Ulrich and Maxeiner 2003).

2.4â•…SUDEP Deaths in the Home or Workplace The most common location for SUDEP deaths is in the home, in locations that bespeak an attack that took place during normal activity (Leestma et al. 1989; Leestma 1990b). The most common of these is in the bedroom. The victim may be found in bed in a normal position, or one that suggests some movement, as in a seizure with disordered bedding apparent. The victim may also be found on the floor in the bedroom dressed in normal

42 Sudden Death in Epilepsy: Forensic and Clinical Issues

clothing or in bed clothes beside the bed or in another position that suggests that the fatal attack took place proximate to going to bed. The association of SUDEP, and for that matter epileptic seizures in general (Laidlaw and Richens 1982; Engel and Pedley 2008), with sleep is well known and it is also not uncommon to ἀnd SUDEP victims dead in an easy chair in a den or living room, sometimes with the television on, which suggests that the victim may have been sleeping or dozing when the attack occurred. Death in the bathroom, discussed earlier with respect to drowning, may have no connection with bathing when the victim is found dead on the bathroom floor. In such circumstances, various injuries from the impact of the body surfaces with bathroom ἀxtures is common and may confuse the interpretation of the death scene, suggesting a homicidal attack or perhaps a suicide. A careful documentation of the death scene and blood spatter or blood flow (DiMaio and DiMaio 2001; James et al. 2005) as well as the autopsy may clear up suspicion of foul play. The body of a SUDEP victim may be found in other areas of the home, in the garage or workshop area, or in a workplace area that raises the issue of other means of death than a seizure-related cause. A careful scene inspection and investigation will go a long way in ruling in or out electrocution or intoxication, be they accidental or self-inflicted. Deaths may not be discovered immediately in SUDEP victims and the body may have begun to decompose, making interpretations complex and making a proper scene investigation even more germane. The process of decomposition has been the subject of careful study by forensic scientists and there is a large body of literature on the subject (Milroy 1999; Knight 1996). Occasionally, a body that is not immediately found in a home may be subject to predation by insects, rodents, or pets. Most experienced forensic pathologists are familiar with these phenomena and can differentiate marks upon the body from premortem injuries.

2.5╅SUDEP Deaths Outdoors While it is not common, SUDEP victims can experience a fatal attack outdoors with prompt or delayed discovery of the body. Obviously, the longer a body has lain outside, the more decomposition and environmental effects such as insects, vermin, and other animals will complicate examination of determinations on the body. Even in decomposed bodies, it may be possible to glean valuable information that may make a diagnosis of SUDEP practicable (Milroy 1999; Knight 1996). As with an indoor death scene investigation, the outdoor death scene can yield important information about what happened to the victim and rule in or€out foul play, suicide, or accident. The following case example (Case A) is illustrative.

2.6â•…Role of SUDEP in Traffic Deaths A not uncommon type of forensic case is that involving vehicular crashes in which the driver appears to have experienced some sort of attack that rendered that person unable to control the vehicle. These may be single-vehicle or multivehicle incidents. Such cases are often very difficult to evaluate from a pathological point of view, owing to the often overlying trauma to the body and brain caused by the accident, and also the coexistence of other disease processes, the most important and common being cardiovascular disease.

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43

Case A A middle-aged man had been complaining of headaches and “strange” feelings and set out toward his automobile to go to his family physician for an examination. The man’s wife observed the man fall to the ground and apparently jerk beside his car. When she reached her husband, he was apparently dead. Autopsy revealed a 2.5-cm unruptured, encapsulated mass ἀlled with brownish greasy material indenting the right inferior frontal lobe anterior to the amygdala. Microscopic examination revealed the mass to be an epidermoid cyst. The remainder of the autopsy was unremarkable. It appeared that this man died from an attack that represented a generalized convulsion (GTC), apparently his ἀrst and last, from a lesion in a commonly epileptogenic region of the brain. From the standpoint of SUDEP criteria, this man was not known to be epileptic, although it appears that at the time of his death he experienced a GTC event and, thus, it could be argued the death was SUDEP.

A not uncommon cause of vehicular accidents is an epileptic attack that causes the driver-victim to lose control of the vehicle and incur injuries that may or may not prove to be fatal. In the case of fatal accidents, an examination of the vehicle, its contents, and condition may provide important information for the forensic pathologist. As is always the case, witness accounts and a medical history of the victim may point the way for further inquiry, especially if the victim was suffering from epilepsy and did not appear to have died from traumatic injuries. As in other cases of SUDEP, an effort should be made to determine what drugs the victim was taking, who prescribed them, and if the victim was compliant. A thorough autopsy examination will generally reveal if there are signiἀcant traumatic injuries and a similar thorough neuropathological examination will reveal any acute lesions, or chronic lesions in the brain that might have been epileptogenic. Examples of such lesions are old traumatic contusions, vascular anomalies, tumors, and congenital malformations (Leestma et al. 1989; Leestma 2009b). Autopsies of non-SUDEP deaths in epileptic persons generally show a relatively low incidence of structural lesions in the brain (about 10%), whereas SUDEP victims have a much higher incidence, between 50% and 70% (Leestma et al. 1985, 1989; Monte et al. 2007; Shields et al. 2002; Thom et al. 1999). Not all studies have shown signiἀcant neuropathology, however (Morentin and Alcaraz 2002). If there are acute traumatic lesions in the central nervous system, it may still be possible to determine if there are more chronic lesions present. It may, however, be unlikely to determine if the older lesions had anything to do with the vehicle crash, although sometimes collateral information may suggest a causal event. Examination of the oropharynx may reveal tongue, lip, or buccal bites that may indicate a recent seizure (Ulrich and Maxeiner 2003). Toxicological examination will reveal if anticonvulsants were present and if they were within therapeutic range. While many studies of SUDEP victims have shown that they have been or are taking multiple anticonvulsant medications, they are more likely than not to be noncompliant with respect to anticonvulsant medications (Bell and Sander 2006; George and Davis 1998; Langan 2000; Langan et al. 2005; Lear-Kaul et al. 2005; Lund and Gormsen 1985; McKee and Bodἀsh 2000; Monte et al. 2007; Nilsson et al. 1999; Tomson et al. 2005; Vlooswijk et al. 2007; Walczak 2003).

44 Sudden Death in Epilepsy: Forensic and Clinical Issues

Not all studies have shown this (Opeskin et al. 1999, 2000; Schwender and Troncoso 1986; Walczak et al. 2001), and some have suggested that toxicological studies may not truly reflect proper or improper drug levels (McGugan 1999), thus the role of medications on the risk of SUDEP is, at present, suggestive but has not been proven. Some have suggested that carbamazepine may play some role in SUDEP, either by some idiosyncratic reaction or in connection with changes in dosage of this drug (Hitiris et al. 2007; Nilsson et al. 1999, 2001; Timmings 1993; Walczak 2003). A thorough pathological examination of the heart must be performed to deἀne the extent of arteriosclerotic cardiovascular disease, previous areas of myocardial scarring or necrosis, and any other morphological abnormality of the heart or its valves. One inevitably encounters some degree of cardiovascular disease in accident victims and in sudden or unexpected deaths, and it becomes difficult to compare the importance of what is found to the death circumstances (Natelson et al. 1998; Scorza et al. 2007). There is a robust literature on the heart and sudden death (Okada and Kawai 1983; Rossi 1982; Schwartz and Gerrity 1975; Schwartz and Walsh 1971; Fineschi et al. 2006; Greenberg and Dwyer 1982; Bharati and Lev 1990) and on the so-called neurocardiology (Armour and Ardell 1984; Johnson et al. 1984), which cannot be reviewed here but the issue of cardiac dysfunction and pathology is discussed in detail elsewhere in this volume. Since SUDEP deaths are apparently physiological in the sense that the process that leads to SUDEP is electrophysiological and, thus, may or may not have a morphological counterpart such as a conduction system defect in the heart, an ion channelopathy, or some other deἀnable and demonstrable disease process, the science of forensic pathology can only go so far in determining the mechanism of death in some traffic-related deaths.

2.7â•…SUDEP and Deaths in Agitated Delirium or Restraint There is a category of sudden death in which the victim dies suddenly and unexpectedly while in a state of delirium that may involve an arrest or restraint circumstance, during which the victim dies. This problem has been the subject of a robust literature over many years and recent monographs by DiMaio and DiMaio (2006) and by Ross and Chan (2006) review much of it. It is germane to this discussion that some victims are epileptic. A typical restraint death circumstance is one where an individual is involved in an assault, robbery, disturbance, or some other event that may result in law enforcement personnel, emergency personnel, or rescue personnel being summoned to the scene. Once on the scene, there may be an apparent offender who is violent, disoriented, or delusional and may seem to need to be restrained or taken into custody to prevent flight, injury to the offender or to others. In the course of the activity of restraining the individual, many personnel may become involved in trying to subdue the violent person and in so doing may place handcuffs or restraint ties to the person and may place the individual in the prone position, “hog tie” them, and perhaps overlie the individual with several people. In this circumstance, the violent person may suddenly become quiet or complain of not being able to breathe and suffer a cardiorespiratory arrest from which the victim may or may not be able to be resuscitated. Such events almost inevitably result in some form of litigation in which the personnel involved in the restraint are held to account for what actions they may or may not have

Forensic Considerations and Sudden Unexpected Death in Epilepsy

Case B This 29-year-old man had apparently had a seizure disorder since childhood, for which he had been treated with a variety of anticonvulsant medications and a vagal nerve stimulator (about 3 years before this admission) in an effort to suppress his frequent seizures. On a recent occasion, he had been admitted to a hospital after having suffered a seizure. During admission the patient experienced a cardio/pulmonary arrest from which he was successfully resuscitated. The patient had a history of respiratory troubles including asthma. A brain CT on this admission was said to be negative. The shortness of breath the patient had complained of was thought possibly to be due to aspiration. As the patient began to emerge from his postictal state and resuscitation procedures, he was disoriented and agitated, for which he was medicated. He recovered from this episode. Seven months later in the presence of his mother, the patient experienced a seizure event and apparently, while postictal, he became delirious and combative and assaulted his mother, who called for assistance. Police and ἀre department personnel responded and subdued the man by placing him in handcuffs and hobbles in a prone position on a litter. Soon afterward, he became unconscious and pulseless. Immediately after emergency medical personnel arrived, the patient had a heart rate of 140 and a respiratory rate of 28, but then became pulseless. Resuscitative treatment was begun and the man was conveyed to an emergency facility where he was reported to be asystolic on admission. During resuscitation, the patient urinated and vomited. Resuscitation did not succeed and the patient was pronounced dead. The victim was known to be hypertensive and to have had temporal lobe epilepsy for many years. When he was postical, it was not uncommon for him to be delusional and agitated. Autopsy examination reported a body weight of 251 lb and a height of about 72 in. A number of bruises and abrasions to the face, arms, and hands were noted. There were petechial hemorrhages of the lip mucosa and right flank. A subcutaneous hemorrhage was noted near the left occiput. There was evidence of food aspiration. Heart–blood toxicological examination revealed 10 µg/ml barbiturates, 40 mS. (From Tigaran, S., Acta Neurol Scand Suppl, 177, 9–32, 2002. With permission.)

1. The changes are due to subendocardial scarring present in the epilepsy patients’ myocardium. However, because of the discrete nature of ἀbrosis found postmortem in the hearts of the epilepsy patients, we may not be able to detect these abnormalities with sufficient sensitivity by means of the present technique. The author must admit that the results following the investigation of the ἀrst ἀve patients enrolled in the study, all of which exhibited positive late potentials, were surprising. Consequently, it was decided to repeat the investigation after the antiepileptic drugs were withdrawn (the patients did not receive any other drugs but antiepileptics), and simultaneously control the antiepileptic drug plasma concentration when investigating the rest of the patients, both in the medicated and in the unmedicated Positive *Vector Butterworth 40–250 Hz

Negative RMS40 : 10.2 µV RMS50 : 19.2 µV QRS : 140 mS

*Vector Butterworth 40–250 Hz

RMS40 : 25.3 µV RMS50 : 40.1 µV QRS : 101 mS

LPD : 46 mS

LPD : 24 mS

Noise : 0.4 µV

Noise : 0.3 µV

200 mm/s 10 µV/10 mm

200 mm/s 10 µV/10 mm

Figure 7.2╇ Example positive versus negative LP image. (From Tigaran, S., Acta Neurol Scand Suppl, 177, 9–32, 2002. With permission.)

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phase. Our ἀrst conclusion, coupled with the delayed depolarization of the left ventricle observed in 47% (positive late potentials) of our patients on drugs when compared with the off-drugs phase, led us to the second working hypothesis. 2. The changes are due to the antiepileptic drugs, thus generating the hypothesis that antiepileptics might also influence the electrical properties of the myocyte due to their electrophysiological effects on the conduction system and the myocardium. As previously shown, many antiepileptic drugs exert their effects by blocking sodium channels, which generally slow conduction. Several cardiac antiarrhythmic drugs also exert their effects by blocking this channel (Anderson et al. 1994). This relationÂ� ship has also been observed in other clinical studies of sodium channel blocker drugs. Antiepileptic drugs may thus, through their as yet unrecognized influence on the depolarization process (Freedman and Steinberg 1991), potentially increase the propensity for malignant arrhythmias. In a larger perspective, this could be a potential so-called proarrhythmic effect, which could precipitate cardiac arrhythmias. To the best of the author’s knowledge, there are no available data describing the relationship between the occurrence of late potentials and antiepileptic drugs. While not claiming to have found the ultimate explanation, the author would like to propose that although the two hypotheses are apparently discordant, both variants may be true. Likewise a combination of both hypotheses would also be a possibility, an idea supported by the ἀndings of the electrocardiographic positive ST segment and the positive late potentials. However, the interpretation of these ἀndings requires much caution, warranting further studies to verify the reproductibility of the described ἀndings (Tigaran et al. 2002). Future studies employing the magnetic resonance imaging (MRI) technique will help in clarifying the questions rained by these two hypotheses.

7.6â•…Evidence of Sinus Tachycardia Associated with Epileptic Seizures More than 25 years ago, Marshall et al. (1983) wrote that, “a seldom-recognized accompaniment of temporal lobe seizures is tachycardia.” They were the very ἀrst authors to document by simultaneous “electroencephalographic, electrocardiographic, and videotape monitoring” the presence of this phenomenon in 12 consecutive patients with spontaneous seizures. Several subsequent articles have described this phenomenon, and as a result of the analysis of more than 1500 seizures from more than 1000 epilepsy patients, all of them established without any doubt that, despite the origin of the epileptic seizure, sinus tachycardia is by far the most common cardiac phenomenon temporally associated with epileptic seizures, as one would expect as part of a normal response to stress. Some of the previous articles in the literature are lacking in details related to the exact brain origin of the seizure or the exact type of seizure, i.e., secondary generalization versus complex versus simple partial seizures. In the older studies, this inconsistency is due to the technical limitations of the imaging methods employed at the time of the study. Unfortunately, at times, the electroencephalographic onset of the seizure can be deceiving due to either rapid propagation of the seizure or inadequacy of the scalp EEG recording(s), as shown by studies using intracranial electrodes or magnetoencephalogram studies (Shibasaki et al. 2007). Overall, the heart rate is thought to be signiἀcantly higher with seizures arising from the temporal than from the frontal lobe (Galimberti et al. 1996; Schernthaner et al.

116 Sudden Death in Epilepsy: Forensic and Clinical Issues

130

1999; Garcia et al. 2001; Opherk et al. 2002; Tigaran et al. 2002; Leutmezer et al. 2003) and to occur earlier in patients whose seizures arise during sleep (Opherk et al. 2002). Of note, Tigaran et al. (2003) showed that epileptic seizures induce a rapid increase in heart rate from resting levels to more than 180 beats/min shortly before the onset of electrocardiographic seizures. This early increase in heart rate indicates that seizures can induce a turning on/off of very high levels of efferent neural cardiac sympathetic activity (see Figure 7.3). Such high levels of sympathetic activity (Tigaran et al. 2001) become toxic principally to the cardiac myocyte and could, in the long run, be a contributing factor to the scarring of the myocardium observed in SUDEP victims (see Figure 7.4) (P-Codrea Tigaran et al. 2005; Natelson et al. 1998; Falconer and Rajs 1976), as well as the formation of cardiac contraction bands (Manno et al. 2005). Moreover, Tigaran et al. (2003) have demonstrated the occurrence of myocardial ischeÂ� mia triggered by high heart rate values, as shown by the presence of electrocardiographic ST-segment depression, which is associated with an epileptic seizure (see Figure 7.5), and could represent an additional contributing factor to the pathologic changes of the myocardium, such as ἀbrotic scarring. Strikingly, the failure of the recorded heart rate to recover to the baseline level for as long as 1 h after seizure cessation can be a possible result of the impaired autonomic function (Ushijima et al. 2009) such as Nei et al. (2000a) have demonstrated to be present in some of their epilepsy patients. It is important to consider that, in epilepsy patients, tachycardia triggering cardiac ischemia may have even more serious consequences, especially in patients who already have cardiac disease. This suggests that methods of addressing it might be important and worthy of investigation, such as, for example, blunting the ischemic and heart rate response with beta-blockers. The observations and present hypothesis represent an exciting challenge with regard to experimental clinical testing. Salutary in this context are studies looking into the association between tachycardia and diverse types of ethnic groups. A pioneer in this ἀeld of research, Wilder-Smith

110 100 90 70

80

Average heart rate

120

No ST-segment change ST-segment change

0

10

20

30

40

50

60

Minutes relative to seizure

Figure 7.3╇ Average heart rate (HR) over time by ST-segment changes. 0 = max HR during seizure. (From Tigaran, S., Acta Neurol Scand Suppl, 177, 9–32, 2002. With permission.)

Sudden Unexpected Death in Epilepsy 9

1

2

117 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

8

3

10

4

7

5

6

11

(a)

X

1 2 3 4 5 6 7 8 9 10 11 12 13

8

3

10

4 5

(b)

9

1

2

7 6

11

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

X X X

Figure 7.4╇ Comparison between the distribution of the fibrotic changes of the deep and sub-

endocardial myocardium in SUDEP versus control patients. (a) Control patients for fibrotic myocardial areas. (b) Fibrotic areas in the hearts of SUDEP patients. 1–15 (vertical), subject’s identification number; 1–11 (horizontal), sections from the transmural tissue blocks containing the deep and endocardial myocardium; 12, longitudinal tissue block from intermedial septum; 13, longitudinal tissue block from the papillary muscle of the left ventricle; X, presence of fibrotic changes in singular areas which are not present in the stylized figure. Light gray: slight fibrosis: 1 patient with fibrotic changes confined to 1 area. Darker gray, moderate fibrosis: 2 patients with fibrotic changes observed in the same area. Darkest gray, severe fibrosis: 3 patients with fibrotic changes observed in the same area. (From P-Codrea, Tigaran, S. et al., Am J Forensic Med Pathol, 26 (2), 99–105, 2005. With permission.)

(Wilder-Smith and Lim 2001), published a study concerning the changes in heart rate amongst non-Caucasian Singaporean patients. Notably, this study concluded that sinus tachycardia was considerably less frequent in non-Caucasian epilepsy patients. Despite being a very comprehensive review of SUDEP and its mechanism, the Nigerian Kwara State article lacked regional ethnic data that could have addressed this particular topic (Sanya 2005). By the same token, it is quite possible that the American melting pot, more than anywhere else, will claim its own speciἀc studies looking at the issue of racial and ethnic differences in epilepsy-related cardiac arrhythmias.

118 Sudden Death in Epilepsy: Forensic and Clinical Issues

00:49:13 Pre start of Event

01:03:57 Pre start of Event

00:49:47 Max. depress.

01:08:28 Max. depress.

00:51:33 Post end of Event

01:12:11 Post end of Event

Figure 7.5╇ Example from Patient 1 (left) and Patient 9 displaying dynamic ST-segment depression in relation to seizure with secondary generalization. (From Tigaran, S., Acta Neurol Scand Suppl, 177, 9–32, 2002. With permission.)

A conceptually different idea, outside of the direct association between heart rate variations and SUDEP, involves the epidemiology of obesity, which is thought to be a speciἀc important risk factor for occult cardiovascular disease. Thus, complications of obesity in epilepsy patients might influence even more the ability of the heart to adjust to abrupt, sudden variations in its rate and represent a contributory mechanism in SUDEP. Obesity is a chronic metabolic disorder associated with cardiovascular disease and increased morbidity and mortality. It is a widely acknowledged risk factor for developing coronary artery disease (Franzosi 2006). The number of deaths per year attributable to obesity is about 30,000 in the United Kingdom, a country that has produced a signiἀcant amount of SUDEP data. This number is 10 times higher in the United States, roughly about 300,000 deaths per year (Allison et al. 1999), where more than half of the adults are overweight (Flegal et al. 1998) and where obesity is thought to have overtaken smoking in 2005 as the main preventable cause of illness and premature death (Franzosi 2006). If we do death rate extrapolations for the United States for obesity, there will be 300,000 deaths per year, 25,000 deaths per month, 5769 deaths per week, 821 deaths per day, and 34 deaths per hour (WrongDiagnosis.com 2009). Moreover, we also have to keep in mind the speciἀc association between obesity and obstructive sleep apnea, which represents an aggravating and important contributing factor to the genesis of cardiovascular diseases (Hiestand et€al. 2006). Since apnea has already been identiἀed to be associated with epileptic seizures and SUDEP (Nashef et al. 1996; So et al. 2000), this association should prompt even more attention and many more research studies. Another notable association, which might be very signiἀcant for epilepsy and SUDEP, is the signiἀcant increase in the older population and the speciἀc increase of epilepsy prevalence in this age group (Velez and Selwa 2003). Accordingly, the speciἀc concurrent morbidities, such as stroke and cardiac diseases, present in this age category will prompt an even higher awareness of the cardiac complications in epilepsy.

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7.7â•…Bradycardia and Asystole Asystole and atrioventricular block are recognized as potentially malignant conduction abnormalities that can lead to ventricular ἀbrillation (Tigaran et al. 2002). Thus, bradyarrhythmia could be particularly risky in patients with coexistent, underlying ischemic heart diseases; this emphasizes the importance of recognizing these cases. Ictal bradycardia, cardiac asystole, and total atrioventricular block associated with epileptic seizures is to date a more seldom but noteworthy complication of epilepsy. This association is probably still underestimated because of the lack of recognition of cardiac complications in epilepsy, as mentioned before. Because of its implication in the pathophysiology of SUDEP, there were two earlier literature reviews on bradyarrhythmias and asystole as cardiac consequences of epileptic seizures (Devinsky et al. 1997; Tinuper et al. 2001). Several other case reports have been published since 2001 (Rocamora et al. 2003; Venugopalan et al. 2001; Mondon et al. 2002; Leutmezer et al. 2003; Toth et al. 2008; Carinci et al. 2007; Strzelczyk et al. 2008; Schuele et al. 2008; Ghearing et al. 2007; Almansori et al. 2006; Mascia et al. 2005; So and Sperling 2007; Rugg-Gunn et al. 2004a; Carvalho et al. 2004), adding valuable information about the occurrence of bradycardia in epilepsy. Of note, in this context, are recent studies from the Mayo Clinic (Britton et al. 2006), which showed no consistent hemispheric lateralization of seizure activity at the onset of bradycardia. Another study (Ghearing et al. 2007) found over a 14-year period that only 29 seizures were associated with ictal bradycardia in 13 patients. Out of the 29 bradycardia episodes, 7 patients had a total of 11 complex partial seizures that were associated with asystole. Despite the apparent multitude of published case reports, this association still seems to be infrequent. A feasible explanation of the paucity of data regarding the association between epilepsy and bradycardia may be an underestimation of this association due to the lack of adequate monitoring of the epilepsy patients, with concurrent electrocardiographic and intracranial electroencephalographic analysis (Leung et al. 2006). Important in this context, Rugg-Gunn et al. (2004b) developed a new monitoring strategy. Epilepsy patients were implanted with subcutaneous electrocardiogram loop recorders for an average of 18 months. Of the 19 patients, 4 (21%) developed bradycardia or asystole, for which a permanent pacemaker was deemed appropriate. Three of these episodes occurred at the time of a clinical seizure and one was not associated with a known clinical event. This study clearly showed how inadequate it is to simply record electroencephalograms and electrocardiograms for a few days or a few seizures. Thus, the ἀndings of Rugg-Gunn and colleagues (2004b) should be applauded. Other investigators should try to replicate these ἀndings in order to acquire more evidence-based data before we apply these ἀndings to the routine care of people with epilepsy (Hirsch and Hauser 2004).

7.8â•…Ictal Cardiac SPECT Imaging Supportive of a Cardiac Mechanism of SUDEP To the best of our knowledge, there is only one study illustrating focal myocardial perfusion defects concurrent with electrocardiographic ST-segment depression at the cessation of an epileptic seizure as an indicator for myocardial ischemia (see Figure 7.6) (Tigaran 2001; Dam et al. 2001). Notably, the criteria and the methods available for the detection of the myocardial ischemia with myocardial perfusion scintigraphy in this study were not

120 Sudden Death in Epilepsy: Forensic and Clinical Issues

Seizure

Rest

Perfusion defect during seizure

Patient 8

Figure 7.6╇ Perfusion defect during epileptic seizure.

used to determine if ischemia could occur globally in the myocardium. For future studies, the limitation of employing this type of imaging technique could be potentially addressed by the use of newer techniques, such as hybrid positron emission tomography/computerized tomography (PET/CT) or PET/magnetic resonance imaging systems, which would be able to detect more accurately any perfusion defects (Slomka et al. 2008). In data from an unpublished study conducted by the author of this chapter, 14 men and 9 women (age range 20–59 years, mean 42) with intractable focal epilepsy for 4 to 55 years (mean age 26 years) participated in this prospective study. All patients had normal baseline results on electrocardiography, Holter monitoring, echocardiography, myocardial scintigraphy at rest, and coronary angiography. Technetium 99m Cardiolite (DuPont Pharma, UK) was injected into 18 unmedicated patients during ictal events in which nine patients experienced secondarily generalized tonic–clonic seizures with a mean of maximum ictal heart rate of 133 beats/min. The other seven patients were injected in relation to complex partial seizures with an average maximal ictal heart rate of 108 beats/min. One patient received the tracer during a simple partial status epilepticus episode, during which the Holter recording was not available. Of the 18 myocardial perfusion studies, there were several ictal studies positive for focal myocardial perfusion defects (n = 3 or 16%). Unfortunately, only one was a positive ictal study in which the tracer was injected in direct relationship to a seizure where a 1-mm ST-segment depression, which is reflective of myocardial ischemia, was detected on the Holter monitor subsequent to a complex partial seizure without any motor phenomenon, recorded at 03:05 p.m. The maximum ictal heart rate during this seizure was 134 beats/min. This patient, a 56-year-old female with MRI-veriἀed right-sided hippocampus gliosis, had both infero- and anteroseptal reversible defects. This particular ἀnding may advocate for SUDEP being more frequent in women than was previously estimated (Walczak et al. 2001). The patient was moderately obese and had a normal 12-lead electrocardiogram, rest and stress test, and myocardial scintigraphy, as well as normal coronary angiography. Her baseline plasma norepinephrine was higher than normal, namely 1033 pg/mL. Her urine norepinephrine was 55,200 pg/mL

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or 135 μg per 24 h. Her baseline plasma epinephrine was also elevated above the normal reference interval, up to 87 pg/mL, and her urine norepinephrine was 13,800 pg/mL or 34€μg per 24€h (diuresis was 2450 mL for 24 h when the values were collected). Normal reference ranges are laboratory-speciἀc, vary according to methodology of testing, and differ between blood and urine samples. Supine (lying down): epinephrine less than 50 pg/ mL, norepinephrine less than 410 pg/mL; reference ranges for urine catecholamines are: epinephrine 0–20 μg per 24 h and norepinephrine 15–80 μg per 24 h (Answers.com 2009). The ἀndings in the above case concur with those of Nei et al. (2004), who suggests “. . . that patients with evidence of a great degree of change in autonomic tone during seizures might be at increased risk for SUDEP.” During the epileptic seizure, an almost threefold increase was noted in both plasma and urine catecholamines (plasma norepinephrine, 2891 pg/mL; plasma epinephrine, 296 pg/mL; urine norepinephrine, 121,300 pg/mL; and urine epinephrine, 29,700 pg/mL) for a total diuresis of 2400 mL. During the seizure, a drop in O2 saturation from 100% to 93% was recorded by the pulse oximeter, which did not represent any signiἀcant drop in the O2 saturation. The oxygen saturation dropped, but not below the limit of 90%. Most physicians would not be concerned when the oxygen saturation is above 90% (93% in this study). The imaging results from a small cohort of drug refractory epilepsy patients, whose antiepileptic drugs were withdrawn during the course of the study, and without any evidence of cardiovascular disease, substantiate the hypothesis that cardiac ischemic abnormalities may exist and could potentially provide some of the pathophysiologic explanation for SUDEP. The data also suggest that epileptic seizures of temporal origin may induce myocardial ischemia in the absence of coronary pathology, presumably by autonomicÂ�mediated vasospasm. This ἀnding points again toward an association between cardiac abnormalities in epilepsy and the sudden, large imbalance in cardiac efferent autonomic activity (Druschky et al. 2001) that may result in autonomic-mediated ischemia and, thus, possible fatal arrhythmia. Unfortunately, this study (Tigaran 2001) has several limitations. The tracer was simultaneously injected during the electrocardiographic detected myocardial ischemia as reflected by the ST-segment changes in one patient out of the 23 who were enrolled in the study. Studies related to the anatomical brain localization of the site of the seizure employing the subtraction ictal SPECT coregistered to MRI (SISCOM) method documented the importance of the timing for the tracer injection (O’Brien et al. 1998). Late injection of the radiotracer (>45 s) after the onset of the epileptic seizure was associated with a falsely localizing or nonlocalizing SISCOM study, a ἀnding that could be extrapolated to our epilepsy study. This might represent the explanation for why 15 of the 18 scans were negative myocardial perfusion studies.

7.9â•…Future Research Avenues for an Underlying Cardiac Mechanism of SUDEP: Epilepsy, Depression, and Cardiac Disease For centuries poets and folklore have asserted that there is a relationship between the mind and body in general, and human moods and the heart in particular. Almost 400 years ago Shakespeare wrote, “. . . My life being made of four, with two alone sinks down to death, oppress’d with melancholy . . . .” (Shakespeare). However, only in the past few years has this

122 Sudden Death in Epilepsy: Forensic and Clinical Issues

conviction been scientiἀcally tested (Glassman and Shapiro 1998). Indeed, it has also been proved that depression is the most frequent psychiatric disorder in patients with epilepsy and that it is more common in patients with partial seizure disorders of temporal or frontal lobe origin and among patients with poorly controlled seizures. In three communitybased studies, prevalence rates of depression ranged between 21% and 33% among patients with persistent seizures and between 4% and 6% among seizure-free patients (LaFrance et al. 2008). Ettinger et al. (2005) reported the results of a population-based survey that investigated a lifetime prevalence of depression, epilepsy, diabetes, and asthma in 185,000 households. Among the 2900 patients with epilepsy, 32% reported having experienced at least one episode of depression. This contrasted with an 8.6% prevalence among healthy respondents, 13% among patients with diabetes, and 16% among people with asthma. For a long time, people speculated about whether depression increases the risk of mortality only in individuals with established coronary disease, or if those without a history of heart disease are at increased risk as well. Glassman and Shapiro (1998) concluded that both groups are at risk, but the risk is higher in groups with established coronary artery disease. This conclusion was validated in a study by Penninx et al. (2001), which concluded that, regardless of the preexistence of coronary artery disease, the effects of depression result from the same mechanisms in both groups. Because sudden cardiac death accounts for most of the excess mortality in association with depression in patients with established coronary artery disease, one should search for proarrhythmic mechanisms associated with depression (Carney et al. 2001). Multiple possibilities exist. Heart rate variability is lower in depressed than in nondepressed patients with established coronary artery disease. In addition, plasma catecholamines, known provokers of arrhythmias and sudden cardiac death, are elevated in depressed patients (Carney et al. 2001). This is also the case in epilepsy patients (Tigaran et al. 2001; Lathers et al. 1984, 2008). Especially supportive of the altered autonomic tone in depression is the study of Sheline et al. (1996) who demonstrated that patients with a history of major depression had signiἀcantly smaller hippocampal volumes bilaterally when compared with matched control subjects. The decrement in hippocampal volume correlates with the cumulative lifetime duration of major depression, possibly as result of a progressive process mediated by glucocorticoid neurotoxicity (Carney et al. 2001). This process may be responsible for an increase in corticotropin-releasing factor secretory drive and may thereby contribute to the elevated hypothalamic–pituitary–adrenal axis activity observed in depression. Corticotropin-releasing factor is also a potent stimulus for sympathetic nervous system activation, which may account for the sympathetic hyperactivity observed in major depression (Carney et al. 1999, 2001) and in epilepsy patients (Nei et al. 2000a). In concert with the hippocampal ἀndings in depression, recent imaging studies in epilepsy patients revealed the existence of similar pathological ἀndings, namely those with right temporal lobe epilepsy and depression have hippocampal atrophy that cannot be explained by epilepsy alone (Shamim et al. 2009). In this context and supportive of this theory is the recent study of Bernhardt et al. (2009), which provides a unique quantitative assessment in patients with temporal lobe epilepsy. The study indicates that regions of the brain remote from the lobe from which the seizure originates may be adversely affected with signiἀcant changes in cerebral cortical structures that may be important in the development of comorbidities (Cascino 2009). Unfortunately, the sample size was too small to allow any conclusions regarding the left side hippocampus. Until now, there have been no studies looking into the association between the size of the hippocampal sclerosis, epilepsy, and depression in SUDEP patients. The ἀndings of

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this recent imaging study (Shamim et al. 2009) may open new research avenues for a better understanding of the SUDEP phenomenon, and a possible explanation of why not all epilepsy patients have an equal risk of dying of SUDEP. Finally, depression is associated with platelet activation and with inflammatory processes that may increase the risk of developing coronary artery disease or, in patients with established coronary artery disease or myocardial infarction (Carney et al. 2001), which might also be the case in epilepsy.

7.10â•…Evidence of Cardiac Arrhythmogenic Substrate for SUDEP: The Influence of Antiepileptic Drugs on the Heart Blumhardt et al. (1986) suggested that treated patients with epilepsy had lower mean rates of the ictal cardiac acceleration than the untreated patients, whereas Opherk et al. (2002) stated that antiepileptic drug regimes were mostly similar in seizure patients with and without cardiac abnormalities. However, due to the small number of patients studied, further conclusions concerning the possible protective effect of antiepileptic drugs were precluded. Others studies evaluated the role of heart rate, but did not specify the part played by antiepileptic drugs upon the heart rate. In contradistinction to the antiepileptic drug protective role theory, Devinsky et al. (1994) showed that patients with epilepsy have greater blood pressure and heart rate variability and reactivity than control patients, with those ἀndings partly attributable to carbamazepine. Conversely, by employing the technique of the electrocardiographic late potentials (see Figure 7.2) (Tigaran et al. 2002), it has been shown, with no preference for any of the antiepileptic drugs, that all may also influence the electrical properties of the myocytes, mostly through an inactivation of the sodium channels, thus potentially precipitating cardiac arrhythmias. The electrocardiographic late potential technique was shown to reveal the presence of diseased myocardium with delayed depolarization, which may serve as the substrate for reentrant arrhythmias causing ventricular tachycardia and sudden cardiac death (Tigaran et al. 2002). Further work is needed to determine whether techniques such as signal-averaged electrocardiography (SAECG) or other, newer techniques will be useful screening tools to identify whether some persons with epilepsy are at risk for SUDEP.

7.11â•…Summary and Clinical Perspectives The concept that abnormal electrical discharges in the brain trigger cardiac arrhythmias does not seem to be widely recognized by clinicians, although it has long been proposed in the neurological literature (Blumhardt et al. 1986; Mameli et al. 2006; Jallon 1997). Unfortunately, even now, electrocardiographic recordings are not always conducted or reviewed during epilepsy monitoring. Thus, the deἀnite relationship between epileptic seizures and cardiac abnormalities is still the subject of an ongoing debate. The diversity of the methods employed in the assessment of this relationship, in contrast to the use of only a single electrocardiogram rhythm monitoring channel that is usually a supplement to the EEG recordings, along with the infrequent use of simultaneous long-term EEG-Holter recordings, presents another limitation of this type of investigation.

124 Sudden Death in Epilepsy: Forensic and Clinical Issues

Of note is the consistent lack of respiratory recordings, which need to be conducted during assessments related to electroencephalographic investigations before epilepsy surgery or admittance for differential diagnosis purposes, since apnea and hypoxia clearly represent a major contributory mechanism to the occurrence of cardiac events (Schulz et al. 2006). Nonetheless, the variable results from studies seeking a relationship between epilepsy and the risk of potentially fatal cardiac events, as discussed in this chapter, support the need for different animal models (Lathers et al. 2008, 2010, Chapter 28) that would provide comparison with clinical study data from patients with epilepsy. Also, studies addressing the association between epilepsy, depression, and cardiac abnormalities and SUDEP are deemed to be of future research importance. We need to encourage cardiologists to exercise caution when concluding from Holter monitoring alone, especially in the setting of ambulatory recordings that presumed cardiogenic arrhythmias, even when they coincide with symptoms, are the primary cause of any patient’s complaints. Only prolonged monitoring, deἀned as at least 24 h of recordings of simultaneous EEG and ECG records, will improve the diagnostic yield and, consequently, optimize the treatment of the patients with seizure-related arrhythmias and also of persons with cardiogenic arrhythmias that can result in seizure like activity. Moreover, besides the determination of the genetic etiology of epilepsy and association with depression, it would be useful to conduct collaborative studies aimed at evaluating both the epileptogenic and the cardiologic aspect of the underlying substrate that may lead to increasing the chance of potentially fatal events. Only by making both doctors and patients aware of the presence of the potential for adverse symbiosis between neurological and cardiac abnormalities will the quality of preventive services, especially as relates to SUDEP, be improved. Only time, education, and interdisciplinary joint efforts will determine whether well-conducted research will be feasible in large population samples.

Acknowledgment For valuable criticism when reviewing this book chapter, I have to thank Allan S. Jaffe, MD, Mayo Clinic, Rochester, MN.

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Forensic Postmortem Examination of Victims of Sudden Unexpected Death in Epilepsy

8

Claire M. Lathers Paul L. Schraeder Steven A. Koehler Cyril H. Wecht

Contents 8.1 Introduction 8.2 Hypothesis and Future Retrospective Studies 8.3 Speciἀc Aims 8.3.1 Year One 8.3.2 Year Two 8.3.3 Year Three 8.4 Questions for Retroprospective Postmortem Studies References

131 135 135 136 136 136 137 139

8.1â•…Introduction Evaluation of all potential cardiac risks for sudden death needs to start with detailed cardiac postmortem examinations. Detailed postmortem examinations of hearts obtained from patients with epilepsy who experienced sudden and unexpected death (SUDEP) will be helpful in identifying associated cardiac risk factors in persons with epilepsy, and also family members that could be predisposed to sudden death. A proἀle of representative pathology associated with sudden death is found in Table 8.1. Research work in the areas of SUDEP suggests that changes in autonomic peripheral and central mechanisms involved in the control and regulation of blood pressure, heart rate, and rhythm may contribute to sudden death. More speciἀcally, changes in postganglionic cardiac sympathetic discharges, which result in nonuniform neural discharges associated with epileptiform discharges, may be part of the mechanism of risk. Another major risk factor seems to be noncompliance with antiepileptic drug use. A national survey of coroners and medical examiners throughout the United States was conducted to determine their depth of understanding of causes of death in persons with epilepsy and, in particular, the phenomenon of sudden death (Schraeder et al. 2006, 2009). The survey concluded that, while there is a valid classiἀcation of SUDEP, it is not routinely used in autopsy reports of patients with known seizures who die suddenly and unexpectedly with no cause of death found on postmortem examination. Instead, the autopsy reports emphasized the negative ἀndings, i.e., that the death might have been 131

132 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 8.1â•… Pathological Findings in Victims of Sudden Death Victims of Sudden Death Victims of stress-related death (Selye 1958) 51 SUDEP cases non-East Asian subjects including indigenous Saudis, 1/1995 to 6/1995; most subcontinent Indians (43%) (Elfawal 2000) Autopsies of sudden death cases in Japan, 5/1994 to 2/1998 Of 271 cases, 176 patients (20 to 59 years old) were sudden death (Owada et al. 1999) 200 cases of sudden death in persons younger than 35 years in Veneto region, Italy – Unexplained deaths occurred in 12 cases (6%) – More than 1 in 20 cases in sudden death not explained by structural risk factors (Basso et al. 1999)

Cardiac Pathology Microscopic myoἀbrillar degeneration or myocytolysis Identical in hearts of patients dying subarachnoid hemorÂ� rhage and other acute strokes Autopsies on 22 victims 7 mild to moderate cardiac hypertrophy and 2 mild to moderate coronary stenosis 4 similar degrees of coronary narrowing but no myocardial hypertorphy Of the sudden death cases, 29 (31.9%) were due to coronary artery disease 18 (19.8%) acute cardiac dysfunction 6 (6.6%) other cardiac diseases 4 (4.4%) acute aortic dissection 163 cases (81.5%) due to cardiovascular etiologies

Obstructive coronary atherosclerosis, 23%; arrhythmogenic right ventricular cardiomyopathy, 12.5%; mitral valve prolapse 10%; conduction system abnormalities, 10%; congenital coronary artery anomalies, 8.5%; myo�carditis, 7.5%; hyper�trophic cardiomyopathy 5.5%; aortic rupture, 5.5%; dilated cardiomyopathy, 5%; nonatherosclerotic-acquired coronary artery disease, 3.5%; postoperative congenial heart disease, 13%; aortic stenosis, 2%

Pulmonary Pathology

Cerebral Pathology

Other

18 of 22 with severe pulmonary congestion and alveolar hemorrhage

10 cases (5%) due to respiratory causes

4 (4.4%) due to cardiovascular disease

30 (32.9%) due to other diseases

15 cases (7.5%) due to cerebral causes

Other causes (2%)

Pulmonary embolism, 2%

caused by a seizure disorder when there was no pathological ἀnding. Two important questions remain: 1. How do we determine if the death of a person is a sudden unexpected death? 2. How do we establish a true prevalence of the phenomenon of SUDEP?

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In addition to the need for establishing the true prevalence of the phenomenon of SUDEP is the importance of looking for evidence of the roles of the brain and the heart in the cause of death when conducting an autopsy on a person with epilepsy who has died suddenly. SUDEP refers to sudden death of an individual with a clinical history of epilepsy, in whom a postmortem examination fails to uncover a gross anatomic, toxicological, or environmental cause of death. Evidence of terminal seizure activity may not be present. In 2002, Shields et al. reported that 1–2% of natural deaths certified by the medical–legal death investigators in the United States are attributed to epilepsy and that increased microscopic examination of the brain postmortem has allowed identification of structural changes representative of epileptogenic foci. They examined 70 death cases, all with known clinical history of seizures, and classified them as: 1. Individuals who lacked a gross brain lesion 2. Those with a brain lesion demonstrable at autopsy 3. Those who lacked neuropathological evaluation because of decomposition so that only an external examination was done. Microscopic ἀndings include neuronal clusters, increased perivascular oligodendrogÂ� lia, gliosis, cystic gliotic lesions, decreased myelin, cerebellar Bergmann’s gliosis, and folial atrophy were found to be present in a higher percentage of the brains of SUDEP victims, when compared to brains from age- and sex-matched control subjects. Additional autopsy results are needed to clarify the role of changes in the heart in SUDEP. Insight into the mechanism of death in persons with epilepsy who die unexpectedly is not much greater than what it was when the ἀrst book (Lathers and Schraeder 1990b) addressed the topic of epilepsy and sudden death in 1990. This chapter emphasizes the need for clinical studies to focus on the contribution of cardiac autonomic dysfunction and/or antiepileptic drug use, with or without other drugs, to the development of cardiac abnormalities to gain an understanding of the mechanism of death in these persons. While most investigators agree that disturbance in the function of the autonomic nervous system may be a contributory cause (Han and Moe 1964; Randall et al. 1968; Lathers 1975; Lathers 1980a, 1980b; Lathers and Roberts 1985; Lathers and Spivey 1987; Spivey and Lathers 1985; Lathers et al. 1977a, 1977b, 1978; Lathers and Schraeder 1982; Lathers and Roberts 1985; Lathers et al. 1986; Lipka et al. 1988), how disruption of autonomic function contributes to the risk of death is not known. There are some clues from clinical observations. For example, the occurrence of seizures is often associated with measurable changes in cardiac conduction and rhythm. Two recent papers are relevant. The ἀrst, by Chin et al. (2004), reports myocardial infarction following brief convulsive seizures. The second paper, also by Chin et al. (2005), describes the occurrence of “postictal neurogenic stunned myocardium,” resulting from the consequence of seizures. A reversible multifocal ventricular dysfunction, developed in a nonvascular pattern, is thought to be the result of a high sympathetic tone. The initiating factor(s) for a fatal outcome in some at-risk individuals has not been deἀned. Experimental evidence indicates that cortical epileptiform activity can affect cardiac autonomic regulatory function (Lathers and Schraeder 1982; Lathers et al. 1987; Lathers and Schraeder 1990a, 1995, 2002; Lathers et al. 2003a; Lathers and Schraeder 1983, 1989, 1995, 2006, 2009; Lathers et al. 1984, 1988,

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1989, 1993, 2008a; Scorza et al. 2008; Carnel et al. 1985; Kraras et al. 1987; Stauffer et al. 1989, 1990; Suter and Lathers 1984; Tumer et al. 1985) and the integrity of pulmonary vasculature function (Simon et al. 1982; Johnston et al. 1995, 1997). In young adults with epilepsy, there is an increased risk for sudden death, often, but not always, as a function of the severity of their seizure disorder. Why there is an increased risk of presumed cardiac arrhythmia in this group is not known. Many investigators assume that death in these patients is a function of neurogenically induced cardiac arrhythmias since, in most cases, no gross pathological explanations are found on postmortem examination. However, there is a small body of literature that suggests that microscopic changes in the subendocardial region of the heart may be a contributory factor to increased risk of death in this population. Natelson et al. (1998) found irreversible pathological changes in the form of subendocardial perivascular and interstitial ἀbrosis in four of seven hearts from persons with epilepsy who died suddenly and unexpectedly. These ἀndings support the premise that patients with epilepsy who die suddenly and unexpectedly have subtle microscopic cardiac pathological conditions that may be responsible for increased risk of neurogenically induced arrhythmias. A series of questions must be addressed to focus on the issue of whether drugs are a beneἀt or a risk for SUDEP (Lathers 2002, 2003; Lathers and Schraeder 1995, 2002; Lathers et al. 2003, 2008a, 2008b; Scorza et al. 2008; Leestma et al. 1997; Schraeder and Lathers 1995). The ἀrst question is: “Do cardiac changes induced by antiepileptic drugs contribute to the risk of sudden death in persons with epilepsy?” A second question is: “Are particular combinations of antiepileptic drugs more likely to be associated with an increased risk of sudden death?” A third question to be addressed is: “Does a combination of antiepileptic drugs with other drugs, i.e., psychotropics, increase the risk of dying in a sudden, unexpected manner?” The FDA recognizes the importance of addressing this series of questions related to the use of pharmacological agents in that most of the new antiepileptic drugs have to be evaluated for the risk of SUDEP. As such, the FDA requires a statement in the package insert addressing the relative risk of occurrence of SUDEP with use of the drug. It is important for postmortem protocols to address the details of types of drugs and dosage schedules and possible adverse interactions as contributing to SUDEP. Speculation as to risk factors for SUDEP and/or contributory causes of SUDEP include the following:

1. Autonomic neurohumoral dysfunction 2. Autonomic cardiac neural dysfunction 3. Cardiac changes of subendocardial perivascular and interstitial ἀbrosis 4. Other cardiac changes (e.g., coronary heart disease, cardiomyopathy, aortic valvular stenosis, right ventricular dysplasia, postictal neurogenic stunned myocardium, coronary artery thrombosis, and postmyocardial infarction ἀbrosis 5. Cardiac changes possibly induced by antiepileptic drugs 6. The likelihood of cardiac changes being induced by particular combinations of antiepileptic drugs and associated with an increased risk of SUDEP 7. Whether a combination of antiepileptic drugs and nonantiepileptic drugs are more likely to increase the risk of dying in SUDEP (nonantiepileptic drugs are deἀned as therapeutic drugs and do include drugs of abuse)

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8. Whether an inherited predisposition to increased risk of cardiac arrhythmias (e.g., long QT and Brugada syndromes) could also be an additional risk factor in persons with epilepsy

8.2â•…Hypothesis and Future Retrospective Studies Autonomic neurohumoral and autonomic cardiac neural dysfunction, in combination with susceptibility associated with cardiac pathological changes, are hypothesized to be risk factors for the development of circumstances that predispose a person with epilepsy to sudden death. The potential risk factors of antiepileptic drug use versus nonantiepileptic drug use also must be examined. Study design should evaluate and differentiate the contribution of intrinsic parameters of autonomic dysfunction and/or cardiac pathological changes from the extrinsic parameter of therapeutic pharmacological agents (antiepileptic drugs and/or nonantiepileptic drugs). Microscopic pathological cardiac markers manifest in the heart in association with autonomic catecholamine-mediated arrhythmias and cardiac damage and/or by the administration of drugs (antiepileptic drugs and nonantiepileptic drugs should be examined). It could be assumed that catecholamine toxicity at the local level in the myocardium is a contributory factor to the development of microἀbrotic changes thought to be a predisposing risk factor for cardiac arrhythmias. Another contributory factor to cardiac arrhythmias and/or sudden death is abnormal cardiac postganglionic discharge. It is theorized that the combination of nonuniform postganglionic cardiac discharge due to abnormal anatomy of the postganglionic nerves in combination with catecholamine toxicity at the local level in the myocardium, possibly in combination with a genetically determined cardiac predisposition, are risk factors that combine to contribute to arrhythmias culminating in a fatal sudden death event. It is unclear whether or not the use of certain antiepileptic drugs such as carbamazepine compound diminish the physiologic risk factors for SUDEP (Devinsky 2004). The role of genetics in epilepsy needs to be considered when evaluating risk factors for SUDEP and/or the role of sodium channel dysfunction. The reader is referred to the following references and chapters discussing the genetics of epilepsy in this book: Chioza et al. (2001, 2002a, 2002b, 2002c), Sisodiya et al. (2007), Hindocha et al. (2008), Helbig et al. (2009), Mullen and Scheffer (2009), Herreros (2010), Ghali and Nashef (2010), and Lathers et al. (2010 Chapter 1).

8.3â•…Specific Aims Study designs should examine the potential contributory role of the following parameters to the risk of SUDEP to determine if: 1. Consistent microscopic, cardiac changes of subendocardial, perivascular, and interstitial ἀbrosis are present and may have contributed to the SUDEP. 2. Changes in postganglionic cardiac sympathetic nerves may be present. 3. Cardiac changes are induced by speciἀc antiepileptic drugs that could contribute to the risk of SUDEP.

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4. Particular combinations of antiepileptic drugs are associated with an increased risk of SUDEP. 5. A combination of antiepileptic and nonantiepileptic drugs is likely to increase the risk of SUDEP. Nonantiepileptic drugs are deἀned as therapeutic agents and will not include drugs of abuse. 6. Controls for the retrospective and prospective arms of the studies will consist of matched persons without a history of epilepsy who have died. See the chapter by Ghali and Nashef (2010) for a discussion of what genetic issues should be considered. To determine the validity of the proposed hypothesis that autonomic neurohumoral and autonomic neural dysfunction, in combination with susceptibility to cardiac pathological changes and/or the use of antiepileptic or nonantiepileptic drugs, are risk factors for the development of circumstances that predispose a person with epilepsy to sudden death, the following timeline and methodology could be used by those designing retrospective postmortem studies. 8.3.1â•…Year One During the ἀrst year, study should be devoted to analyzing retrospectively the frozen samples of heart tissue obtained from victims of SUDEP in order to determine the optimal parameters of analysis of samples obtained from the prospective arm of the study. Collection of prospectively obtained samples of cardiac tissue and preparations for postmortem examination of cardiac postganglionic innervations, using the method of Druschky et al. (2001), in persons who have died suddenly and unexpectedly should be initiated during year one. Likewise, methods should be utilized to determine the presence or absence of genetic defects at the Na+ channel level (Mullen and Scheffer 2009; Herreros 2010; Lathers and Schraeder 2010). 8.3.2â•…Year Two During the second year, the retrospective analysis should be completed and the prospective acquisition of samples should be completed. 8.3.3â•…Year Three During the third year, analysis of the pathological materials should be completed. The following analyses should be done: • Microscopic histopathology of the heart, especially the conduction system and subendocardial tissue. • Transmission electron microscopy, scanning transmission electron microscopy, scanning electron microscopy, and laser scanning fluorescence confocal microscopy. • Use 123I-metaiodobenzylguanidine-SPECT to look for sympathetic changes in the postganglionic cardiac sympathetic innervation in patients with chronic temporal lobe epilepsy, since the study of Druschky et al. (2001) suggested that altered

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postganglionic cardiac sympathetic innervation may increase the risk of cardiac abnormalities and/or SUDEP.

8.4â•…Questions for Retroprospective Postmortem Studies

1. What was the gender of the victim? 2. What was the victim’s age? 3. Did the victim of sudden, unexpected death have a known seizure disorder? 4. Was the victim witnessed exhibiting seizure(s) at the time of death? If so, what type of seizure was observed? 5. What was the actual date of death? How does the date of death for this victim compare with the date of the last known seizure? 6. Was any other cause of death found upon autopsy for any of these patients, such as cardiomyopathy and glial tumor? Did the victim have a terminal illness or any known associated illnesses? 7. What was the extent of postmortems? Were microscopic examinations done of the heart, lungs, brain, and other organs? 8. What was the microscopic pathology of the lungs and the hearts? 9. How did you interpret ἀndings of “heavy lungs” and data from hearts obtained in the postmortem autopsy? What do these ἀndings mean in terms of mechanism and signiἀcance (see Terrence 1990)? 10. Did the autopsy conduct postmortem examination of postganglionic cardiac sympathetic innervation of the heart? 11. Were quantitative antiepileptic drug levels found in the toxicological screen conducted postmortem? What assay method was used? 12. What were the actual antiepileptic drug levels postmortem? Were they within the therapeutic range or were they subtherapeutic? Were any levels below the lower level of quantiἀcation of the assay method? 13. Did the postmortem examine tears and aqueous humor or just aqueous humor for antiepileptic drug levels? 14. Were hair samples obtained to examine antiepileptic drugs? 15. Was the patient considered to be a compliant patient prior to death? 16. Was any genetic testing for entities that predispose an individual to cardiac arrhythmias done on the victim and/or the victim’s family prior to death? 17. How can the diagnosis of a seizure-induced death be differentiated from a diagnosis of a SUDEP death? 18. Was there any prior history of cardiac rhythm irregularities? 19. Was there any family history of cardiac rhythm irregularities or any history of sudden deaths?

Sympathetic changes in the postganglionic cardiac sympathetic innervation in patients with chronic temporal lobe epilepsy suggest that altered postganglionic cardiac sympathetic innervation may increase the risk of cardiac abnormalities and/or SUDEP (Druschky et al. 2001). Developmental and regulatory mechanisms determining density and pattern of cardiac sympathetic innervation are still unclear. Likewise, the exact role of innervation

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in arrhythmogenesis is unclear. The clinical study of Druschky et al. (2001) conἀrms the animal studies conducted by Lathers and colleagues (Lathers 1975, 1980a, 1980b; Lathers and Roberts 1985; Lathers and Spivey 1987; Spivey and Lathers 1985; Lathers et al. 1977a, 1977b, 1978; Lathers et al. 1986; Lathers and Schraeder 1982, 1983, 1987, 1989, 1990a, 2002; Lathers et al. 1984, 1987, 2003a, 1989, 1993, 2008a; Scorza et al. 2008; Lathers et al 2008b) in which postganglionic cardiac sympathetic neural discharge was monitored before and as arrhythmias developed. When considering likely mechanisms of SUDEP, it is important to consider whether there is any underlying, undeἀned genetic predisposition to arrhythmias and, thus, the mechanism of sudden death. Obviously, genetic predisposition to arrhythmias varies from patient to patient. The status of any subtle symptomatic disease present at the time of death will also vary from patient to patient and emphasize the importance of a genetic component to the autopsy. Animal data (Lathers et al. 1987; Staufferet al. 1989, 1990; O’Rourke and Lathers 1990; Dodd-O and Lathers 1990) demonstrated the lockstep phenomenon, i.e., postganglionic cardiac sympathetic discharge time locked to cortical epileptiform activity. The lockstep phenomenon may explain propagation of electrical impulses to autonomic nervous system regulatory centers, thus initiating arrhythmogenic potentials. During the lockstep phenomenon, cardiac postganglionic sympathetic and vagal discharges were synchronized with both ictal and interictal discharges and premature ventricular contractions, ST/T changes, and conduction blocks occurring concurrent with interictal spikes at a time when nonuniform cardiac sympathetic and vagal discharges were also observed. These experimental observations suggest that altered cardiac sympathetic innervation of hearts in patients who die suddenly and unexpectedly may contribute to nonuniform neural discharge, arrhythmias, and/or death. Detailed microscopic pathologic examination of cardiac autonomic nerves should be part of an autopsy study of SUDEP. A regulatory response, resulting from increased awareness of SUDEP, occurred in 1993 when the FDA focused the attention of practitioners and pharmaceutical manufacturers on the question of whether the use of anticonvulsant drugs contributes to or prevents sudden unexpected death in epileptic persons (Lathers 2002, 2003; Lathers and Schraeder 1995, 2002; Lathers et al. 2008a, 2008b; Scorza et al. 2008; Leestma et al. 1997; Schraeder and Lathers 1995). The FDA-convened panel of scientists considered the prevalence of sudden unexpected death in patients involved in studies associated with developing new anticonvulsant drugs and reviewed data on the risk of sudden unexpected death in patients taking lamotrigine. The risk of SUDEP was no different from that found in the young epilepsy population in general. Estimated SUDEP rates in patients receiving the new anticonvulsant drugs lamotrigine, gabapentin, topiramate, tigabine, and zonisamide were found to be similar to those in patients receiving standard anticonvulsant drugs, suggesting that SUDEP rates reflect population rates and not a speciἀc drug effect. The FDA requires warning labels on the risk of SUDEP in association with the use of each of the above-mentioned drugs. However, little data is available on the relative risk associated with the older, commonly prescribed antiepileptic drugs. The reader is referred to the chapters by Lathers and Schraeder (2010) and by Lathers, Schraeder, and Claycamp (Lathers et al. 2010) in this book for an in-depth discussion of the possible role of antiepileptic drugs in the cause and/or prevention of SUDEP. Widdes-Walsh and Devinsky (2007) discuss drug-resistant epilepsy, stating that it is a prevalent problem in spite of the fact that multiple ADE drug options are available. Mimics of drug-resistant epilepsy exist and cause diagnostic confusion. Fortunately, advances in epilepsy research and pharmacogenomics

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prove that new understandings of the mechanisms of drug resistance and tolerance allow rational antiepileptic drug strategies to prevent drug resistance. A different question regarding the clinical pharmacology of SUDEP has been raised by Tigaran and coauthors (Tigaran et al. 1997; Tigaran 2002; Tigaran et al. 2002; Tigaran et al. 2003). The question to be addressed is whether some persons with severe drug-resistant epilepsy, and without any indication of previous cardiac disease, may experience a beneἀcial effect of prophylactic treatment with cardioactive drugs to reduce the risk of sudden death (Tigaran et al. 1997). These investigators found ECG changes and ST-segment depression—many of which were closely related to the occurrence of epileptic seizures— that were suggestive of myocardial ischemia in the patients with severe drug-resistant epilepsy and no previous indication of cardiac disease. Of twelve patients with medically intractable epilepsy in studies with both ECG and EEG recordings, the ECG recording found in one person with chest pain minor yet morphologically conspicuous changes in the ECG, suggestive of myocardial infarction. This person with epilepsy died in cardiac arrest. In two publications in 2002, these authors reported atrio-ventricular block occurring as a life threatening cardiac arrhythmia complicating epileptic seizures in one person with medically intractable epilepsy (Tigaran et al. 2002) and cardiac abnormalities in patients with refractory epilepsy (Tigaran 2002). In another study, Tigaran et al. (2003b) examined 23 patients with drug-refractory epilepsy and found ST-segment depression in 40% of the patients and this was associated with a higher maximum heart rate during seizures, indicative of myocardial ischemia occurring in these individuals. These studies emphasize the importance of conducting both EEG and ECG in persons with severe drug-resistant epilepsy and the necessity of evaluating whether these patients would beneἀt from prophylactic treatment with cardioactive drugs to reduce the risk of sudden death. This chapter focuses on the need for retrospective forensic postmortem examination of not only the brains but also the hearts, myocardial autonomic innervations, and antiepileptic drug levels obtained from patients with epilepsy who die suddenly. A recent series of publications has addressed the multiple risk factors for sudden death in cardiac patients and in persons with epilepsy who have died suddenly and unexpectedly (Lathers and Schraeder 2010; Lathers et al. 2008a, 2008b; Scorza et al. 2008; (Herreros 2010). An evaluation of all potential risks for sudden death requires that risk assessments be done (Lathers 2002). These risk assessment efforts will aid all working in clinical and research ἀelds as they work to unravel the mystery of SUDEP. We recommend that retrospective postmortem examinations, including genetic determinations, be done using hearts and, of course, brains, obtained from patients who have died suddenly and unexpectedly. In addition, an effort should be made to obtain data on preexisting diatheses for cardiac arrhythmias in SUDEP victims and family members. The ἀndings from these rÂ�etrospective studies will allow prospective identiἀcation of persons in families of patients with epilepsy who have died suddenly. Finally, in the event that a physical autopsy was not conducted, the value of verbal autopsies must be determined as a relative substitute (Aspray 2005; Nashef et al. 1998; Lathers and Schraeder 2009; Nashef and Sahloldt 2010; Schraeder et al. 2010).

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142 Sudden Death in Epilepsy: Forensic and Clinical Issues Lathers, C. M., L. J. Lipka, and H. Klions. 1988. Digitalis glycosides: A discussion of the similarities and differences in actions and existing controversies. Rev Clin Basic Pharm 7 (1-4): 1–108. Lathers, C. M., A. Z. Stauffer, N. Tumer, C. M. Kraras, and B. D. Goldman. 1989. Anticonvulsant and antiarrhythmic actions of the beta blocking agent timolol. Epilepsy Res 4 (1): 42–54. Lathers, C. M., P. L. Schraeder, and N. Tumer. 1993. The effect of phenobarbital on autonomic function and epileptogenic activity induced by the hippocampal injection of penicillin in cats. J Clin Pharmacol 33 (9): 837–844. Lathers, C. M., P. L. Schraeder, and H. G. Claycamp. 2003a. Clinical pharmacology of topiramate versus lamotrigine versus phenobarbital: Comparison of efficacy and side effects using odds ratios. J Clin Pharmacol 43 (5): 491–503. Lathers, C. M., S. A. Koehler, C. H. Wecht, and P. L. Schraeder. 2003b. Forensic antiepileptic drug levels in 2001 autopsy cases of sudden, unexpected deaths in persons with epilepsy in Allegheny County Pennsylvania. Paper read at the Annual Meeting of American College of Clinical Pharmacology, September, Orlando, FL. Lathers, C. M., P. L. Schraeder, and M. W. Bungo. 2008a. The mystery of sudden death: Mechanisms for risks. Epilepsy Behav 12 (1): 3–24. Lathers, C. M., P. L. Schraeder, and M. W. Bungo. 2008b. Sudden death: Neurocardiologic mystery. In Psychological Factors and Cardiovascular Disorders, ed. L. Sher, Chapter 13. Hauppauge, NY: Nova Science. Lathers, C. M., P. L. Schraeder, and M. W. Bungo. 2010. Sodium channel dysfunction: Common pathophysiologic mechanism associated with sudden death ECG abnormalities in Brugada Syndrome and some types of epilepsy. Case histories. In Sudden Death in Epilepsy: Forensic and Clinical Issues, Chapter 20. ed. C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leestma. Boca Raton: CRC Press. Leestma, J. E., J. F. Annegers, M. J. Brodie, S. Brown, P. Schraeder, D. Siscovick, B. B. Wannamaker, P. S. Tennis, M. A. Cierpial, and N. L. Earl. 1997. Sudden unexplained death in epilepsy: Observations from a large clinical development program. Epilepsia 38 (1): 47–55. Lipka, L. J., C. M. Lathers, and J. Roberts. 1988. Does chlorpromazine produce cardiac arrhythmia via the central nervous system? J Clin Pharmacol 28 (11): 968–983. Mullen, S. A., and I. E. Scheffer. 2009. Translational research in epilepsy genetics: Sodium channels in man to interneuronopathy in mouse. Arch Neurol 66 (1): 21–26. Nashef, L., and L. Sahloldt. 2010. Bereavement and sudden unexpected death in epilepsy. In Sudden Death in Epilepsy: Forensic and Clinical Issues, Chapter 58. ed. C. M. Lathers, P.€Schraeder, M. W. Bungo, and J. Leestma. Boca Raton: CRC Press. Nashef, L., S. Garner, J. W. Sander, D. R. Fish, and S. D. Shorvon. 1998. Circumstances of death in sudden death in epilepsy: Interviews of bereaved relatives. J Neurol Neurosurg Psychiatry 64€(3): 349–352. Natelson, B. H., R. V. Suarez, C. F. Terrence, and R. Turizo. 1998. Patients with epilepsy who die suddenly have cardiac disease. Arch Neurol 55 (6): 857–860. O’Rourke, D. K., and C. M. Lathers. 1990. Interspike interval histogram characterization of synchronized cardiac sympathetic neural discharge and epileptogenic activity in the electrocorticogram of the cat. In Epilepsy and Sudden Death, ed. C. M. Lathers and P. Schraeder, Chapter 15. New York, NY: Marcel Dekker. Randall, W. C., M. Szentivanyi, J. B. Pace, J. S. Wechsler, and M. P. Kaye. 1968. Patterns of sympathetic nerve projections onto the canine heart. Circ Res 22 (3): 315–323. Schraeder, P. L., and C. M. Lathers. 1983. Cardiac neural discharge and epileptogenic activity in the cat: An animal model for unexplained death. Life Sci 32 (12): 1371–1382. Schraeder, P. L., and C. M. Lathers. 1989. Paroxysmal autonomic dysfunction, epileptogenic activity and sudden death. Epilepsy Res 3 (1): 55–62. Schraeder, P. L., and C. M. Lathers. 1995. Clinical pharmacology of antiepileptic drug use: Clinical pearls about the perils of patty. J Clin Pharmacol 35 (12): 1120–1135.

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Schraeder, P. L., K. Delin, R. L. McClelland, and E. L. So. 2006. Coroner and medical examiner documentation of sudden unexplained deaths in epilepsy. Epilepsy Res 68 (2): 137–143. Schraeder, P. L., K. Delin, R. L. McClelland, and E. L. So. 2009. A nationwide survey of the extent of autopsy in sudden unexplained death in epilepsy. Am J Forensic Med Pathol 30 (2): 123–126. Schraeder, P. L., E. L. So, and C. M. Lathers. 2010. Forensic case identiἀcation. In Sudden Death in Epilepsy: Forensic and Clinical Issues, Chapter 6. ed. C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leestma. Boca Raton: CRC Press. Scorza, F. A., R. M. Arida, and E. A. Cavalheiro. 2008. Preventive measures for sudden cardiac death in epilepsy beyond therapies. Epilepsy Behav 13 (1): 263–264; author reply 265. Shields, L. B., D. M. Hunsaker, 3rd, J. C. Hunsaker, and J. C. Parker Jr. 2002. Sudden unexpected death in epilepsy: Neuropathologic ἀndings. Am J Forensic Med Pathol 23 (4): 307–314. Simon, R. P., L. L. Bayne, R. F. Tranbaugh, and F. R. Lewis. 1982. Elevated pulmonary lymph flow and protein content during status epilepticus in sheep. J Appl Physiol 52 (1): 91–95. Sisodiya, S., J. H. Cross, I. Blumcke, D. Chadwick, J. Craig, P. B. Crino, P. Debenham et al. 2007. Genetics of epilepsy: Epilepsy research foundation workshop report. Epileptic Disord 9 (2): 194–236. Spivey, W. H., and C. M. Lathers. 1985. Effect of timolol on the sympathetic nervous system in coronary occlusion in cats. Ann Emerg Med 14 (10): 939–944. Stauffer, A. Z., J. Dodd-O, and C. M. Lathers. 1989. The relationship of the lock-step phenomenon and precipitous changes in mean arterial blood pressure. Electroencephalogr Clin Neurophysiol 72 (4): 340–345. Stauffer, A. Z., J. Dodd-O, and C. M. Lathers. 1990. Relationship of the lockstep phenomenon and precipitous changes in blood pressure. In Epilepsy and Sudden Death, Chapter 14. New York, NY: Marcel Dekker. Suter, L. E., and C. M. Lathers. 1984. Modulation of presynaptic gamma aminobutyric acid release by prostaglandin E2: Explanation for epileptogenic activity and dysfunction in autonomic cardiac neural discharge leading to arrhythmias? Med Hypotheses 15 (1): 15–30. Terrence, C. F. 1990. Unexpected, unexplained death of epileptic persons: clinical correlation including pulmonary changes. In Epilepsy and Sudden Death, ed. C. Lather and P. Schraeder, Chapter€6. New York, NY: Marcel Dekker. Tigaran, S. 2002. Cardiac abnormalities in patients with refractory epilepsy. Acta Neurol Scand Suppl 177: 9–32. Tigaran, S., V. Rasmussen, M. Dam, S. Pedersen, H. Hogenhaven, and B. Friberg. 1997. ECG changes in epilepsy patients. Acta Neurol Scand 96 (2): 72–75. Tigaran, S., H. Molgaard, and M. Dam. 2002. Atrio-ventricular block: A possible explanation of sudden unexpected death in epilepsy. Acta Neurol Scand 106 (4): 229–233. Tigaran, S., A. Cascino Fuglsang-Frederiksen, and G. D. Cascino. 2003a. Temporal distribution of partial seizures during the sleep–wake cycle: possible signiἀcance for sudden unexpected death. Epilepsia 44: 123. Tigaran, S., H. Molgaard, R. McClelland, M. Dam, and A. S. Jaffe. 2003b. Evidence of cardiac ischeÂ� mia during seizures in drug-refractory epilepsy patients. Neurology 60 (3): 492–495. Tumer, N., P. L. Schraeder, and C. M. Lathers. 1985. The effect of phenobarbital upon autonomic function and epileptogenic activity induced by hippocampal injection of penicillin in cats. Epilepsia 26: 520. Widdess-Walsh, P., and O. Devinsky. 2007. Antiepileptic drug resistance and tolerance in epilepsy. Rev Neurol Dis 4 (4): 194–202.

One-Year Postmortem Forensic Analysis of Deaths in Persons with Epilepsy

9

Steven A. Koehler Paul L. Schraeder Claire M. Lathers Cyril H. Wecht

Contents 9.1 Introduction 9.2 Methods 9.3 Results 9.4 Discussion Acknowledgments References

145 148 148 155 158 158

9.1â•…Introduction Individuals with epilepsy can die from the progression of the primary underlying brain process, status epileptics, trauma, drowning precipitated by a seizure, or causes totally unrelated to the epilepsy (Earnest et al. 1992). The medical literature reports sudden, unexpected and unexplained deaths among individuals with epilepsy (Earnest et al. 1992). This disorder has been termed sudden unexpected death in epilepsy (SUDEP). SUDEP has been deἀned as a sudden, unexpected, witnessed or unwitnessed death, nontraumatic and nondrowning, in patients with epilepsy, with or without evidence of a seizure, excluding documented status epileptics, in whom postmortem examination does not reveal an anatomical or toxicological cause of death (Nashef and Shorvon 1997). SUDEP occurs most frequently among young individuals with a history of generalized tonic-clonic seizures. SUDEP has been reported in the literature to be responsible for 1.7–17% of all deaths among individuals with epilepsy (Ficker et al. 1998; Ficker 2000). However, these prior studies to ascertain the incidence of SUDEP suffered from selection bias and methodological limitations resulting in a tenfold difference between the various studies. Populationbased and forensic (medical examiner or coroner’s office) studies are few. Postmortem examinations of victims of SUDEP fail to establish the cause of death and toxicological analysis reveals subtherapeutic antiepileptic drug blood levels (Earnest et al. 1992). Some of the commonly reported features of SUDEP are highlighted in Table 9.1. Previous postmortem-based studies have reported the following changes. The brains in these series showed increased weight. The cerebral hemispheres were anemic and congested, and there were signs of hypoxia in the hippocampal regions. The hearts showed 145

146 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 9.1â•… Characteristics of SUDEP Characteristics History of epilepsy Age Sex Race Seizure event Death Location found dead Postmortem ἀndings Toxicological ἀndings

Features of SUDEP Victims 8–17% of deaths Average age is 28–35 years, rare in children Number of male victims is twice the number of female victims More frequent among blacks Witnesses to the seizure event are rare Occurred within minutes Bed Autopsies do not reveal a cause of death Heavier than normal weights of the heart, lungs, and liver Postmortem antiepileptic drug (AED) levels were either subtherapeutic or absent

ἀbrosis localized in the conductive system around the atrioventriclular bundle, edema of the conductive tissue, perivascular and interstitial ἀbrosis, and reversible myocyte vacuolization. The lungs showed increased weight, mild to moderate pulmonary edema, and alveolar hemorrhage (Leestma et al. 1989; Terrence et al. 1981; Jallon 1999; So 2008). The livers showed increased weight and venous congestion (Leestma et al. 1989). Leestma stated that the degree of passive congestion in both the liver and lungs, as well as the edema in the lungs, suggests some element of acute backward cardiac failure in SUDEP cases (Leestma 1990). The true incidence of SUDEP is not known and the estimates vary greatly. Possible reasons for this may be linked to the fact that SUDEP is not a diagnosis as such, since it is assigned when all other possible diagnoses have been eliminated, making it a default label. Another may be the general lack of understanding by medical examiners and coroner’s office personnel of what deἀnes a SUDEP death and when they should list it on the death certiἀcate. One method of investigating the protocol used within a medical examiner’s or coroner’s office regarding SUDEP deaths is to examine the death scene investigation, the autopsy and toxicology results, and the resulting death certiἀcate. In addition, by examining all the deaths at the medical examiner’s or coroner’s office and calculating the number of deaths that conform to the SUDEP deἀnition, an approximate incidence rate of SUDEP can be ascertained. All deaths that are sudden, unexpected, and unexplained by past medical history are investigated by the medical examiner or coroner’s offices. They typically conduct a detailed death scene investigation, a forensic autopsy, and a toxicological analysis of the body fluids. The level of investigation and the anatomical and toxicological data collected by the medical examiner or coroner’s office offer investigators studying SUDEP a wealth of information. The Allegheny County Coroner’s Office was selected for several reasons. First, it was the site of a previous examination of SUDEP death and, second, the forensic examination of these types of deaths involves a thorough death scene investigation, complete postmortem examination, and a comprehensive toxicological analysis of body fluids. The ἀrst study to examine SUDEP deaths at the Allegheny County Coroner’s Office was a retrospective study conducted in 1981 (Terrence et al. 1981). The study examined SUDEP cases that occurred between January 1, 1978 and December 31, 1979 and located a total of 8 cases: 4 male, 4 female, 4 white, and 4 black, ranging in age from 9 to 31 years. The pathological ἀndings at autopsy are shown in Table 9.2 (Terrence et al. 1981). While, the

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147

Table 9.2â•… Pathological Findings Heart Weight Normal Weight Range (250–350 g)

Combined Lung Weight Normal Weight Range (650–1140 g)

1 2 3 4 5

275 400 360 370 200

1090 850 800 1250 755

6 7 8

374 300 110

1325 930 350

Patient Number

Neuropathological Findings None Cerebral edema None None Old contusion of L temporal pole, olfactory bulb, and orbitofrontal surfaces None None Cerebral edema

Source: Terrence, C. F., Rao, G. R., and Perper, J. A., Ann Neurol, 9 (5), 458–464, 1981.

normal heart weight by sex could not be calculated, using the overall range of 250–350€g as the normal heart weight, 50% of the cases had an enlarged heart (Cotran et al. 1994). No signiἀcant abnormalities in the brain were noted. Using the range of 650–1140 g as a normal weight range of the combined lung weight, 25% of the cases had heavy lungs. The type, number of prescription medications, and the postmortem blood levels are shown in Table 9.3 (Terrence et al. 1981). Phenytoin and phenobarbital was prescribed to all 8€patients,€primidone prescribed to 4, and carbamazepine, valproic acid, and mephenytoin prescribed to one patient. Toxicological analysis revealed subtherapeutic or absent blood levels of phenytoin in 7 cases and phenobarbital in 4 out of the 8 cases. Levels for carbaÂ� mazepine, valproic acid, and mephenytoin were also measured postmortem. The purpose of the current study was to present an overview of all deaths examined at the Allegheny County Coroner’s Office among individuals with epilepsy in AlÂ�Â� legheny County during 2001, to describe epidemiological, anatomical, pathological, and Table 9.3â•… Prescribed Medications and the Postmortem Drug Levels Patient Number 1 2 3 4 5 6 7 8

Postmortem Drug Levels Drug Prescribed Phenytoin, phenobarbital Phenytoin, phenobarbital, primidone Phenytoin, phenobarbital, primidone Phenytoin, phenobarbital, primidone Phenytoin, phenobarbital, primidone Phenytoin, phenobarbital Phenytoin, phenobarbital Phenytoin, phenobarbital, carbamazepine, valproic acid, mephenytoin

Phenytoin

Phenobarbital

Other

None detected None detected

None detected None detected

None detected None detected

None detected

Therapeutic

None detected

Subtherapeutic

Therapeutic

None detected

Therapeutic

Therapeutic

None detected

None detected Subtherapeutic None detected

None detected Subtherapeutic Therapeutic

None detected None detected None detected

Source: Terrence, C. F., Rao, G. R., and Perper, J. A., Ann Neurol, 9 (5), 458–464, 1981.

148 Sudden Death in Epilepsy: Forensic and Clinical Issues

toxicological features of each SUDEP case, and to determine if SUDEP is present on the death certiἀcates issued by the coroner’s office.

9.2â•…Methods The Allegheny County Coroner’s Office has jurisdiction to investigate all deaths within Allegheny County, which is located in western Pennsylvania and encompasses a population of ~1.2 million individuals. All deaths investigated by the Allegheny County Coroner’s Office were reviewed from January 1, 2001 to December 31, 2001. This office investigates more than 6000 cases and conducts more than 1200 autopsies annually. All cases were identiἀed by conducting a computer and hand search of all the case reports by the Chief Forensic Epidemiologist (SAK) for all deaths with the words “seizure disorders,” “epilepsy,” or “SUDEP” appearing in Part I or Part II of the death certiἀcate. The following epidemiological information was collected: age, sex, race, time and date last seen alive, and the time and date of death. Seizure-related information collected included past medical€ history, prescribed medications, and who witnessed the event. Pathological information collected included the weights of the internal organs obtained from the forensic autopsy report. The normal weight parameters of the internal organs are based on published data and, where possible, separated by age and sex. Toxicological analysis was conducted on the blood, bile, urine, and eye fluid recovered during the autopsy. The blood used for the toxicological analysis was collected from the heart during the autopsy. The number and level of drugs detected in the body fluids were obtained from the toxicological report. The data was entered and analyzed by Statistical Package for the Social Sciences® (11.0 Chicago, IL). The anatomical and toxicological data for all deaths with a diagnosis of epilepsy were summarized. Based upon the summarized data, the cases that meet the classiἀcation criteria for SUDEP were determined.

9.3â•…Results A total of 12 deaths were identiἀed in which seizure disorder was listed as either the immediate cause of death or contributed to the death during the study period. Epidemiological characteristics are shown in Table 9.4. Among the 12 cases, 58.3% were male, 41.7% were female, and all cases were white. All cases were between the ages of 38 and 54 years old with the mean age of the males being slightly higher than that of the females. Overall, more than 90% of the seizures were unwitnessed events. The only witnessed seizure was that of a 42-year-old female. She was in her residence when she had a sudden seizure and became unresponsive. She was pronounced dead at the emergency room one hour after the seizure. Among the males, four were found in their bathroom and three in bed. Among the females, all were found in their residence (one on the kitchen floor, one on the bed, one in a chair, and one outside on the rear deck). Deaths were most frequent in January among the males and in September for the females. According to information contained within the death investigation report, all 12 cases had a past medical history for either a diagnosis of seizures or epilepsy. All cases would be considered as having a seizure disorder. A complete postmortem examination was conducted on all but one case, due to an advanced level of decomposition.

One-Year Postmortem Forensic Analysis of Deaths in Persons with Epilepsy

149

Table 9.4â•… Epidemiological Characteristics: Age, Sex, Race, Seizure Events, Month of Event, Medical History, and Type of Postmortem Examination Epidemiological Characteristics Total number of cases (all were Caucasian) Age range (mean) Seizure event witnessed Month of seizure

Medical history of seizures disorder or epilepsy Manner of death Type of postmortem examination a

Males

Females

7 38–50 (x = 45.4) Yes: 0 No: 7 January: 3 February: 1 March: 1 August: 1 October: 1 Yes: 7

5 39–54 (x = 44.8) Yes: 1 No: 4 June: 1 July: 1 August: 1 September: 2

Natural: 6 Accident: 1 Complete: 6 External only: 1a

Natural: 5

Yes: 5

Complete: 5 External only: 0

Decomposed.

An examination of the information contained on Part I or Part II of the death certiἀcate by sex is shown in Tables 9.5 and 9.6. The immediate cause of death is the event that directly and immediately resulted in the death. The contributory cause of death consists of conditions that play a role in causing the death, but do not cause immediate death. The section criteria for this study included any death where seizure disorder appeared on the death certiἀcate. Seizure disorder was listed as the immediate cause of death in 83.3% of the cases (6 males and 4 females), cardiomyopathy was listed in one male case, and a glial brain tumor was listed in one female case (Tables 9.5 and 9.6). Among males, seizure disorder was the immediate cause of death among 6 of the 7 deaths. In Male Case #7, the seizure disorder was considered by the forensic pathologist conducting the examination to have played a signiἀcant role in contributing to the death. The manner of death was ruled natural in six cases (85.7%) and accidental in one (14.3%). Among the females, seizure disorder Table 9.5â•…Immediate and Contributory Causes of Death for Males Death Certiἀcate Part I Immediate cause of death

Part II Contributory cause of death

Case No. 1

2

3

Seizure Seizure Seizure disorder disorder disorder (clinical)

4 Seizure disorder

5 Seizure disorder

6 Seizure disorder

Chronic Liver Liver Chronic cirrhosis cirrhosis obstructive obstructive disease pulmonary pulmonary disease disease

7 Dilated cardiomyopathy with arteriosclerotic cardiovascular disease, acute pneumonia, emphysema Seizure disorder

150 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 9.6â•…Immediate and Contributory Causes of Death for Females Case No.

Death Certiἀcate Part I Immediate cause of death

1

2

Seizure disorder

Seizure disorder (clinical)

3

4 Seizure disorder with hypertensive and arteriosclerotic cardiovascular disease

Seizure disorder (clinical) with arteriosclerotic cardiovascular disease

5 Convulsive seizure developed from grade II glial tumor

Part II Contributory cause of death

was the immediate cause of death among four of the ἀve deaths. In one case, the immediate cause of death was a convulsive seizure that developed in association with a grade II glial tumor. The manner of death was ruled natural in all ἀve cases. Overall, the incidence of death in persons with a history of seizures in which no cause of death was found on postmortem was 0.83% (10 in 1200 autopsies). The 2001 Allegheny County Coroner’s data found 0.833% (10 of 1200) of the autopsy cases met SUDEP criteria. Among the 12 cases, 85.7% (six of all males) and 80% (four of all females) represented SUDEP deaths. Autopsies were performed on all ἀve females and six of the seven males. The weights of the internal organs were available in 92% of the cases. The weights of the hearts, thicknesses of the left ventricles, lungs, and brains, and brain pathologies by sex are shown Table 9.7â•…Observed and Normal Organ Weights of the Heart, Lungs, and Brain by Sex

Sex

Weight (lb)

Heart Weight (g) (Normal Weight)a

Left Ventricle Thickness (cm)

Combined Lung Weight (g)b

Brain Weight (g)c

Male

118

310 (281)

1.2

1440

1070

121 131 145 240

445 (292) 360 (302) 400 (317) 455 (406)

1.4 1.2 1.2 1.5

1095 1200 1510 955

1240 1275 1760 1570

268 99.5 108 160 226

575 (432) 300 (230) 345 (243) 445 (284) 395 (329)

1.6 1.5 1.2 1.7 1.2

2065 915 550 1055 975

1760 1215 1205 1450 920

300

400 (371)

1.4

970

1365

Female

a b c

Normal heart range (mean expected heart weight based on body weight and sex). Normal combined weights of lungs: males, 720–1140 g; females: 650–960 g. Normal brain weights: males, 1100–1700 g; females: 1050–1550 g.

Brain Pathology Craniotomy, patchy subarachnoid hemorrhage Normal Slight swelling Normal Congestion, periventricular white matter Normal Chronic mild swelling Normal Normal Small crowded gyri, w/o atrophy Congested, mild swelling

One-Year Postmortem Forensic Analysis of Deaths in Persons with Epilepsy

151

700 600 500 400

Actual

300

Normal

200 100 0 1

2

3

4

5

6

Figure 9.1╇ Normal and actual heart weight (g) among males.

in Table 9.7. The normal ranges of the internal organs are also shown in Table 9.7. The observed weight of the heart was above the expected mean weight based on body weight and sex in all cases. Figures 9.1 and 9.2 show the normal and actual heart weights among males and females, respectively. The normal range was based on the weight and sex of the subjects. The weight of the heart was above the expected weight, after adjusting for body weight and sex in all cases. Left-ventricle hypertrophy was seen in two cases. The combined weight of the right and left lungs showed that more than 66% of the male and 60% of the female lungs exceeded normal parameters. The normal range of combined lung weights was based on sex. The mean weight for all the female lungs was normal (449.2 g), while that of the males was elevated (688.75 g). Figures 9.3 and 9.4 show the weight of the normal and actual combined lung weights by sex. Among males, the combined lung weight exceeds the upper limits of normal in four cases. Among females, the combined lung weight exceeds the upper limits of normal in three cases and dropped below the lower limits in one case. Examinations of the brains of the males showed that 33% were above normal limits, 50% were within normal limits, and 16% were below. The normal range of brain weights was based on sex. Examinations of the brains of the females showed that 80% were within

500 450 400 350 300

Actual

250

Normal

200 150 100 50 0 1

2

3

4

Figure 9.2╇ Normal and actual heart weight (g) among females.

5

152 Sudden Death in Epilepsy: Forensic and Clinical Issues 2500 2000 Actual

1500

Lower Limit Upper Limit

1000 500 0 1

2

3

4

5

6

Figure 9.3╇ Actual and normal upper and lower ranges of the combined weight of lungs (g) among males.

normal limits and 16% were below. Figures 9.5 and 9.6 show the normal and actual brain weight by sex. In the male group, the past medical history, prescribed medications, drugs identiἀed by the toxicology screen, level of postmortem compounds, and pathological factors are shown in Table 9.8. All seven had a history of seizures or epilepsy disorder. In ἀve cases (71%), antiepileptic drugs were prescribed (clonazepam, phenytoin). The death scene investigation failed to ascertain a list of prescription medications in two deaths. Toxicological analysis revealed that AED medications were detected in 57% of the cases, with phenytoin the most frequently detected. All the detected AED were at subtherapeutic levels. In only one case was the toxicological analysis negative. The bodies in three of the cases were in varying stages of decomposition. In the female group, the past medical history, prescribed medications, drugs identiἀed by the toxicology screen, level of postmortem compounds, and pathological factors are shown in Table 9.9. All cases had a past medical history of seizures. In two cases (40%), medications for seizures were prescribed (Dilantin, Lamotrigine, Tegretol). The death 1200 1000 800

Actual Lower Limit

600

Upper Limit

400 200 0 1

2

3

4

5

Figure 9.4╇ Actual and normal upper and lower ranges of the combined weight of lungs (g) among females.

One-Year Postmortem Forensic Analysis of Deaths in Persons with Epilepsy

153

2000 1800 1600 Male

1400

Lower Upper

1200 1000 800

118

121

131

145

240

268

Figure 9.5╇ Actual and normal upper and lower ranges of brain weight (g) among males by body weight (lb).

scene investigation failed to ascertain a list of prescription medications in one death. Toxicological analysis revealed that AED medications were detected in 60% of the cases, with phenytoin the most frequently detected. Toxicological analysis showed that the AED medications were at therapeutic levels in three, subtherapeutic in one, and above the therapeutic level in one case. Even though all the female cases had a diagnosis of seizure disorder, no information was collected as to why three of them were not taking any antiepileptic medications. This omission is one of the pitfalls of a retrospective study. This category of information (i.e., why a person with a diagnosis of epilepsy is not on medication) should be a speciἀc issue addressed in future studies.

1600 1500 1400 1300

Female

1200

Lower

1100

Upper

1000 900 800

99.5

108

160

226

300

Figure 9.6╇ Actual and normal upper and lower ranges of brain weight (g) among females by body weight (lb).

154 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 9.8â•… Medical History, Prescribed Medication, Toxicology Screen, and Pathological Features among Males

Medical History

Prescribed Medications

Drugs Identiἀed (with Levels) in Toxicology Screen (AED Drugs in€Bold)

Seizures

Dilantin

Acetone (6 mg%) Alcohol (5 mg%)

Seizures

Prinvil Clonazepam K-Dur Oramorph Depo Medrol Provential inhaler

Doxylamine (0.014 mg%) Benzodiazepines: ╇ Nordiazepam (0.01€mg%) ╇ Chlordiazepoxide (0.013 mg%) ╇ Demoxepam (0.023 mg%) ╇ Oxazepam (0.010 mg%) ╇ Clonazepam (too low to quantify) Morphine (0.087 μg/mL) Dextromethorphanpositive Ibuprofen-positive Diphenhydraminepositive Phenytoin (8.31 μg/mL)

Seizures

Dilantin

DVT, seizures, alcoholism

Dilantin Keflex

None detected

Seizures, alcoholism

Celexa Neurontin Phenytoin Indomethacin Unknown

Ethanol (0.04%) Phenytoin (1.05 μg/mL)

HIV, seizures, chronic lung disease Bipolar depression Epilepsy, depression

Unknown

Citalopram-positive Desmethylcitaloprampositive Ethanol (0.02%) Phenytoin (2.45 μg/mL) Olanzapine (0.041 mg%) Sertraline (0.021 mg%) Valproic acid (TDX) (8.99 μg/mL)

Levels of Postmortem Compounds — —

Above therapeutic levels Therapeutic level Subtherapeutic level — Subtherapeutic level — Subtherapeutic level — — — Subtherapeutic level —

— Subtherapeutic level — — — Subtherapeutic level Above therapeutic level Therapeutic level Subtherapeutic level

Pathological Features Alive: 1/7/01 Found dead: 1/11/01 12:30 p.m. Body moderately decomposed Alive: 1/17/01 4:30€p.m. Dead: 1/18/01 12:30 p.m.

Alive: 1/18/01 7:30€a.m. Found dead: 1/18/01 4:50 p.m. Alive: 2/11/01 1:00€a.m. Found dead: 8:00€p.m. Decomposed

Putriἀcation

Alive: 10/16/01 11:00 p.m. Found dead: 10/16/01 12:00€p.m.

One-Year Postmortem Forensic Analysis of Deaths in Persons with Epilepsy

155

Table 9.9â•… Medical History, Prescribed Medication, Toxicology Screen, and Pathological Features among Females

Medical History

Prescribed Medications

Drugs Identiἀed in Toxicology Screen (AED Drugs in Bold)

Level of Postmortem Compounds Subtherapeutic level Therapeutic level Subtherapeutic level Above therapeutic level

Hysterectomy, seizures

Dilantin Lamotrigine

Phenytoin (5.36 μg/mL) Lamotrigine (0.79 mg%) Ibuprofen (0.81 mg%)

Seizures

Neurontin Tegretol Dilantin

Clonazepram (8.37 μg/ mL)

Amyotrophic lateral sclerosis, depression, seizures

Bupropion Ditropanxl Zanaflex Baclofen Rilutek Unknown

Bupropion (0.006 mg%) Threoaminobupropionpositive

Therapeutic level —

Trazodone (0.296 mg%) Venlfaxine (0.175 mg%) O-Desmethylvenlafaxine (0.025 mg%) Carbamazepine (4.56 μg/mL) Phenytoin (14.68 μg/ mL) Butalbital (0.246 mg%) Acetaminophen (14.05 mg%)

Therapeutic level Therapeutic level —

Diabetes, ╇ seizures, ╇ hypertension, ╇ asthma Hypertension, ╇ seizures, TMJ, ╇ osteoporosis, ╇ cervical fusion ╇ psychiatric history

Prempro Gybutynin Butslbitalapac-caff-tap

Therapeutic level Therapeutic level Subtherapeutic level Nearly toxic

Pathological Features Alive: 6/7/01 evening Found dead: 6/8/01 3:30 p.m. Alive: 7/6/01 12:20€a.m. Found dead: 7/6/01 12:21 a.m. Witnesses to seizure Alive: Unknown Found dead: 8/7/01 5:37 p.m. Moderate putriἀcation Alive: 9/28/01 11:30€p.m. Found dead: 9/29/01 9:31 a.m. Alive: 9/4/01 2:30€p.m. Found dead: 9/5/01 11:32 p.m.

9.4â•…Discussion The sudden and unexpected deaths among individuals with a history of epilepsy are cases that fall under the jurisdiction of the medical examiner or coroner’s office for a forensic investigation. These investigations involve a detailed review of the victims’ past medical history, a list of current medications with dosage levels, and a determination of the events immediately surrounding the time of death. The body, in most cases, also undergoes a complete forensic autopsy and toxicological analysis. All these factors can provide a fairly accurate representation of the events at the time of death, including any anatomical or disease processes that might have contributed to the death and the circulating blood levels of any medications or other compounds at the time of death. Therefore, those studying SUDEP via forensic data will be provided with not only the circumstances surrounding the death, but the weights and state of the internal organs, and a detailed toxicological analysis of the body fluids. The difficulty is locating these types of cases within the medical examiners’ or coroners’ ἀles. When medical examiner’s or coroner’s offices are confronted with a death where the autopsy and toxicological analyses fail to identify a speciἀc cause of death, and that individual has a well-documented history of seizures, the cause of death on the death certiἀcate would be listed as seizure disorder and not as SUDEP. A lack of any other

156 Sudden Death in Epilepsy: Forensic and Clinical Issues

explanation for the cause of death indicates that these victims should be considered more appropriately as having a deἀnite classiἀcation of SUDEP. However, some authors have highlighted concerns with the death certiἀcate generated from the medical examiner and coroner data. If the diagnosis of epilepsy and/or seizure disorder is not stated on death certiἀcates with accuracy, many SUDEP deaths will go undetected. Coyle et al. (1994) examined 40 cases of SUDEP identiἀed in the United Kingdom in 1992. Postmortem reports and witness statements were examined to look at the accuracy of the coroners’ diagnoses. In 70% of those cases, the type of seizure either was not known or was not referred to. The review also found inconsistent reports of the position of the victim’s body, examination of the organs, especially the brain, details of the medication history, and the toxicology examinations conducted. Epilepsy or seizure disorder as an attributed cause of death was used in less than half of the cases even though the victims had a history consistent with this diagnosis. All of these ἀndings raise issues of the quality of data included in postmortem reports. Within the United States, the majority of medical examiners’ and coroners’ offices traditionally list such deaths as seizure disorders rather than epilepsy. This practice of not using the diagnosis of SUDEP on the death certiἀcate is not due to a lack of understanding or acknowledgment of SUDEP as a valid classiἀcation of the cause of death. The lack of utilization of SUDEP as a ἀnal diagnosis in appropriate cases is in agreement with data obtained in a recent nationwide survey (Schraeder et al. 2006) that found most medical examiners and coroners did not use the diagnosis of SUDEP when entering the cause of death on the death certiἀcate in those seizure disorder cases where no cause of death was identiἀed on postmortem. This lack of use of SUDEP on the death certiἀcates results in an underreporting of SUDEP and overreporting of deaths from seizure disorder. This study highlights the increased need to educate medical examiners’ and coroners’ offices regarding when the category of SUDEP should be used. Forensic pathologists face their greatest challenge when attempting to determine causes of death that rely on exclusion criteria, such as in SUDEP. In these types of cases it is important for the examination to attempt to rule out other possible causes before classifying the death as SUDEP on the death certiἀcate. In a case that is likely to be SUDEP, the following should be part of the standard protocol. First, conduct a detailed death scene investigation with an emphasis on collecting prescription medicines at the residence. Second, obtain a detailed past medical history with a thorough review of the medical history. Third, conduct a meticulous forensic autopsy with a comprehensive examination of the heart and its conductive system. Finally, review the results of the toxicological analysis of the body fluids with special attention to the postmortem levels of AED medications. When comparing the results of the study conducted in 1981 (Terrence et al. 1981) with our data, there were some similarities and some differences. Enlarged hearts were reported in 50% of the victims in the earlier study; our study reported that all victims had an enlarged heart. However, a retrospective case control study in a medical examiner’s population by Davis and McGwin (2004) found no difference in mean heart mass between the two groups. With increasing age, they did ἀnd competing causes of death in patients with epilepsy. Their ἀndings support the concept that SUDEP occurs in young adults. Opeskin et al. (2000) conducted cardiac pathology exams in 10 victims of SUDEP and in 10 controls. They found no abnormalities in the conduction system nor in the other cardiac pathological parameters studied. In contrast, the ἀndings in our study showed above-normal heart weights. Other studies found cardiac pathological changes obtained

One-Year Postmortem Forensic Analysis of Deaths in Persons with Epilepsy

157

Table 9.10â•… Questions to Be Asked by Death Investigators Relating to Possible Seizure-â•›Related Deaths Questions 1 2 3 4 5 6 7 8 9 10

Was the deceased diagnosed with a seizure disorder? At what age was the deceased diagnosed with a seizure disorder? Was the deceased taking any antiepileptic drugs? Do you have a list of the deceased’s antiepileptic drugs? Was the deceased compliant with taking his/her medication? What was the date of the deceased’s last seizure? Were the deceased’s seizures well-controlled? Is there a family history of seizures in the deceased’s family? When was the last time the deceased took his/her antiepileptic drugs? Do you have the name of the deceased’s treating physician?

from SUDEP victims. George and Davis (1998) looked at the pathology of arrhythmogenic right ventriclular cardiomyopathy/dysplasia. Inflammatory inἀltrates (i.e., lymphocytes) were observed in 60% of cases while myocyte necrosis was found in only one case. In the current study, 63% of the deaths had above-normal lungs weights while the earlier data reported that only 25% had heavy lungs. Both studies showed that the levels of AED medications detected during toxicological analysis were typically at the subtherapeutic level, or absent entirely. In this study, 7 of the 12 deaths were determined to have occurred in patients who had been prescribed anticonvulsant medications. Based on the postmortem analysis for antiepileptic drugs, ἀve were at subtheraputic levels, one was within the therapeutic range, one was€above therapeutic levels, and ἀve were totally absent of antiepileptic drugs. Based on these results and supported by the Terrence et al. (1981) study, a high percentage were either due to individuals being noncompliant with their medications or the detection methods of the antiepileptic drugs; levels in postmortem samples were below the lower limit of quantiἀcation of the assay method. The issue of using postmortem blood to estimate the circulating blood level in the living due to the phenomena of redistribution is a concern in forensic€toxicology. In this study, all the analyses were conducted on blood collected from the chambers of the heart. This blood typically shows a higher concentration of the drug than does peripheral blood. Therefore, the recoded levels of the antiepileptic drugs were lower in the circulating blood, meaning that the individuals with subtherapeutic heart blood levels have an even lower level of the drug in their circulating blood. The current observation of increased lung weights has also been reported to be present in SUDEP by other investigators. Noncompliance of anticonvulsants has been suggested as a risk factor for neurogenic pulmonary edema and the ἀnding of pulmonary edema is thought to be associated with an adrenergic component in the death event (Lathers and Schraeder 2002; Tomson et al. 2005; Hughes 2009). For future studies, there is a need to have more detailed data collection, for example, about seizure types, the premorbid antiepileptic drug levels, the general level of compliance, and any stressful circumstances preceding death. In essence, the need for detailed information could be obtained with oral autopsy data (Lathers and Schraeder 2009). Finally, there is a need to emphasize the importance of prospective data collection. Those investigating a possible death related to a seizure-related medical history should obtain a detailed description of the events leading up to the death from the next of kin and obtain all medical records and a complete list of prescription

158 Sudden Death in Epilepsy: Forensic and Clinical Issues

medications. To ensure that the important information is ascertained, Table 9.10 lists the key questions.

Acknowledgments The authors thank Shaum Ladham, MD, Leon Rozin, MD, Abdulrezak Shakir, MD, and Joseph Dominick, RN, LFD, for technical support in the data collection process.

References Cotran, R. S., V. Kumar, S. L. Robbins, and F. J. Schoen. 1994. Robbins Pathological Basis of Disease, 5th ed. Philadelphia, PA: W. B. Saunders. Coyle, H. P., N. Baker-Brian, and S. W. Brown. 1994. Coroners’ autopsy reporting of sudden unexplained death in epilepsy (SUDEP) in the UK. Seizure 3 (4): 247–254. Davis, G. G., and G. McGwin Jr. 2004. Comparison of heart mass in seizure patients dying of sudden unexplained death in epilepsy to sudden death due to some other cause. Am J Forensic Med Pathol 25 (1): 23–28. Earnest, M. P., G. E. Thomas, R. A. Eden, and K. F. Hossack. 1992. The sudden unexplained death syndrome in epilepsy: Demographic, clinical, and postmortem features. Epilepsia 33 (2): 310–316. Ficker, D. M. 2000. Sudden unexplained death and injury in epilepsy. Epilepsia 41 (Suppl 2): S7–S12. Ficker, D. M., E. L. So, W. K. Shen, J. F. Annegers, P. C. O’Brien, G. D. Cascino, and P. G. Belau. 1998. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology 51 (5): 1270–1274. George, J. R., and G. G. Davis. 1998. Comparison of anti-epileptic drug levels in different cases of sudden death. J Forensic Sci 43 (3): 598–603. Hughes, J. R. 2009. A review of sudden unexpected death in epilepsy: Prediction of patients at risk. Epilepsy Behav 14 (2): 280–287. Jallon, P. 1999. Sudden death of epileptic patients. Presse Med 28 (11): 605–611. Lathers, C. M., and P. L. Schraeder. 2002. Clinical pharmacology: Drugs as a beneἀt and/or risk in sudden unexpected death in epilepsy? J Clin Pharmacol 42 (2): 123–136. Lathers, C. M., and P. L. Schraeder. 2009. Verbal autopsies. Epilepsy Behav 14: 573–576. Leestma, J. E. 1990. Sudden unexpected death associated with seizures: A pathological review. In Epilepsy and Sudden Death, ed. C. M. Lathers and P. L. Schraeder. New York, NY: Marcel Dekker. Leestma, J. E., T. Walczak, J. R. Hughes, M. B. Kalelkar, and S. S. Teas. 1989. A prospective study on sudden unexpected death in epilepsy. Ann Neurol 26 (2): 195–203. Nashef, L., and S. D. Shorvon. 1997. Mortality in epilepsy. Epilepsia 38 (10):1059–1061. Opeskin, K., A. Thomas, and S. F. Berkovic. 2000. Does cardiac conduction pathology contribute to sudden unexpected death in epilepsy? Epilepsy Res 40 (1): 17–24. Schraeder, P. L., K. Delin, R. L. McClelland, and E. L. So. 2006. Coroner and medical examiner documentation of sudden unexplained deaths in epilepsy. Epilepsy Res 68 (2): 137–143. So, E. L. 2008. What is known about the mechanisms underlying SUDEP? Epilepsia 49 (Suppl 9): 93–98. Terrence, C. F., G. R. Rao, and J. A. Perper. 1981. Neurogenic pulmonary edema in unexpected, unexplained death of epileptic patients. Ann Neurol 9 (5): 458–464. Tomson, T., T. Walczak, M. Sillanpaa, and J. W. Sander. 2005. Sudden unexpected death in epilepsy: A review of incidence and risk factors. Epilepsia 46 (Suppl 11): 54–61.

Drug Abuse and SUDEP Steven B. Karch

10

Contents 10.1 Introduction 10.2 Channelopathies and Abused Drugs 10.2.1 QT Interval Prolongation 10.2.2 QT Shortening 10.3 QT Dispersion 10.4 Abnormal Catecholamine Metabolism References

159 161 161 164 164 165 165

10.1â•…Introduction Nearly a quarter century ago, Leestma et al. (1985) described the ἀndings seen at autopsies of 66 epileptics who had died unexpectedly during or just after experiencing a seizure. The autopsy ἀndings were insufficient to explain the cause of death in any of the cases. The syndrome of sudden death during or immediately after a seizure has come to be called sudden unexplained death in epilepsy (SUDEP). Over a 10-year period, the mean age of epileptics with SUDEP in Leestma’s studies was 31.4 years. Of these, 37% were found dead in bed, 49% were black males, 25% were white males, 11% were black females, and 15% were white females ranging in age from 10 months to 60 years (mean age, 28 years); nearly half of the decedents were found “dead in bed,” a description that applies equally well to deaths from long QT syndrome (LQTS), an entity due to heritable channelopathies (Ackerman et al. 2001), or to diabetes with hypoglycemia (Rothenbuhler et al. 2008; Tu et al. 2008). By convention, the abbreviation sudden unexplained death syndrome (SUDS) is used to describe the death of anyone older than 2 years who dies in this fashion, whereas for children 2 years and younger, the diagnosis that is used is sudden infant death syndrome (SIDS). More recently, a similar syndrome has been recognized in young diabetics (Gill et al. 2009). As with SUDEP, the cause of death is not apparent in any of these disorders, although it seems probable that an explanation is to be found only at the molecular level. One popular hypothesis holds that SUDEP victims may have died because of QT interval prolongation (QTd) and that SUDEP is just another variety of LQTS. The presence of prolonged QT intervals reflects delayed cardiac repolarization. It can be caused by a variety of different abnormalities, including acute hypoglycemia, superimposed upon the presence of cardiac autonomic neuropathy (Tu et al. 2008). This process may account for the death of young diabetics as noted above, although why the QT interval in young diabetics should be prolonged has never really been explained. Other factors, such as channelopathies and cardiomyocyte membrane abnormalities, may also be involved. The notion that the same abnormality might account for both SUDEP and LQTS (Aurlien et al. 2009) has the potential to open up new areas of research. 159

160 Sudden Death in Epilepsy: Forensic and Clinical Issues

Numerous risk factors for SUDEP have been proposed and a few have been consistently identiἀed, including young age, early seizure onset, refractory seizures, generalized tonic clonic seizures, and male gender. Studies have found that many of these individuals are in bed, presumably asleep, at the time of death, that anticonvulsant blood levels are subtherapeutic, and that a structural brain lesion often can be identiἀed (Leestma et al. 1985). The current consensus seems to be that SUDEP is primarily a seizure-related cause of death, but the mechanisms underlying SUDEP are unknown (Jehi and Najm 2008; Hughes 2009). Most SUDEP victims are found alone in a room at home and only rarely have they been vigorously exercising. A recent meta-analysis, which included a review of the Cochrane database (Monte et al. 2007), found that patients were more likely to be discovered asleep or, at least, in their beds. Subtherapeutic concentrations of antiseizure medications were found in nearly 70% of Leestma’s cases, many of the decedents having no medications detectable at all. Signiἀcant but nonprogressive brain abnormalities were present in more €than half the decedents. Leestma et al. (1985) estimated the prevalence of seizureassociated SUDEP was between 1:525 and 1:2100 epileptics (Tellez-Zenteno et al. 2005). Other retrospective studies have reported both slightly higher and slightly lower incidence rates (Tellez-Zenteno et al. 2005; Hughes 2009), but the fact remains that SUDEP is the most common cause of death in persons with epilepsy. SUDEP is rare in those who have only recently been diagnosed with epilepsy, and it is equally uncommon in those who are in remission. Many theories accounting for the etiology of SUDEP have been proposed (Kloster and Engelskjon 1999; Lathers and Schraeder 2006; So and Sperling 2007; Aurlien et al. 2009). Most involve cardiac arrhythmias, mediated by sympathetic autonomic events, which are thought to occur during the seizures. The possibility of heritable channelopathy is receiving much closer scrutiny than in the past. Some candidate genes make the QT interval longer and some make it shorter, but both abnormalities are associated with a sudden arrhythmia-related death. These changes are important not only because they have been identiἀed in epileptics (Akalin et al. 2003), but also because they are associated with the use of some abused drugs, in particular cocaine and alcohol (Gamouras et al. 2000; Karle and Kiehn 2002; Uyarel et al. 2005; Yap et al. 2009). The possibility that genetic polymorphisms may be responsible for SIDS, SUDS, and even SUDEP cannot be ignored, but neither can the process known as myocardial remodeling, which causes the QT interval to be longer in some parts of the heart than in others. This phenomenon is referred to as QT interval dispersion; if the difference between the longest and shortest QT interval measured in a 12-lead electrocardiogram exceeds 80 ms, a state of QT dispersion (QTd) is said to exist (Anderson 2003). QTd has the same strong association with sudden cardiac death as interstitial ἀbrosis and channelopathy (Cuddy et al. 2009). The process of myocardial remodeling has received relatively little attention from neurologists, but is increasingly recognized as a cause of sudden death by cardiologists and electrophysiologists (Fischer et al. 2007). Stimulant drugs initiate the same remodeling process as seen in states of chronic catecholamine excess, and such a state can be said to exist during recurrent seizure activity (Meierkord et al. 1994; Henning and Cuevas 2006). Hypertension (Haider et al. 1998), catecholamine excess (Rona 1985), and stimulant drug abuse (Karch et al. 1998 1999) always lead to myocardial ἀbrosis and left ventricular hypertrophy (i.e., myocardial remodeling). Either or both of these processes can provide

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the substrate for sudden arrhythmia death (John et al. 2004; Haider et al. 1998). Ventricular hypertrophy and ἀbrosis are both common ἀndings in SUDEP victims (P-Codrea Tigaran et al. 2005) and it may well be that QTd is responsible for some cases of SUDEP.

10.2â•…Channelopathies and Abused Drugs 10.2.1â•…QT Interval Prolongation Ackerman and others have proposed that perturbations of the hERG channels (“rapid delayed repolarizing channel”) can confer a susceptibility for seizures themselves or, alternatively, cause QT prolongation, resulting in syncopal episodes that trigger seizures (Johnson et al. 2009; Nemec et al. 2009). This is not an unreasonable theory given that many patients who have seizures and QT prolongation are often confused with patients suffering from primary seizure disorders, and are treated with antiepileptic drugs instead of the internal deἀbrillators they really need (Lathers et al. 2010). In a recently published controlled case study, seizure phenotype was recorded in 98 of 343 (29%) patients who were randomly checked for the most common channelopathies. A seizure phenotype was more common in individuals with LQT2 (36 of 77 or 47%) than those with LQT1 (16 of 72 or 22%, p < 0.002) and LQT3 (7 of 28 or 25%, p < 0.05, not signiἀcant). LQT1 and LQT3 combined cohorts did not differ signiἀcantly from the expected background rates of a seizure phenotype, but a personal history of seizures was much more commonly found in those individuals with LQT2 (30 of 77 or 39%) than all other subtypes of LQTS (11 of 106 or 10%, p < 0.001) (Johnson et al. 2009). If this connection can be proven in other studies, the observation is potentially very signiἀcant. The gene, KCNH2, is responsible for LQT2. The KCNH2 channel was cloned originally from the hippocampus; it encodes a potassium channel active in hippocampal astrocytes and in the heart (Zehelein et al. 2004). Not only can this channel interact with some antiepileptic medications, e.g., phentoyin, phenobarbital, toprimate, and flunariÂ� zine (Danielsson et al. 2003; Trepakova et al. 2006; Yang et al. 2008), but it also interacts with abused drugs such as cocaine, methamphetamine, methadone, anabolic steroids, and even alcohol. This observation suggests that, in some cases of SUDEP, drug abuse may be the cause of death. That this observation has not yet been recorded in the literature only reflects the fact that full toxicology screening for abused drugs is not part of the routine investigation of SUDEP. Indeed, the autopsy is often performed even before a history of epilepsy is established (Kloster and Engelskjon 1999). Lathers et al. (1990) suggest, “… since both cocaine and epilepsy alone are associated with sudden unexpected death and since both are capable of modifying cardiac sympathetic neural discharge to produce changes in heart rate and rhythm, the question of whether the use of cocaine in the epileptic person places this individual at risk for sudden death must be raised.” It is also known that alcohol use is associated with an increased risk of autonomic dysfunction, seizure, and sudden death (Chan et al. 1990). It is clear that no single neurochemical system can adequately explain the complex nature of epileptic seizures. The same can be said for the neurochemical mechanisms that underlie alcohol withdrawal reactions in that there are complex, dynamic interactions among the neurotransmitters and neuromodulator systems in the brain. Another complicating factor is that

162 Sudden Death in Epilepsy: Forensic and Clinical Issues

occurrence of withdrawal seizures is only one component of the withdrawal syndrome. The challenge is to separate the neurochemical changes that may trigger seizures from those that are actually the result of the seizures themselves, or some other complication of the withdrawal reaction. Some of these factors include the individual’s genetic makeup, seizure threshold, health status, malnutrition, polydrug abuse, a history of epilepsy, prior alcohol withdrawal seizures, and trauma. Despite the difficulties associated with interpreting the neurochemical changes associated with ethanol withdrawal, there do appear to be similarities between the abnormalities observed in alcoholics and those postulated to be involved in the mechanism of epileptic seizures (Lathers et al. 1990). Twenty years have lapsed since Lathers et al. (1990) and Chan et al. (1990) discussed the possible interactions of cocaine and alcohol and SUDEP. The time is long overdue for us to answer these questions. The results of very recent discoveries make the effort to answer these questions even more worthwhile. When genome-wide data from ἀve different population-based cohorts, composed of 15,842 individuals of European ancestry, were analyzed, a total of 10 loci associated with the occurrence of LQTS were identiἀed. Four of these loci map near the monogenic LQTS genes: KCNQ1, KCNH2, SCN5A, and KCNJ2. Two other loci, ATP1B1 and PLN, have already been shown to be genes with established electrophysiological functions, whereas three of the newly discovered genes map to RNF207, near LITAF and within the NDRG4–GINS3–SETD6–CNOT1 complex, respectively. Until this study was undertaken, not a single one of these genes was thought to have anything to do with cardiac function (Newton-Cheh et al. 2009; Pfeufer et al. 2009). Any one of these genes could be responsible for LQTS, torsades de pointes, and sudden cardiac death (Pfeufer et al. 2009). The most striking thing about this new discovery is that it was replicated within the same week by another group of scientists who came up with exactly the same results (Newton-Cheh et al. 2009). If this sequence of events were to occur in a person with epilepsy, it would be called SUDEP, since the genetic component would not be detected by the medical examiner.€Even though these new discoveries very strongly suggest a nexus between SUDEP, channelopathies, and drug abuse, further understanding of the pathophysiology is required. Associations between LQT2 and epilepsy that had not previously been suspected are now known to exist. This raises the possibility that LQT2 perturbations in the KCNH2-encoded potassium channel may confer susceptibility for recurrent seizure activity (Johnson et al. 2009). When a cardiomyocyte depolarizes, the rapid component of the delayed rectiἀer K+ current, abbreviated as IKr, plays a key role in cell repolarization. During the plateau phase of the depolarization and repolarization cycle, the current generated through the IKr channel is small. As repolarization proceeds, a transient increase in the IKr outward current occurs due to fast recovery from inactivation and slow deactivation, ultimately leading to repolarization of the cardiac cell. The LQTII or hERG gene controls the IKr channel (Thomas et al. 2006). In congenital forms of LQTII syndrome, flow through the channel is slowed because the structure of the potassium pore itself is abnormal. As a consequence, the action potential is prolonged. This leads to the occurrence of early after depolarization currents that, in turn, can lead to lethal arrhythmias (torsades de pointes, literally “twisting of the points,” a form of ventricular tachycardia). However, LQTS can occur even in someone with a perfectly normal hERG gene because so many drugs, both licit and illicit, such as ἀrst and second generation antidepressants, interact with the channel (Sala et al. 2006). Since the

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majority of antiepileptic drugs block voltage-dependent sodium and calcium channels, enhance GABAergic transmission, and/or antagonize glutamate receptors, it only seems reasonable to assume that an epileptic who abuses drugs is at far greater risk for arrhythmia, even if the effects of their antiseizure medications predominate. Although there is nothing in the literature to suggest that any of the commonly used anti-seizure medications cause QT prolongation, there is ample evidence that some abused drugs do. Cocaine, alcohol, and cocaethylene (a cocaine metabolite that is formed only in the presence of signiἀcant amounts of alcohol) all block the hERG potassium channel, effectively producing an acquired form of LQTII (Karle and Kiehn 2002). Whether they interact with any of the other recently discovered channels is not known. When hERG currents are measured in vitro using the patch-clamp technique, cocaethylene (the only metabolite of cocaine that is psychoactive) increases the QT interval and causes torsades de pointes (Ferreira et al. 2001; O’Leary 2002). Other studies have shown cocaethylene accelerates the inactivation of hERG current without affecting recovery from inactivation. Depending on the molecular conἀguration of an ion pore, there are several different ways to disrupt normal IKr function. Cocaine and its metabolite, cocaethylene, produce what is called open channel block, which prevents the channel closing by putting a “foot in the door” (Wang et al. 2000). Much the same mechanism has been proposed for quaternary ammonium compounds. Study of cocaethylene is particularly important because the IKr current is found to be altered, even at realistic plasma drug concentrations (O’Leary 2002). hERG K+ channels have also been found in neurons, putatively contributing to the neuropsychological behavior of individuals who have been drinking alcohol and/or using cocaine. Methamphetamine abuse also causes QT prolongation, even though it does not interact with the hERG channel (or any other known cardiac channel) (Haning and Goebert 2007). This somewhat perplexing result may be a consequence of catecholamine toxicity, as it is well established that epinephrine induces LQTS (Urao et al. 2004), and methamphetamine usage causes catecholamine release from synaptic vesicles, thereby increasing circulating levels of catecholamines (Stuerenburg et al. 2002). Central sympathetic stimulation, such as occurs during seizures, also causes release of catecholamines and could provide a plausible explanation for this phenomena (Eckard et al. 1999). Clinical studies show that cerebral infarction causes various cardiovascular and electrocardiographic abnormalities, depending on the location and the size of the infarct. The two most frequently encountered abnormalities in patients with stroke are QT interval prolongation and widening of the QRS complex. Disease of the insular cortex seems to be very important for activation of the sympathetic nervous system. Patients with brain stem infarction have substantially higher mean plasma norepinephrine levels than patients with hemispheric infarction; on the other hand, hemispheric lesions are associated with a signiἀcantly higher incidence of cardiac arrhythmias when compared to patients with brain stem infarction (Klingelhofer and Sander 1997). Whether any of these changes can be related to the mechanism that causes arrhythmias in epileptics is not known. Methadone has recently been added to the list of drugs shown to produce QT prolongation, arrhythmias, and sudden death. It has been known for several years that highdose methadone can induce QT prolongation (Kornick et al. 2003) by hERG inhibition. However, new evidence shows that QT prolongation can occur at much lower doses of methadone, even when the drug is not given intravenously. Methadone is a chiral€drug, but only (R)-methadone provides any pain relief. Laboratory experiments have shown that

164 Sudden Death in Epilepsy: Forensic and Clinical Issues

(S)-methadone, which does not bind the mu receptor or provide pain relief, blocks the hERG current three-and-a-half times more potently than (R)-methadone. If an individual is a CYP2B6 slow metabolizer (SM), they can still metabolize (R)-methadone normally, but they cannot metabolize the (S) form. Concentrations of the (S) form of methadone will continue to rise, eventually leading to hERG blockade and, potentially, torsades de pointes (Eap et al. 2007). 10.2.2â•…QT Shortening Pathologic reduction in the QT interval is much less common than prolongation but it is also associated with sudden death. Brugada et al. (2004) linked SQTS to a KCNH2 gene mutation, the same gene responsible for QT prolongation. This disorder is characterized by a corrected QT (QTc) interval that is shorter than normal (QTc ≤€320 ms), and it is often associated with atrial ἀbrillation, syncopal episodes, and/or sudden cardiac death in patients who are said to have no anatomic evidence of heart disease (Zareba and Cygankiewicz 2008). While there is general agreement about what constitutes a prolonged QT interval, the deἀnition of short QT (SQTS) remains somewhat controversial, though most accept that the lower boundary of normal is on the order of 320 ms. Unlike the mutations in LQTS, which result in loss of function, mutations in SQTS cause an increase in function with rapid repolarization; cardiac arrest may be the ἀrst symptom (Giustetto et al. 2006). The recent discovery that anabolic steroid abuse is associated with a reduction in the QT interval (Bigi et al. 2009) is most provocative, given the repeated observation that abnormalities of reproductive endocrine hormones are more often found in men with epilepsy than in the general population (Roste et al. 2005). There is an ongoing debate whether this increased risk in males can be attributed to the use of antiepileptic drugs or the epilepsy itself. The corrected QT interval in proven anabolic steroid abusers is signiἀcantly shorter than the QT interval of drug-free bodybuilders and that of sedentary men. In this recently study, sedentary men were found to have a QTc interval of 418 ± 23.6 ms, drug-free bodybuilders had a QTc interval of 422 ± 24.5 ms, and steroid abusing bodybuilders had a QTc interval of 367 ± 17.1 ms (p < 0.01). In fact, the correlation between steroid abuse and QT interval is so strong that some have recommended EKG screening as a method of detecting steroid abusers (Bigi et al. 2009). Similar ἀndings have been produced by the administration of anabolic steroids to experimental animals (Fulop et al. 2006; Liu et al. 2003).

10.3╅QT Dispersion Animal studies suggest that hippocampal norepinephrine transporters are downregulated when chronically exposed to cocaine (Kitayama et al. 2006), and human studies have shown a decrease in dopamine and serotonin transporters in the same areas (Mash et al. 2000). It should not be forgotten that all local anesthetics are Na channel blockers, both in the brain and the heart, and cocaine is a local anesthetic. Thus, it might be reasonable to postulate that some drug abusers who also have epilepsy, of which there appear to be more than a few (Opeskin et al. 2000),€die as a consequence of the drug abuse acting in synergy with their primary disease to cause seizure-related death.

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10.4â•…Abnormal Catecholamine Metabolism Disruption of postganglionic reuptake is thought to be the mechanism that leads to bradyarrhythmia or even asystole during epileptic seizures. In the heart, as opposed to the brain, the action of norepinephrine is terminated primarily by reuptake (Kloner et al. 1992; Schafers et al. 1998) by the actions of catechol-O-methyl transferase (COMT). Recent studies of epileptics who have experienced bradyarrhythmia or asystole have shown that these individuals have dramatically abnormal postganglionic cardiac norepinephrine uptake (Kerling et al. 2009), suggesting impaired sympathetic cardiac innervation, resulting in a limited ability to adjust and modulate heart rate, or even cause asystole. A large number of commonly abused drugs (cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine) profoundly disrupt catecholamine metabolism, and their use may well be responsible for the death of an occasional drug abuser who also has epilepsy. However, the most current studies suggest variations in COMT activity are more likely due to genetic polymorphisms and, no doubt, more work will be done in this area in the near future (Haile et al. 2009).

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166 Sudden Death in Epilepsy: Forensic and Clinical Issues Fischer, R., R. Dechend, A. Gapelyuk, E. Shagdarsuren, K. Gruner, A. Gruner, P. Gratze et al. 2007. Angiotensin II-induced sudden arrhythmic death and electrical remodeling. Am J Physiol Heart Circ Physiol 293 (2): H1242–H1253. Fulop, L., T. Banyasz, G. Szabo, I. B. Toth, T. Biro, I. Lorincz, A. Balogh, K. Peto, I. Miko, and P. P. Nanasi. 2006. Effects of sex hormones on ECG parameters and expression of cardiac ion channels in dogs. Acta Physiol (Oxf) 188 (3–4): 163–171. Gamouras, G. A., G. Monir, K. Plunkitt, S. Gursoy, and L. S. Dreifus. 2000. Cocaine abuse: Repolarization abnormalities and ventricular arrhythmias. Am J Med Sci 320 (1): 9–12. Gill, G. V., A. Woodward, I. F. Casson, and P. J. Weston. 2009. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—The ‘dead in bed’ syndrome revisited. Diabetologia 52 (1): 42–45. Giustetto, C., F. Di Monte, C. Wolpert, M. Borggrefe, R. Schimpf, P. Sbragia, G. Leone et al. 2006. Short QT syndrome: Clinical ἀndings and diagnostic–therapeutic implications. Eur Heart J 27€(20): 2440–2447. Haider, A. W., M. G. Larson, E. J. Benjamin, and D. Levy. 1998. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol 32 (5): 1454–1459. Haile, C. N., T. R. Kosten, and T. A. Kosten. 2009. Pharmacogenetic treatments for drug addiction: Cocaine, amphetamine and methamphetamine. Am J Drug Alcohol Abuse 35 (3): 161–177. Haning, W., and D. Goebert. 2007. Electrocardiographic abnormalities in methamphetamine abusers. Addiction 102 (Suppl 1): 70–75. Henning, R. J., and J. Cuevas. 2006. Cocaine activates calcium/calmodulin kinase II and causes cardiomyocyte hypertrophy. J Cardiovasc Pharmacol 48 (1): 802–813. Hughes, J. R. 2009. A review of sudden unexpected death in epilepsy: Prediction of patients at risk. Epilepsy Behav 14 (2): 280–287. Jehi, L., and I. M. Najm. 2008. Sudden unexpected death in epilepsy: Impact, mechanisms, and prevention. Cleve Clin J Med 75 (Suppl 2): S66–S70. John, B. T., B. K. Tamarappoo, J. L. Titus, W. D. Edwards, W. K. Shen, and S. S. Chugh. 2004. Global remodeling of the ventricular interstitium in idiopathic myocardial ἀbrosis and sudden cardiac death. Heart Rhythm 1 (2): 141–149. Johnson, J. N., N. Hofman, C. M. Haglund, G. D. Cascino, A. A. Wilde, and M. J. Ackerman. 2009. Identiἀcation of a possible pathogenic link between congenital long QT syndrome and epilepsy. Neurology 72 (3): 224–231. Karch, S. B., B. G. Stephens, and C. H. Ho. 1999. Methamphetamine-related deaths in San Francisco: Demographic, pathologic, and toxicologic proἀles. J Forensic Sci 44 (2): 359–368. Karch, S. B., B. Stephens, and C. H. Ho. 1998. Relating cocaine blood concentrations to toxicity—An autopsy study of 99 cases. J Forensic Sci 43 (1): 41–45. Karle, C. A., and J. Kiehn. 2002. An ion channel ‘addicted’ to ether, alcohol and cocaine: The HERG potassium channel. Cardiovasc Res 53 (1): 6–8. Kerling, F., M. Dutsch, R. Linke, T. Kuwert, H. Stefan, and M. J. Hilz. 2009. Relation between ictal asystole and cardiac sympathetic dysfunction shown by MIBG-SPECT. Acta Neurol Scand 120€(2): 123–129. Kitayama, T., L. Song, K. Morita, N. Morioka, and T. Dohi. 2006. Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local-anesthetics–induced convulsions and the counteraction by coadministration with local anesthetic. Brain Res 1096 (1): 97–103. Klingelhofer, J., and D. Sander. 1997. Cardiovascular consequences of clinical stroke. Baillieres Clin Neurol 6 (2): 309–335. Kloner, R. A., S. Hale, K. Alker, and S. Rezkalla. 1992. The effects of acute and chronic cocaine use on the heart. Circulation 85 (2): 407–419. Kloster, R., and T. Engelskjon. 1999. Sudden unexpected death in epilepsy (SUDEP): A clinical perspective and a search for risk factors. J Neurol Neurosurg Psychiatry 67 (4): 439–444.

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Kornick, C. A., M. J. Kilborn, J. Santiago-Palma, G. Schulman, H. T. Thaler, D. L. Keefe, A. N. Katchman et al. 2003. QTc interval prolongation associated with intravenous methadone. Pain 105 (3): 499–506. Lathers, C. M., and P. L. Schraeder. 2006. Stress and sudden death. Epilepsy Behav 9 (2): 236–242. Lathers, C. M., P. L. Schraeder, and M. W. Bungo. 2010. Neurocardiologic mechanistic risk factors in sudden unexpected death in epilepsy. Ch. 1 in Sudden Death in Epilepsy: Forensic and Clinical Issues, eds. C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leestma. Boca Raton: CRC Press. Lathers, C. M., M. M. Spino, I. Agarwal, L. S. Y. Tyau, and W. B. Pickworth. 1990. Chapter 27. Cocaine-induced seizures, arrhythmias, and sudden death. In Epilepsy and Sudden Death, ed. C. M. Lathers and P. Schraeder. New York, NY: Marcel Dekker. Leestma, J. E., J. R. Hughes, S. S. Teas, and M. B. Kalelkar. 1985. Sudden epilepsy deaths and the forensic pathologist. Am J Forensic Med Pathol 6 (3): 215–218. Liu, X. K., A. Katchman, B. H. Whitἀeld, G. Wan, E. M. Janowski, R. L. Woosley, and S. N. Ebert. 2003. In€vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectiἀer potassium currents in orchiectomized male rabbits. Cardiovasc Res 57 (1): 28–36. Mash, D. C., J. K. Staley, S. Izenwasser, M. Basile, and A. J. Ruttenber. 2000. Serotonin transporters upregulate with chronic cocaine use. J Chem Neuroanat 20 (3–4): 271–280. Meierkord, H., S. Shorvon, and S. L. Lightman. 1994. Plasma concentrations of prolactin, noradrenaline, vasopressin and oxytocin during and after a prolonged epileptic seizure. Acta Neurol Scand 90 (2): 73–77. Monte, C. P., J. B. Arends, I. Y. Tan, A. P. Aldenkamp, M. Limburg, and M. C. de Krom. 2007. Sudden unexpected death in epilepsy patients: Risk factors. A systematic review. Seizure 16 (1): 1–7. Nemec, J., M. Buncova, V. Shusterman, B. Winter, W. K. Shen, and M. J. Ackerman. 2009. QT interval variability and adaptation to heart rate changes in patients with long QT syndrome. Pacing Clin Electrophysiol 32 (1): 72–81. Newton-Cheh, C., M. Eijgelsheim, K. M. Rice, P. I. de Bakker, X. Yin, K. Estrada, J. C. Bis et al. 2009. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet 41 (4): 399–406. O’Leary, M. E. 2002. Inhibition of HERG potassium channels by cocaethylene: A metabolite of cocaine and ethanol. Cardiovasc Res 53 (1): 59–67. Opeskin, K., A. S. Harvey, S. M. Cordner, and S. F. Berkovic. 2000. Sudden unexpected death in epilepsy in Victoria. J Clin Neurosci 7 (1): 34–37. P-Codrea Tigaran, S., S. Dalager-Pedersen, U. Baandrup, M. Dam, and A. Vesterby-Charles. 2005. Sudden unexpected death in epilepsy: Is death by seizures a cardiac disease? Am J Forensic Med Pathol 26 (2): 99–105. Pfeufer, A., S. Sanna, D. E. Arking, M. Muller, V. Gateva, C. Fuchsberger, G. B. Ehret et al. 2009. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet 41 (4): 407–414. Rona, G. 1985. Catecholamine cardiotoxicity. J Mol Cell Cardiol 17 (4): 291–306. Roste, L. S., E. Tauboll, L. Morkrid, T. Bjornenak, E. R. Saetre, T. Morland, and L. Gjerstad. 2005. Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy. Eur J Neurol 12 (2): 118–124. Rothenbuhler, A., C. P. Bibal, S. Le Fur, and P. Bougneres. 2008. Effects of a controlled hypoglycaemia test on QTc in adolescents with Type 1 diabetes. Diabet Med 25 (12): 1483–1485. Sala, M., F. Coppa, C. Cappucciati, P. Brambilla, G. d’Allio, E. Caverzasi, F. Barale, and G. M. De Ferrari. 2006. Antidepressants: Their effects on cardiac channels, QT prolongation and Torsade de Pointes. Curr Opin Investig Drugs 7 (3): 256–263. Schafers, M., D. Dutka, C. G. Rhodes, A. A. Lammertsma, F. Hermansen, O. Schober, and P. G. Camici. 1998. Myocardial presynaptic and postsynaptic autonomic dysfunction in hypertrophic cardiomyopathy. Circ Res 82 (1): 57–62. So, N. K., and M. R. Sperling. 2007. Ictal asystole and SUDEP. Neurology 69 (5): 423–424.

168 Sudden Death in Epilepsy: Forensic and Clinical Issues Stuerenburg, H. J., K. Petersen, T. Baumer, M. Rosenkranz, C. Buhmann, and R. Thomasius. 2002. Plasma concentrations of 5-HT, 5-HIAA, norepinephrine, epinephrine and dopamine in ecstasy users. Neuro Endocrinol Lett 23 (3): 259–261. Tellez-Zenteno, J. F., L. H. Ronquillo, and S. Wiebe. 2005. Sudden unexpected death in epilepsy: Evidence-based analysis of incidence and risk factors. Epilepsy Res 65 (1–2): 101–115. Thomas, D., C. A. Karle, and J. Kiehn. 2006. The cardiac hERG/IKr potassium channel as pharmaÂ� cological target: Structure, function, regulation, and clinical applications. Curr Pharm Des 12€(18): 2271–2283. Trepakova, E. S., S. J. Dech, and J. J. Salata. 2006. Flunarizine is a highly potent inhibitor of cardiac hERG potassium current. J Cardiovasc Pharmacol 47 (2): 211–220. Tu, E., S. M. Twigg, and C. Semsarian. 2008. Sudden death in type 1 diabetes: The mystery of the ‘dead in bed’ syndrome. Int J Cardiol. Urao, N., H. Shiraishi, K. Ishibashi, M. Hyogo, M. Tsukamoto, N. Keira, S. Hirasaki, T. Shirayama, and M. Nakagawa. 2004. Idiopathic long QT syndrome with early after depolarization induced by epinephrine. A case report. Circ J 68 (6): 587–591. Uyarel, H., C. Ozdol, A. M. Gencer, E. Okmen, and N. Cam. 2005. Acute alcohol intake and QT dispersion in healthy subjects. J Stud Alcohol 66 (4): 555–558. Wang, J., C. D. Myers, and G. A. Robertson. 2000. Dynamic control of deactivation gating by a soluble amino-terminal domain in HERG K(+) channels. J Gen Physiol 115 (6): 749–758. Yang, Z. Q., J. C. Barrow, W. D. Shipe, K. A. Schlegel, Y. Shu, F. V. Yang, C. W. Lindsley et al. 2008. Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels. J Med Chem 51 (20): 6471–6477. Yap, Y. G., E. R. Behr, and A. J. Camm. 2009. Drug-induced Brugada syndrome. Europace 11 (8): 989–994. Zareba, W., and I. Cygankiewicz. 2008. Long QT syndrome and short QT syndrome. Prog Cardiovasc Dis 51 (3): 264–278. Zehelein, J., D. Thomas, M. Khalil, A. B. Wimmer, M. Koenen, M. Licka, K. Wu et al. 2004. Identiἀcation and characterisation of a novel KCNQ1 mutation in a family with Romano–Ward syndrome. Biochim Biophys Acta 1690 (3): 185–192.

Cocaine-Induced Seizures, Arrhythmias, and Sudden Death

11

Claire M. Lathers Michelle M. Spino Isha Agarwal Laurie S. Y. Tyau Wallace B. Pickworth

Contents 11.1 Introduction 11.2 Mechanisms of Action of Cocaine 11.3 Cocaine-Induced Sudden Death 11.3.1 Cocaine-Induced Changes in Mean Arterial Blood Pressure and Heart Rate 11.3.2 Cocaine-Induced Myocardial Ischemia, Infarction, Arrhythmia, and Cardiomyopathies 11.3.3 Cocaine-Induced Changes in Postganglionic Cardiac Sympathetic Neural Function 11.3.4 Central Actions of Cocaine 11.3.5 Cocaine-Induced Seizures 11.4 Treatment of Cocaine-Induced Arrhythmias and Seizures 11.5 Use of Cocaine in Persons with Epilepsy 11.6 Summary References

169 170 172 172 174 176 176 179 180 181 181 182

11.1â•…Introduction The presence of coca leaves in the tombs of South American Indian mummies suggests that cocaine was used as early as a .d. 600. The use of cocaine is prevalent in modern society. Cregler and Mark (1986a) reviewed the demographics of current cocaine users and found that approximately 1 out of every 10 Americans, have used cocaine at least once (Cregler and Mark 1987). The fallacy that cocaine is a benign, nonaddicting substance may be part of the reason for the alarming rise in abuse (Cregler and Mark 1986b). Although cocaine has been found to be a cardiotoxin, the pathogenesis of this toxicity is not well deἀned (Cregler and Mark 1987). Cocaine use has also been linked to the occurrence of subarachnoid hemorrhage, hypertension, ventricular arrhythmia, tachycardia, acute myocardial infarction, seizure, and sudden death (Lichtenfeld et al. 1984; Nahas et al. 1985; Tazelaar et al. 1987; Young and Glauber 1947). Persons with epilepsy have been shown to manifest autonomic dysfunctions similar to those manifested by cocaine users, 169

170 Sudden Death in Epilepsy: Forensic and Clinical Issues

including changes in blood pressure and heart rate and rhythm, phenomena that may be contributory to sudden unexpected death (Leestma et al. 1984; Penἀeld and Erickson 1941; Phizackerly et al. 1954; Walsh et al. 1968). Thus, one must ask whether the use of cocaine in individuals with epilepsy places these individuals at risk of dying in a sudden unexplained manner.

11.2â•…Mechanisms of Action of Cocaine Cocaine (Figure 11.1), extracted from the leaves of Erythroxylon coca, is a potent local anesthetic agent (Cregler and Mark 1986a; Gould et al. 1985) possessing membrane-stabilizing effects at low plasma levels (Tazelaar et al. 1987). It is also a sympathomimetic agent at higher plasma concentrations (Benchimol et al. 1978; Duke 1986). Cocaine ampliἀes the effect of catecholamines by blocking the reuptake at the synaptic junctions, causing a local excess of norepinephrine at the synaptic cleft. As a result of the excess of norepinephrine at the nerve terminal, there is a prolongation and potentiation of the activity of norepinephrine (Weiss 1986). Norepinephrine is the primary neurotransmitter of the sympathetic nervous system. Excitation of the sympathetic nervous system produces physiological characteristics, such as mobilization of adrenal catecholamines, causing an increase in blood pressure and the heart rate, dilatation of the pupils, a rise in blood sugar levels, vasoconstriction of vessels in the brain and muscles, tightening of the sphincters, and an elevation of body temperature. The intense peripheral vasoconstriction retards reabsorption. Drug effects include intense euphoria and elation, garrulousness, excitability, and irritability; with repeated administration, paranoid ideation, delirium, and assaultiveness occur. Table 11.1 summarizes the actions of cocaine on the cardiovascular, respiratory, and central nervous system (Gay 1982). Cocaine as a hydrochloride salt is brought into the United States with purity ranging up to 95% (Gay 1982). The purity is decreased to 25–90% of its original state through the addition of diluents and adulterants such as procaine, lidocaine (Cregler and Mark 1986b), caffeine, benzocaine, amphetamines, heroin, quinine, talc, and phencyclidine. All adulterants contribute to the toxicity of cocaine. Finally, it is combined with sugars such as mannitol, lactose, and glucose to attain a ἀnal volume and weight (Gay 1982). The resulting cocaine street product can be administered by various routes, including intravenous and subcutaneous injections, intranasal inhalation (snorting), and the current vogue of smoking a “freebase” form of cocaine (crack). Freebase smoking or intravenous injections of

CH3 N

COOCH3

OOCC6H5 H

Figure 11.1╇ Structure of cocaine (C17 H 21NO4).

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Table 11.1â•… The Cocaine Reaction Phase I: Early stimulation

II: Advanced stimulation

III: Depressive

Central Nervous System

Cardiovascular System

Euphoria: stated feelings of “soaring,” well-being Elation, expansive good humor, laughing, mydriasis Talkative, garrulous Excited, flighty, emotionally unstable Restless, irritable, apprehensive, unable to sit still Stereotyped movements (such as “picking” or “stroking”), bruxism Nausea, vomiting, vertigo Sudden headache Cold sweats Tremor (nonintentional) Twitching of small muscles, especially of the face, ἀngers, and feet Tics, generalized Preconvulsive, tonic and clonic jerks Possible psychosis, hallucinations Core body temperature rises Verbalization of impending doom (precedes imminent total collapse) Unresponsive to voice; decreased responsiveness to all stimuli Increased deep tendon reflexes Generalized hyperreflexia Convulsions: tonic and clonic Status epilepticus Incontinence Malignant encephalopathy possible

Pulse vanes at ἀrst, may immediately slow because of reflex vagal effect; will increase 30% to 50% above normal with system absorption of 25 mg of cocaine Blood pressure usually elevates 15% to 20% above normal with similar dosages as noted above Skin pallor caused by vasoconstriction Premature ventricular contractions

Increased respiratory rate and depth Dyspnea

Increased pulse and blood pressure: high output failure possible Blood pressure falls as ventricular dysrhythmias supervene and inefficient cardiac output results Pulse becomes rapid, weak, and irregular Peripheral, then central cyanosis Ventricular ἀbrillation Circulation failure Ashen gray cyanosis No palpable pulse Cardiac arrest Paralysis of medullary brain center Exitus

Gasping, rapid, or irregular respiration (Chevne–Stokes)

Flaccid paralysis of muscles Coma Pupils ἀxed and dilated Loss of reflexes Loss of vital support functions Paralysis of medullary brain center Exitus

Respiratory System

Agonal gasps Respiratory failure Gross pulmonary edema Paralysis of medullary brain center Exitus

cocaine cause a euphoric or “rush” experience, which occurs within 45 s and is associated with a rapid increase in plasma cocaine concentrations. The effect lasts for approximately 20 min. In contrast, intranasal administration results in euphoria occurring within 3 to 5 min of administration and lasts for 1 to 1.5 h (Van Dyke and Byck 1983). Regardless of the route of administration, accounts of cocaine-induced sudden death have become common.

172 Sudden Death in Epilepsy: Forensic and Clinical Issues

11.3â•…Cocaine-Induced Sudden Death Sudden death has been shown to be induced by cocaine (Amon et al. 1986; Estroff and Gold 1986; Mittleman and Welti 1987; Welti and Fishbain 1985). Reports indicate 1.2 g to be a lethal dose; however, severe toxic effects have been reported with doses as low as 20 mg (Estroff and Gold 1986). Because it is so sudden, medical personnel do not ordinarily witness cocaineinduced death; victims usually collapse and die before resuscitation efforts can begin. Confusion or convulsions precede death induced by cocaine. Estroff and Gold (1986) reported seven cases of sudden death associated with the use of cocaine, in whom a state of excited delirium was the fatal symptom. The initial symptom was intense paranoia, followed by bizarre and violent behavior necessitating the use of force to restrain the patient. The unexpected outbursts of strength were associated with hyperthermia, which was thought to be due to a direct effect of cocaine on the central nervous system center for temperature regulation, and due to peripheral vasoconstriction, with resultant reduction in heat (Ritchie and Greene 1980). Status epilepticus, respiratory paralysis, or cardiac arrhythmias genrally precede sudden death induced by cocaine. Abramowicz (1986) suggested that most sudden deaths associated with cocaine use are caused by seizures leading to anoxia. Recent clinical data have been correlated with pathological ἀndings, generating several hypotheses that attempt to deἀne forensically the pathological mechanisms of cocaine-induced sudden death. 11.3.1â•…Cocaine-Induced Changes in Mean Arterial Blood Pressure and Heart Rate The circulatory effects of cocaine are believed to be of both central and peripherally induced vasoconstriction and cardioacceleration (Young and Glauber 1947). Change in heart rate is a sensitive measure of cocaine-induced cardiovascular effect (Fischman et al. 1976). Cocaine results in dose-related changes in heart rate (Javiad et al. 1978), with small doses decreasing heart rate via central vagal action and moderate doses increasing heart rate via atrial and peripheral sympathetic stimulation (Benchimol et al. 1978). Extremely high intravenous doses have direct toxic effects on the heart and cause immediate death (Nanji and Filipenko 1984; Young and Glauber 1947). The duration of the cardiovascular action is dependent on the dose of cocaine. Fischman et al. (1976) showed that an increase in heart rate was evident after intravenous injections of varying doses of cocaine; the increase began 2–5 min after infusion, peaked at 10 min, and rapidly returned to baseline (Figure 11.2). Cocaine also increased blood pressure in a dose-related manner, but more variability is seen in this measure. In one study (Pitts et al. 1987), cocaine was administered intravenously and evoked a rapid, transient, dose-dependent rise in mean arterial pressures (Figure 11.3). Jain et al. (1987) reported that the administration of cocaine (0.25 mg/kg, i.v.) to anesthetized cats increased systolic and diastolic blood pressure by 33 ± 11 and 31 ± 7 mm Hg, respectively. The dose also enhanced the pressor responses to intravenous norepinephrine and to bilateral carotid occlusion. Doses of 0.5 and 1.0 mg/kg (i.v.) also caused an increase in blood pressure and responses to intravenous norepinephrine but did not increase the blood pressure response to bilateral carotid occlusion. Higher doses had no additive effect on the blood pressure, but rather slowed the heart rate, attenuated blood pressure responses to norepinephrine, prolonged the QRS duration, and decreased tidal volumes. All effects

Mean heart rate (beats/min)

Cocaine-Induced Seizures, Arrhythmias, and Sudden Death 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50

173 4 mg 8 mg 16 mg 32 mg Saline

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8

16

24

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40

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56

Time since drug injection (min)

Figure 11.2╇ Mean heart rate as a function over time after cocaine is injected. 40 20 (a)

0 –20 –40 –60

Mean percent change

40 20 (b)

0 –20 –40 –60 40 20

(c)

0 –20 –40 –60

0

M 1

2

3

5 10 15 30

(min)

Figure 11.3╇ Time course for the cardiovascular and respiratory effects of three different doses of

cocaine: 0.312, 1.25, and 5 mg/kg (i.v.) depicted in (a) (N = 6), (b) (N = 5), and (c) (N = 4), respectively. The ordinate scale is percentage of change and the abscissa scale is time in minutes. M€= period during maximal pressor response. Squares represent mean values for arterial pressure. Vertical lines represent standard error of the mean. All animals were anesthetized with pentobarbital (6.5 mg/kg, i.p.). (From Pitts, D.K., Udom, C.E., and Marwah, J., Life Sci., 40, 1099–1111, 1987.)

174 Sudden Death in Epilepsy: Forensic and Clinical Issues

were increased after a dose of 4 mg/kg or greater of cocaine i.v., with arrhythmias occurring with 4 and 8 mg/kg. Doses as low as 0.25 mg/kg (i.v.) evoked substantial cardiovascular responses and lethal responses of apnea. In another study, the administration of cocaine intravenously to conscious rats increased arterial blood pressure (Rockhold et al. 1987). The heart rate was elevated initially but subsequently was decreased. With the onset of cocaine-induced seizures, a further elevation in heart rate and blood pressure occurred, ultimately progressing to cardiovascular collapse and death. Preliminary studies utilizing intravenous administration of cocaine to anesthetized dogs elicited a dose-dependent increase in blood pressure and heart rate and alterations in the ST segment (Tackett and Jones 1987). These changes were associated with elevated cerebrospinal fluid levels of norepinephrine and dopamine, ἀndings that suggest a role for central catecholaminergic mechanisms in the cardiovascular actions of cocaine. Therefore, as cocaine raises the blood pressure and heart rate to excessively high levels, there is an increased risk of aneurism, arteriovenous malformation, and stroke or hemorrhage from ruptures of cerebral arteries weakened by drug-related arteritis. 11.3.2â•…Cocaine-Induced Myocardial Ischemia, Infarction, Arrhythmia, and Cardiomyopathies There has been a recent and dramatic increase in cardiac abnormalities among cocaine users (Duke 1986; Wiener and Putnam 1987; Wiener et al. 1986) that has raised questions concerning the effect of cocaine on the cardiovascular system. Indeed, cocaine is clearly cardiotoxic, being temporally linked to myocardial ischemia, arrhythmias, and many cardiomyopathies. Cocaine use in the presence of preexisting coronary artery disease may predispose the individual to the development of angina, arrhythmias, or myocardial infarction (Coleman et al. 1982; Young and Glauber 1947). It is possible that a patient with hypercholesterolemia who is using cocaine may be further increasing the likelihood of coronary artery spasm (Rosendorff et al. 1981), leading to myocardial ischemia and necrosis. Numerous cases of suspected cocaine-induced myocardial ischemias and infarctions have been reported (Isner et al. 1985, 1986; Kassowsky and Lyon 1984; Mathias 1986; Rod and Zucker 1987; Rollingher et al. 1986; Schachne et al. 1984; Simpson and Edwards 1986). Simpson and Edwards (1986) reported a case of a 21-year-old man with a history of recreational intravenous cocaine abuse who developed chest pain within 1 min and cardiopulmonary collapse within 1 h after injection of cocaine. Postmortem ἀndings revealed severe coronary obstructive lesions and acute platelet thrombosis, with secondary chronic and acute myocardial ischemic lesions, focal endothelial injury, and platelet aggregations being observed. The author proposed that coronary artery spasm induced by cocaine caused the endothelial lesions and favored platelet adherence and aggregation. The chronic obstructions that were also found may have resulted from a similar mechanism. According to Weiss (1986), ἀxed coronary atherosclerotic lesions play a permissive role in the induction of coronary vasospasm. It has been proposed that the ability of both intrinsic atherosclerotic plaques and cocaine-induced norepinephrine uptake blockade increases local levels of catecholamine, producing coronary vasospasms. Furthermore, preexisting coronary artery disease sensitizes the vascular smooth muscle to norepinephrine-induced vasoconstriction, predisposing the cocaine user to life-threatening ischemia (Gould et al. 1985; Weiss 1986). Also, with chronic cocaine abuse, the excessive accumulation of norepinephrine may prime the myocardium for a fatal arrhythmia (Tazelaar et al. 1987).

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Cocaine increases the local concentrations of catecholamines from blocked adrenergic nerve endings to other cell receptors by inhibiting the neuronal uptake of norepinephrine. Thus the adrenergic response in susceptible organs is increased, leading to the development of catecholamine supersensitivity (Benchimol et al. 1978; Trendelenburg 1968). Therefore, cocaine is capable of eliciting both an inhibitory and an excitatory response of sympathetically innervated structures to endogenous and exogenous catecholamines (Pitts et al. 1987). It has also been suggested that cocaine accentuates the action of norepinephrine on beta receptors in the heart (Nanji and Filipenko 1984) by increasing the concentration of norepinephrine at the synaptic cleft. Beta stimulation increases automaticity, heart rate, and the conduction velocity of the His–Purkinje system and decreases atrioventricular nodal refractoriness (Tazelaar et al. 1987). Tazelaar et al. (1987) characterized cocaine-induced pathophysiology in a postmortem study of 30 cocaine-related deaths. Morphologic characteristics of acute ischemia were observed in 93% of the cases. These involved the formation of myocardial contraction bands in association with polymorphonucleocytes in the initial 12–24 h; they were replaced with lymphocytes by 24–48 h. The formation of contraction bands and myocardial interstitial ἀbrosis may be one pathogenic mechanism for fatal arrhythmias. These contraction bands may also represent an anatomical route for reentrant mechanism, thus priming the heart for fatal arrhythmias. It is quite possible that arrhythmias may be generated by cocaine through a decrease in the refractoriness of the myocardial ἀbers, accumulation of excess norepinephrine, formation of contraction bands, and production of interstitial ἀbrosis. Cocaine causes myocardial ischemia by direct and indirect actions (Vitullo et al. 1987). Direct effects are the stimulation of the sinoatrial node, with an increase in heart rate, contractility, and wall tension. Indirectly, the effects can be due to the sympathetic vasoconstriction of the peripheral smooth muscle vasculature. Arterial vasoconstriction leads to an increase in afterload and blood pressure, which, in turn, increases the work that the heart must pump against. Both the direct and the indirect actions increase the oxygen consumption of the myocardium, with an ischemic event occurring when the demand for oxygen supersedes the supply (Tyau and Lathers 1988). Pasternack et al. (1985) reported three male patients in their middle to late thirties who were referred for coronary angiography after having angina pectoris and/or an acute myocardial infarction, coincident with an increase in the frequency of cocaine abuse. The onset of angina and acute myocardial infarctions may have been caused by a cocaineinduced potentiation of the activities of the central nervous system resulting in systemic hypertension and tachycardia. Isner et al. (1986) reported a temporal relationship between cocaine and cardiac sequelae in seven nonintravenous cocaine abusers. It was concluded that cocaine may precipitate fatal arrhythmias, myocarditis, acute infarctions, and possible sudden death in patients with either anatomically normal or abnormal coronary arteries. In these cases there was a temporal relationship between the administration of cocaine and the onset of a myocardial ischemia and/or infarction. Because of many other medical factors involved, it is difficult to discern the actual etiological mechanisms of the infarctions. However, in a case report by Howard et al. (1985), a young woman with normal coronary arteries, blood glucose, and lipid levels and no history of cardiovascular disease or smoking was admitted to the hospital for loss of consciousness and epigastric pain; 5€h earlier, she had inhaled 1.5 g of cocaine. On admission, an ECG showed precordial ST segment elevation and a loss of R waves. On the day following admission, an echocardiography revealed akinesis and dyskinesis of the left ventricle apex and septum. In this

176 Sudden Death in Epilepsy: Forensic and Clinical Issues

healthy individual with no coronary risk factors or demonstrable coronary artery disease, infarction occurred. This ἀnding suggests that cocaine-induced myocardial infarctions should be considered when examining individuals who may not appear to be vulnerable. The cardiovascular events produced through cocaine abuse can be seen to involve a range of pathological responses, including coronary vasospasm, arrhythmia, myocardial ischeÂ� mia, infarction, and cardiomyopathies. Therapeutic use of cocaine is not without risk. For example, Chiu et al. (1986) reported a patient who was anesthesized for a closed reduction of a nasal fracture by spraying 2 ml of 1% cocaine solution into the nasal airways. The patient complained of an acute onset of chest pain and shortness of breath. An electrocardiogram indicated ST-T wave changes in the precordial leads, suggestive of an acute coronary ischemic event. The rise in the MB creatine kinase fraction and reversed LDH isoenzyme fractional values were consistent with a small nontransmural myocardial infarction. The published accounts of cardiovascular events, myocardial infarction, and mortality related to cocaine use as described here and consist mostly of case reports (Loveys 1987). Experimental research looking into the cardiovascular effects of cocaine is warranted. 11.3.3â•…Cocaine-Induced Changes in Postganglionic Cardiac Sympathetic Neural Function Cocaine potentiates the ganglionic blocking action of norepinephrine (Christ et al. 1982). In the isolated hamster stellate ganglia preparation, cocaine exaggerated the inhibitory action of exogenously applied norepinephrine. In pithed rats, cocaine potentiated the pressor effect of norepinephrine more than it potentiated the pressor effect of sympathetic stimulation (Bayorh et al. 1983). Cocaine increased plasma norepinephrine levels and extended the inotropic and chronotropic responses to sympathetic neural stimulation in anesthetized dogs (Matsuda et al. 1980). These actions were attributed to the inhibition of the neuronal catecholamine uptake by cocaine (Matsuda et al. 1980). It is possible that cocaine-induced exaggeration of sympathetic discharge may enhance the arrhythmias experimentally caused by ouabain (Lathers et al. 1977), coronary occlusion (Lathers et al. 1978), and seizures (Lathers and Schraeder 1982; Schraeder and Lathers 1983). Experimental arrhythmias are hypothesized to be a useful model to study possible mechanisms of sudden death associated with myocardial infarctions (Lathers et al. 1986) and epilepsy (Lathers and Schraeder 1987; Schraeder and Lathers 1989). Consequently, any changes induced by cocaine in cardiac sympathetic neural discharge may well augment the development of arrhythmias and/or sudden death. On the other hand, Dart et al. (1983) demonstrated that stimulation of postganglionic cardiac sympathetic nerves in a Langendorff rat–isolated heart preparation produced a stimulation frequency-dependent overflow of endogenous norepinephrine into the venous effluent with an increase in the heart rate. Cocaine signiἀcantly reduced the norepinephrine outflow while the heart rate continued to increase. 11.3.4â•…Central Actions of Cocaine Many of the effects of cocaine result from actions in the central nervous system. Cocaineinduced euphoria, for example, was among the ἀrst effects described (Freud 1884) and is the most well-known central effect. Generalized convulsions, which often precede

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cocaine-induced death, unfortunately are less well-known outside the medical community. It has been shown that seizures are a major determinant of cocaine-induced death (Catravas and Waters 1981; Catravas et al. 1978). The common concomitants of generalized seizures, including hyperthermia, acidosis, increased blood pressure, cardiac arrhythmia, and hypoventilation, may be responsible for the lethality. In animal studies, many of the effects of cocaine have been localized to limbic structures. For example, Castellani et al. (1983) found that cocaine initiated high-voltage spindles that began in the amygdala 5–25 s after the injection of cocaine (Figure 11.4) and spread within seconds to other olfactory sites in synchronous bursts. Cocaine induced an increase in spindle frequency in the olfactory bulb and amygdala that was inhibited by atropine administration. Yasuda et al. (1984) reported that low concentrations of cocaine potentiated a norepinephrine-induced increase in spike amplitude of hippocampal splices. The authors concluded that the action was due to the inhibition of catecholamine uptake based on the observation that other inhibitors had the same effect. Lesse and Collins (1979) found that cocaine increased the speed at which epileptiform discharges spread to the amygdala and hippocampus. They postulated that subconvulsive doses of cocaine have an excitatory effect on limbic structures, which increases their sensitivity to repetitive discharges from distant foci. Matsuzaki (1978) reported that chronic high doses of cocaine in the rhesus monkey engendered persistent behavioral depression, with cortical and limbic slowing of EEG. They concluded that it was the action of cocaine on limbic structures that played an important role in the persistence of these effects. Overall, the evidence indicates that cocaine enhances the propagation of limbic seizures. Since such activity has been associated with cardiac arrhythmia (Lathers and Schraeder 1982; Schraeder and Lathers 1983), it is quite possible that cocaine-induced seizures could be a factor in the deaths of persons using the drug. The cortical EEG effects of cocaine in humans were among the earliest documented effects of the drug (Berger 1937). Cocaine increases power in the fast frequency (beta bands) of the resting EEG after subcutaneous, intravenous, or oral administration (Berger 1937; Herning et al. 1985). Four-hour intravenous infusions of high doses of cocaine in humans sustains the increase in EEG beta power (Pickworth et al. 1986). The increase of power in

1 min after injection

7th week after cocaine initiation

µV/mm 15

L OLF BULB

7.5

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7.5

L AMYG

15

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Figure 11.4╇ Electrographic amygdala–olfactory spindling and spike response to 5 mg/kg (i.v.) cocaine during preseizure behaviors.

178 Sudden Death in Epilepsy: Forensic and Clinical Issues

the fast EEG frequency bands is ordinarily associated with increased attention, vigilance, or arousal. Pickworth et al. (1986) measured subjective, cardiovascular, and EEG effects of large (60 mg) intravenous doses of cocaine in human volunteers. Although the subjective report of “rush” lasted for only a few moments, the pressor effect and tachycardia persisted for up to 60 min (Figure 11.5). The rush, or intense cocaine-induced euphoria, is the effect for which the drug is self-administered. It is quite probable that inadvertent overdosage may occur when subjects readminister cocaine at a time when the cardiovascular and central nervous systems are at jeopardy. In reviewing the effect of cocaine on the electrophysiology of the central monoaminergic neurons, Pitts and Marwah (1986) found that intravenous cocaine activated cerebellar Purkinje neurons and inhibited serotonergic dorsal raphe and noradrenergic locus coeruÂ� leus neurons. The authors concluded that cocaine-induced increases in the mean arterial blood pressure were correlated with changes in the discharge of the central neurons. Pitts and Marwah (1987) also found that reserpine pretreatment diminished the inhibitory effects of intravenous cocaine on neuronal discharges in the locus coeruleus and dorsal raphe as well as the excitatory action of cocaine on the cerebellar Purkinje neurons. Thus, although stimulation of the inhibitory locus coeruleus afferent input to the cerebellar Purkinje neurons can reduce the activity of the Purkinje neurons via a betaadrenoceptor mechanism, intravenous cocaine (1 mg/kg) did not precipitate the inhibitory actions of locus coeruleus stimulation on cerebellar Purkinje neurons. This dose of cocaine also did not potentiate the inhibitory effects of iontophoretically applied norepinephrine or GABA on cerebellar Purkinje neurons. Locus coeruleous neurons were inhibited by intravenous cocaine (1 mg/kg) in conscious animals paralyzed with gallamine. It was proposed that intravenous cocaine (1 mg/kg) reduced impulse flow in locus coeruleus neurons, possibly through an alpha2-autoreceptor mechanism, without augmenting the effect

Systolic pressure (mm Hg)

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Figure 11.5╇ Effects of intravenous cocaine (60 mg) in seven drug-experienced volunteers. The high dose caused a transient “rush” (drug-induced euphoria) but prolonged increases in blood pressure and heart rate.

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of norepinephrine at the level of the noradrenergic terminals impinging on postsynaptic cerebellar Purkinje neurons. The action of cocaine on norepinephrine-containing locus coeruleus neurons was also evaluated in freely moving, unanesthetized cats (Trulson and Trulson 1987). Cocaine eÂ�licited a dose-dependent reduction in the activity of the neurons, which was suppressed by a prior administration of an alpha2 antagonist, piperoxane. Also, the activity of the locus coeruleus remained unchanged by the administration of the structurally related local anesthetic agent procaine. It was concluded that the local anesthetic actions of cocaine were not the inhibitory factor in its effect on the activity of norepinephrine-containing nÂ�eurons. Nevertheless, as Yasuda et al. (1984) stated, “It is remarkable that its effects upon the electrophysiological activity of the brain remain virtually unknown.” Whether cocaineiÂ�nduced changes in the activity of central neurons contributes to sudden death remains to be determined. 11.3.5â•…Cocaine-Induced Seizures Seizures have been shown to play an essential role in the pathophysiology of cocaine toxicity. A major determinant of lethality in cocaine-treated dogs was the presence of seizures (Catravas and Waters 1981; Catravas et al. 1978). Cocaine infusions produced prolonged seizures that led to lactic acidosis and hyperthermia prior to death while cardiac output, systemic vascular resistance, respiration, and oxygenation were stable just prior to death. Seizures and death could have been prevented with pretreatment using diazepam, highdose chlorpromazine, or neuromuscular blockade with pancuronium (Antelman et al. 1981; Fekete and Borsy 1971). The use of diazepam is particularly important since it also counteracts the sympathomimetic action of cocaine on the heart. Treatment of acidosis alone did not prevent death, unless the animals were maintained in a hypothermic state. Jonsson et al. (1983) reported one patient who, as a result of cocaine intoxication, showed combined metabolic and respiratory acidosis consequent to seizures and hypoventilation. Improved ventilation and the administration of bicarbonate reversed the hypotension and accelerated idioventricular rhythm to sinus rhythm. Blood pH increased from 6.33 to normal and the pCO2 decreased from 70 to 46 mm Hg. Jonsson et al. concluded that respiratory arrest compounded the acidosis in patients intoxicated with cocaine and may have contributed signiἀcantly to their deaths. Acidosis has a particularly negative effect on myocardial contractility (Fabiato and Fabiato 1978; Spivey et al. 1985) and acidosis can heighten the effects of catecholamines on the heart (Ford et al. 1968; Lathers et al. 1988; Spivey et al. 1985), and thereby contribute to the initiation of arrhythmias by cocaine. Carbamazepine is an antiepileptic drug that seems to be particularly effective in treating limbic system seizures. In experimental studies, repeated high doses of cocaine produce a convulsive response classiἀed as pharmacologic kindling. Weiss et al. (1987) reported that chronic carbamazepine administration inhibited the development of lidocaine- or cocaine-kindled seizures and lethality. Chronic, but not acute, pretreatment with carbaÂ� mazepine inhibited the high-dose cocaine seizures. It was suggested that carbamazepine may interact with local anesthetic mechanisms mediating the progressive development of seizures and that the effects of this antiepileptic drug at the level of the sodium channels should be further explored since both carbamazepine and the local anesthetics are believed to interact at this site. Investigation of the mechanism responsible for this effect should be undertaken, as it may prove clinically useful in preventing cocaine toxicity.

180 Sudden Death in Epilepsy: Forensic and Clinical Issues

11.4â•…Treatment of Cocaine-Induced Arrhythmias and Seizures Treatment of cocaine toxicity must ultimately involve deconditioning therapy to reduce drug craving and drug-seeking behavior (Kumor et al. 1988). Tricyclic antidepressants, bromocriptine, amantadine, methylphenidate, and lithium may decrease cocaine selfmedication. The hypertension and tachycardia that follow administration of cocaine are mediated by both alpha-adrenergic and beta-adrenergic receptors to induce vasoconstriction and an increase in heart rate and cardiac output, respectively (Olsen et al. 1983). One clinical management procedure of the adrenergic cocaine crisis involves the judicious use of intravenous propranolol, given in doses of 1 mg at 1-min intervals to a total of up to 6€mg (Gay 1982). Although intervention calms the excitable patient and decreases tachyÂ� arrhythmias, the efficacy of propranolol is limited by its receptor sensitivity. It has been argued that although propranolol effectively blocks beta receptors to decrease heart rate, it leaves the alpha-adrenergic receptors unopposed (Olsen et al. 1983). Thus stimulation of the alpha1-adrenergic receptors in the smooth muscle vasculature results in a worsening of vasoconstriction with resultant dangerous hypertension. Olsen et al. (1983) propose the use of phentolamine or nitroprusside to effect rapid vasodilatation. However, Gay (1983) argues that the nonselective alpha-adrenergic blockade properties of phentolamine may, in fact, further aggravate matters. Indeed, phentolamine will block alpha1 postsynaptic receptors to decrease vasoconstriction, but it will also block alpha2 presynaptic receptors. This blocks the normal regulatory control of the catecholamines, resulting in an increase in synthesis and output of norepinephrine, and may even spur a reflex sympathetic response to the heart. One agent recently used to treat cocaine toxicity is labetalol, which possesses both alpha- and beta-blocking capabilities. Thus the establishment of the alpha blockade counters the cocaine-induced vasoconstriction and hypertension while the beta blockade decreases the tachyarrhythmias (Gay and Loper 1988). The use of chlorpromazine and haloperidol to calm the hyperkinetic state is contraindicated in the cocaine user as they can lower seizure threshold activity and cause cardiac arrhythmias and/or sudden death (Lathers and Lipka 1986, 1987; Lipka and Lathers 1987). Instead, an effective means of quieting the stimulatory phase of cocaine intoxication is the use of diazepam, 15–20 mg orally every 8 h. Antelman et al. (1981) serendipitously found that amytriptiline, a tricyclic antidepressant, protected against sudden cardiac death due to cocaine intoxication in animals. Amytriptiline, 10 mg/kg, administered experimentally in animals 1 h before intraperitoneal injection of cocaine (35 mg/kg) resulted in no protection against sudden death. However, 24-h pretreatment with a single injection of amytriptiline markedly increased survival, while 10-day pretreatment conferred complete protection against sudden death. The mechanism of action, to date, has not been deἀned. However, pretreatment is not a useful tool in the management of clinical toxicity associated with cocaine use. It has recently been suggested that Ca2+ channel blockers may be a useful antidote for cocaine toxicity (Duke 1986; Mittleman and Welti 1987; Trouve and Nahas 1986). Ca2+ channel blockers inhibit the vasoconstrictive effects of norepinephrine by blocking the release of Ca2+ into the smooth muscle of the vasculature. Trouve and Nahas (1986) studied the cocaine antagonistic effects of nitrendepine, a Ca2+ channel blocker, in animals. Nitrendipine was selected for its lack of myocardial depressant activity and its ability to cause coronary vasodilatation. Nitrendipine (1.46 × 10−3 mg/kg/min) was concomitantly administered with 2 mg/ kg/min of cocaine and caused an inhibition of cocaine-induced tachycardia, pressor, and

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vasoconstriction. Nitrendipine also suppressed the cocaine-induced arrhythmias observed in control animals. In a comparative study, nitrendipine and propranolol were able to slow cocaine-induced tachycardia while nitrendepine alone increased coronary flow and pulse pressure. Nitrendipine, alone and in combination with propranolol, decreased coronary flow and performance (Trouve and Nahas 1986). In addition to its cardioprotective properties, nitrendipine appears to possess central activity. Nitrendipine prevented motor tremors, convulsions, and seizures (Trouve and Nahas 1986). It was concluded that the sympatho� mimetic properties of cocaine can be antagonized by Ca2+ channel blockers. Ca2+ channel blockers may become the drugs of choice for the treatment of cocaine intoxication.

11.5â•…Use of Cocaine in Persons with Epilepsy Since cocaine use has been reported to produce hypertension, ventricular arrhythmias, tachycardia, myocardial infarction, seizures, and sudden death (Nahas et al. 1985; Tazelaar et al. 1987), and since persons with epilepsy have been shown to manifest autonomic dysfunction, including changes in blood pressure, heart rate, and rhythm (Leestma et al. 1984; Penἀeld and Erickson 1941; Phizackerly et al. 1954; Walsh et al. 1968), one must raise the question of whether the use of cocaine in individuals with epilepsy places them at risk of dying in a sudden, unexplained manner. Furthermore, dysfunction in the activity of peripheral cardiac autonomic neural discharge contributes to the production of cardiac arrhythmias (Gillis 1969; Gillis et al. 1972; Lathers et al. 1974, 1977, 1978; Verrier and Lown 1978; Weaver et al. 1976) and to sudden death (Lown and Verrier 1978). Lathers et al. (1977, 1978) and Lathers (1980) reported that nonuniform discharge in the cardiac postganglionic nerves, i.e., simultaneous increases and decreases in the various sympathetic branches innervating the myocardium, contributes to the production of arrhythmias by altering ventricular automaticity and excitability in the manner reported by Han and Moe (1964). Similar autonomic cardiac neural dysfunction was reported in association with arrhythmias and interictal and ictal discharges (Carnel et al. 1985; Lathers and Schraeder 1982, 1987; Lathers et al. 1984, 1987; Schraeder and Lathers 1983, 1988). Cocaine also modiἀes postganglionic cardiac sympathetic neural function, increasing the inotropic and chronotropic responses to sympathetic neural stimulation (Matsuda et al. 1980). Thus it is possible that the actions of cocaine and the autonomic cardiac neural dysfunction associated with epileptogenic activity may combine to produce cardiac arrhythmias and, at worst, sudden unexpected death. The question of whether cocaine use in the individual with epilepsy places the individual at risk for sudden death should be examined.

11.6â•…Summary This chapter has reviewed the incidence, characteristics, risk factors, and clinical management of cocaine-induced toxicity. Cocaine causes death by actions on the cardiovascular system, including cardiomyopathy, arrhythmia production, accelerated heart rate, and increased blood pressure. Seizures often accompany cocaine toxicity, leading to death. Cocaine is known to activate the EEG in humans, cause seizures in animals, and lower the seizure threshold. Patients with preexisting risk factors for cardiovascular pathology (high cholesterol, high blood pressure, cardiac arrhythmia, etc.) and those with epilepsy may

182 Sudden Death in Epilepsy: Forensic and Clinical Issues

be especially sensitive to cocaine-induced toxicity. Most research in animals suggests that cocaine-induced cardiovascular responses are due to enhanced noradrenergic response on the heart and arteriolar smooth muscles. While there is controversy surrounding the management of cocaine-induced toxicity, a symptomatic approach involves controlling the seizures with diazepam, the cardiovascular response with beta-adrenergic blockers or labetolol, a combined alpha- and beta-blocking agent, while correcting the systemic acidosis and hyperthermia. Use of the Ca2+ channel blockers may represent a new, more effective treatment. Finally, since both cocaine and epilepsy alone are associated with sudden unexpected death and since both are capable of modifying cardiac sympathetic neural discharge to produce changes in heart rate and rhythm, the question of whether the use of cocaine in the epileptic person places this individual at risk for sudden death must be raised.

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184 Sudden Death in Epilepsy: Forensic and Clinical Issues Lathers, C. M., and L. J. Lipka. 1987. Cardiac arrhythmia, sudden death and psychoactive agents. J Clin Pharmacol 27: 1–14. Lathers, C. M., and P. L. Schraeder. 1982. Autonomic dysfunction in epilepsy. Characterization of autonomic cardiac neural discharge associated with pentylenetetrazol-induced epileptogenic activity. Epilepsia 23: 633–648. Lathers, C. M., and P. L. Schraeder. 1987. Review of autonomic dysfunction, cardiac arrhythmias, and epileptogenic activity. J Clin Pharmacol 27: 346–356. Lathers, C. M., N. Turner, and J. M. Schoffstall. 1989. The effect of different routes of sodium bicarbonate administration on plasma catecholamines, pH, and blood pressure during cardiac arrest in pigs. Resuscitation 18: 59–74. Lathers, C. M., J. Roberts, and G. J. Kelliher. 1974. Relationship between the effect of ouabain on arrhythmia and interspike intervals (ISI) of cardiac accelerator nerves. Pharmacologist 16: 201. Lathers, C. M., J. Roberts, and G. J. Kelliher. 1977. Correlation of ouabain-induced arrhythmia and nonuniformity in the histamine-evoked discharge of cardiac sympathetic nerves. J Pharmacol Exp Ther 203: 467–479. Lathers, C. M., G. J. Kelliher, J. Roberts, and A. B. Beasley. 1978. Nonuniform cardiac sympathetic nerve discharge: Mechanism for coronary occlusion and digitalis-induced arrhythmia. Circulation 57: 1058–1065. Lathers, C. M., W. H. Spivey, L. E. Suter, J. P. Lerner, N. Turner, and R. M. Levin. 1986. The effect of acute and chronic administration of timolol on cardiac sympathetic neural discharge, arrhythmias, and beta receptor density associated with coronary occlusion in the cat. Life Sci 39: 2121–2141. Lathers, C. M., P. L. Schraeder, and S. B. Cornel. 1984. Neural mechanisms in cardiac arrhythmias associated with epileptogenic activity: The effects of phenobarbital. Life Sci 34: 1919–1936. Lathers, C. M., P. L. Schraeder, and F. L. Weiner. 1987. Synchronization of cardiac autonomic neural discharge with epileptogenic activity: The lockstep phenomenon. Electroencephalogr Clin Neurophysiol 67: 247–259. Lathers, C. M., W. H. Spivey, and N. Turner. 1988. The effect of timolol given ἀve minutes post coronary occlusion on plasma catecholamines. J Clin Pharmacol 28: 289–299. Leestma, J. E., M. G. Kalelkar, S. S. Teas, G. W. Jay, and J. R. Hughes. 1984. Sudden unexpected death associated with seizures: Analysis of 66 cases. Epilepsia 25: 84–88. Lesse, H., and J. P. Collins. 1979. Effects of cocaine on propagation of limbic seizure activity. Pharmacol Biochem Behav 11: 689–694. Lichtenfeld, P. J., D. B. Rubin, and R. S. Feldman. 1984. Subarachnoid hemorrhage precipitated by cocaine snorting. Arch Neurol 41: 223–224. Lipka, L. J., and C. M. Lathers. 1987. Psychoactive agents, seizure production, and sudden death in epilepsy. J Clin Pharmacol 27: 169–183. Loveys, B. J. 1987. Physiologic effects of cocaine with particular reference to the cardiovascular system. Heart Lung 16: 175–181. Lown, B., and R. L. Verrier. 1978. Neural factors and sudden death. In Perspectives in Cardiovascular Research. Vol. 2. Neural Mechanisms in Cardiac Arrhythmias, ed. P. J. Schwartz, A. M. Brown, A. Malliani, and A. Zanchetti, 87–98. New York, NY: Raven Press. Mathias, D. W. 1986. Cocaine associated myocardial ischemia. Am J Med 81: 675–678. Matsuda, Y., Y. Masuda, B. Blattberg, and M. N. Levy. 1980. The effects of cocaine, chlorpheniramine and tripelennamine on the cardiac responses to sympathetic nerve stimulation. Eur J Pharmacol 63: 25–33. Matsuzaki, M. 1978. Alteration in pattern of EEG activities and convulsant effect of cocaine following chronic administration in the rhesus monkey. EEG Clin Neurophysiol 45: 1–15. Mittleman, R. E., and C. V. Welti. 1987. Cocaine and sudden “natural” death. J Forensic Sci 32: 11–19. Nahas, G., R. Trouve, J. F. Demus, and M. von Sitbon. 1985. A calcium-channel blocker as antidote to the cardiac effects of cocaine intoxication. New Engl J Med 313: 519–520.

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Nanji, A. A., and J. D. Filipenko. 1984. Asystole and ventricular ἀbrillation associated with cocaine intoxication. Chest 85: 132–133. Olsen, K., N. Benowitz, and P. Pentel. 1983. Management of cocaine poisoning. Ann Emerg Med 10: 655–656. Pasternack, P. F., S. B. Colvin, and F. G. Baumann. 1985. Cocaine-induced angina pectoris and acute myocardial infarction in patients younger than 40 years. Am J Cardiol 55: 847. Penἀeld, W., and T. C. Erickson. 1941. Epilepsy and Cerebral Localizations, 320–362. Springἀeld, IL: Charles C. Thomas. Phizackerly, P. J. R., E. W. Poole, and C. W. M. Whitty. 1954. Sinoauricular heart block as an epileptic manifestation: A case report. Epilepsia 3: 89–91. Pickworth, W. B., R. I. Herning, K. Kumor, and M. Sherer. 1986. Spontaneous EEG during chronic cocaine infusion. Pharmacologist 28: 236. Pitts, D. K., and J. Marwah. 1986. Electro physiological effects of cocaine on central monoaminergic neurons. Eur J Pharmacol 131: 95–98. Pitts, D. K., and J. Marwah. 1987. Cocaine inhibits central monoaminergic neurons and activates cerebellar Purkinje neurons. Fed Proc 46: 400. Pitts, D. K., C. E. Udom, and J. Marwah. 1987. Cardiovascular effects of cocaine in anesthetized and conscious rats. Life Sci 40: 1099–1111. Ritchie, J. M., and N. M. Greene. 1980. Local anesthetics. In The Pharmacological Basis of Therapeutics, ed. L. S. Goodman and A. Gilman, 302–321. New York, NY: Macmillan. Roberts, D. C. S., M. E. Corcoran, and H. C. Fibiger. 1977. On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav 6: 615–620. Rockhold, R. W., B. Hoskins, and I. K. Ho. 1987. Spontaneously hypertensive rats are resistant to convulsive and lethal actions of cocaine. Fed Proc 46: 402. Rod, J. L., and R. P. Zucker. 1987. Acute myocardial infarction shortly after cocaine inhalation. Am J Cardiol 59: 161. Rollingher, I. M., A. S. Belzberg, and I. L. MacDonald. 1986. Cocaine-induced myocardial infarction. Can Med Assoc 135: 45–46. Rosendorff, C., J. T. E. Hoffman, E. D. Verrier, J. Rouleau, and L. E. Boerboom. 1981. Cholesterol potentiates the coronary artery response to norepinephrine in anesthetized and conscious dogs. Circ Res 45: 320–329. Schachne, J. S., B. H. Roberts, and P. D. Thompson. 1984. Coronary-artery spasm and myocardial infarction associated with cocaine use. New Engl J Med 310: 1665–1666. Schraeder, P. L., and C. M. Lathers. 1983. Cardiac neural discharge and epileptogenic activity in the cat: An animal model for unexplained sudden death. Life Set 32: 1371–1382. Schraeder, P. L., and C. M. Lathers. 1989. Paroxysmal cardiovascular dysfunction and epileptogenic activity. Epilepsy Res 3: 55–62. Simpson, R. W., and W. D. Edwards. 1986. Pathogenesis of cocaine-induced ischemic heart disease. Arch Pathol Lab Med 110: 479–484. Spivey, W. H., C. M. Lathers, D. R. Malone, H. D. Unger, S. Blat, R. M. McNamara, J. Schroffstall, and N. Turner. 1985. A comparison of intraosseous, central and peripheral routes of sodium bicarbonate administration during CPR in pigs. Arch Pathol Lab Med 14: 1135–1139. Tackett, R. L., and L. F. Jones. 1987. Central catecholaminergic changes and cardiovascular responses following acute administration of cocaine. Pharmacologist 29: 159. Tazelaar, H. D., S. B. Karch, B. G. Stephens, and M. E. Billingham. 1987. Cocaine and the heart. Hum Pathol 18: 195–199. Trendelenburg, U. 1968. The effect of cocaine on the pacemaker of isolated guinea-pig atria. J Pharmacol Exp Ther 161: 222–231. Trouve, R., and G. Nahas. 1986. Nitrendipine: An antidote to cardiac and lethal toxicity of cocaine. Proc Soc Exp Biol Med 183: 392–397. Trulson, T. J., and M. E. Trulson. 1987. Cocaine suppresses the activity of noradrenergic locus coeruÂ� leus neurons in freely moving cats. Pharmacologist 29: 159.

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Risk Factors for Sudden Death in Epilepsy Thaddeus s. Walczak

12

Contents 12.1 12.2 12.3 12.4 12.5

Introduction Epidemiologic Sources and Biases Traditional Risk Factors for SUDEP: Epilepsy Severity and Seizure Type SUDEP Is Not Conἀned to Severe Epilepsy Other Traditional Risk Factors 12.5.1 Age and Gender 12.5.2 Symptomatic Causes of Epilepsy 12.5.3 Sleep, Sleep Position, and Supervision during Sleep 12.5.4 Psychotropic Drugs 12.6 AED Use and SUDEP 12.6.1 AED Compliance and SUDEP 12.6.2 AED Polytherapy and SUDEP 12.6.3 Individual AEDs and SUDEP 12.7 Novel SUDEP Risk Factors: Recent Work 12.7.1 SCN1A Mutations 12.7.2 Heart Rate Variability and Cardiac Autonomic Instability 12.7.3 Anatomic and Electrophysiologic Substrates of SUDEP 12.7.3.1 Anatomic Substrates of Postictal Apnea 12.7.3.2 Anatomic Substrates of Cardiac Arrhythmia in SUDEP 12.7.3.3 Electrophysiologic Substrates of Cardiac Arrhythmia in€SUDEP 12.8 The Next Steps in the Study of SUDEP Risk Factors References

187 188 189 192 192 192 193 193 193 194 194 194 194 195 196 196 196 196 196 197 197 198

12.1â•…Introduction Understanding risk factors for sudden unexpected death in epilepsy (SUDEP) is important for both research-oriented and practical reasons. Current thinking regarding the pathophysiology and prevention of SUDEP remains largely speculative. Deἀning circumstances surrounding SUDEP and the patient and epilepsy characteristics associated with SUDEP could help direct investigations of pathophysiology. Risk factors can sometimes be modiἀed and could offer an approach to prevention, though we must remember that additional prospective studies with active intervention are necessary to demonstrate that modifying risk factors is effective. More practically, a consistent set of risk factors could deἀne a population that may be especially prone to SUDEP. This group can then be targeted for more detailed discussion of SUDEP and for any potential interventions. 187

188 Sudden Death in Epilepsy: Forensic and Clinical Issues

Growing interest in SUDEP over the past 25 years has prompted a series of investigations into the risk factors associated with this condition. This chapter attempts to review and synthesize this information. Such a synthesis is challenging because of differences in deἀnitions, study populations, and study design. However, the picture that emerges is remarkably consistent and corresponds well to what we are beginning to learn about pathophysiology.

12.2â•… Epidemiologic Sources and Biases Deἀning risk factors is initially a task for epidemiology. Selection and other biases associated with various epidemiologic approaches can signiἀcantly affect results. This is especially true when investigating an uncommon condition such as SUDEP. Different results in various studies may be due to the differing methodologies used. Before considering results, it is important to consider the biases associated with the various epidemiologic approaches used to determine SUDEP risk factors. Initial reports of SUDEP were uncontrolled case series collected at medical examiners’ offices (Leestma et al. 1989; Terrence et al. 1975; Freytag and Lindenberg 1964). These solidiἀed belief in SUDEP as an entity and provided an initial guess at risk factors. However, these populations are not representative of the great majority of people with epilepsy. Risk factor assessments based on this material are likely to be affected by selection bias, especially given the absence of control populations. Subsequent studies have evaluated SUDEP risk factors in more representative populations, including large prescription databases, cohorts of developmentally delayed persons with epilepsy, larger cohorts of persons with epilepsy at epilepsy centers, and drug and device development programs. These also do not represent the general population with epilepsy, though risk factors in SUDEP subjects are usually compared to nested controls in these studies, which reduces bias due to selection. A SUDEP population derived from a cohort of incident epilepsy would provide the best information on risk factors. However, such information is very difficult to obtain because SUDEP is rare in a population-based cohort with prevalent epilepsy (Ficker et al. 1998) and even rarer in a group with incident epilepsy (Lhatoo et al. 2001). Even if a reasonable number of cases were to be found in a large community-based cohort, it would be extremely difficult to assess circumstances of death and risk factors in retrospect. Less information is typically available about people with epilepsy drawn from a community; often the diagnosis of epilepsy is not secure. More information is usually available in groups followed in epilepsy clinics, where the diagnosis of epilepsy is probably more reliable. Most information regarding SUDEP risk factors is derived from retrospective SUDEP ascertainment. These studies often do not fully deἀne the cohort from which the deaths are drawn, so the population in which SUDEP is being described is often unclear. Further potential sources of bias include: 1. The possibility that not all deaths are ascertained 2. Difficulty in elucidating the circumstances of death several years later 3. Uncertainty about when risk factors for SUDEP and controls should be ascertained in the course of clinical follow-up 4. Difficulty in ascertaining risk factors in retrospect

Risk Factors for Sudden Death in Epilepsy

189

The general availability of mortality indices in developed countries allows reliable determination of whether a given individual is alive or not. However, determination of whether SUDEP occurred or not is very much dependent on a thorough understanding of the circumstances of death and this can be very difficult to reconstruct several years later. Deἀning a cohort and potential risk factors prospectively, assessing for death at regular intervals, and assessing for SUDEP promptly after death reduces these biases; however, such studies are more costly and challenging to perform as they need to utilize case investigators using a standardized set of questions to be asked of family and healthcare providers, as well as performance of autopsies for most, if not all, persons with a history of epilepsy who died. Choice of controls can also influence results. Some studies use people with epilepsy dying from causes other than SUDEP as controls. This is thought to provide information regarding circumstances of death (Tellez-Zenteno et al. 2005). However, mortality in the epilepsy population is mostly related to underlying causes of epilepsy. It is not clear that comparison of SUDEP deaths to epilepsy deaths (which are mostly related to the causes of epilepsy) adds much to understanding why SUDEP occurs. If the goal is determining which people with epilepsy are at risk for SUDEP, comparing risk factors in live people with epilepsy and SUDEP victims is more appropriate (Tomson et al. 2008). Finally, individual risk factors potentially associated with SUDEP may be related to other potential risk factors. An important example is seizure frequency, seizure severity, and anticonvulsant drug polytherapy, all of which may influence one another (Nilsson et al. 1999; Walczak et al. 2001; Langan et al. 2005). Establishing that a risk factor is independently responsible requires multivariate analysis, which, in turn, requires a reasonable number of cases and controls.

12.3â•…Traditional Risk Factors for SUDEP: Epilepsy Severity and Seizure Type Many potential risk factors have been examined (Table 12.1). Epilepsy severity and correlates such as epilepsy duration, seizure type, and seizure frequency have perhaps been most intensely studied. SUDEP risk has been consistently associated with more severe epilepsy, longer duration of epilepsy, and more frequent seizures. Table 12.2 summarizes SUDEP incidence in several populations with differing epilepsy severity. SUDEP incidence is very low in new onset (incident) epilepsy cohorts and somewhat increased in community-based prevalence cohorts. SUDEP incidence is higher in cohorts of persons with epilepsy at referral centers where more severe epilepsy cases may be expected to congregate. Incidence rates are still higher in drug and device development programs, which are usually limited to patients who have failed treatments with several antiepileptic drugs (AEDs). SUDEP incidence is highest in persons with epilepsy undergoing epilepsy surgery, where epilepsy is especially refractory. Furthermore, the percentage of all reported deaths due to SUDEP also increases with increasing epilepsy severity (Table 12.2). These two ἀndings establish a clear gradient of risk that strongly supports the idea that SUDEP risk increases with epilepsy severity. Most studies with live patient controls report that SUDEP is associated with higher seizure frequency (Table 12.1). The larger controlled studies (Nilsson et al. 1999; Langan et al. 2005; Walczak et al. 2001) all demonstrate progressively increased relative risk with

0

ns

20/80

154/616

62/124

+

0

18

0

0

0

ns

+

0

Male Sex

11/?

ns

0

14/1806

57/171

ns

11/20

Young Age

0

+

ns

+

0

ns

Epilepsy Duration

+

+

+

ns

+

+

ns

0

Frequent Seizures

ns

+

+

ns

+

+

0

ns

0

+

+

nsa

ns

ns

+

Mental Retardation

0

0

+

+

+

+

0

ns

AED Polytherapy at Time of Death

0

0

ns

ns

ns

ns

0

Lack of€super� vision at night, treatment with CBZ

Rx with€anti� psychotic drugs

Treatment with CBZ, lack of supervision at night Rx with€anti� psychotic drugs Nonambulatory status

Noncompliance with AED Treatment Other Risk Factors

Note: SUDEP, sudden unexpected death in epilepsy; AED, antiepileptic drug; CBZ, carbamazepine. 0, item was not a risk factor for SUDEP; +, item was a risk factor for SUDEP; ns, item was not studied. a All SUDEP cases had mental retardation in this study.

Hiltris et al. (2007)

Nilsson et al. (1999) McKee and Bodἀsh (2000) Tennis et al. (1995) Walczak et al. (2001) Langan et al. (2005)

Jick et al. (1992) Timmings (1993)

Cases/ Controls

Frequent Tonic– Clonic Seizures

Table 12.1â•…Risk Factors for SUDEP in Some Studies with Living Persons with Epilepsy as Controls

190 Sudden Death in Epilepsy: Forensic and Clinical Issues

Risk Factors for Sudden Death in Epilepsy

191

Table 12.2â•… SUDEP Incidence with Increasing Epilepsy Severity

Study Lhatoo et al. (2001) Ficker et al. (1998) Jick et al. (1992) Tennis et al. (1995) Timmings (1993) Lip and Brodie (1992) Leppik (1995) Leestma et al. (1997) Annegers et al. (2000) Sperling et al. (1999) Dashieff (1991)

Population

Incidence (per 1000 patient years)

Percentage of Deaths That Are SUDEP (%)a

Population-based cohort of incident epilepsy Population-based cohort of prevalent epilepsy Large prescription database Large prescription database Epilepsy clinic Epilepsy clinic

0.09

0.5

0.35

8.6

1.3 1.35 2.0 4.9

26 11 nr

Tiagabine clinical trial Lamotrigine clinical trial Vagus nerve stimulator clinical trial Patients who underwent epilepsy surgery Candidates for epilepsy surgery

3.9 3.5 4.1 4.0

29 40 52 54

10.0

Source: Leestma et al., Epilepsia, 38, 47–55, 1997. Note: nr, not reported. a SUDEP included deἀnite and probable SUDEP cases.

higher seizure frequencies. When multivariate models include generalized tonic–clonic seizures, other seizure types, and AEDs, SUDEP risk appears associated with generalized tonic–clonic seizures rather than partial seizures (Walczak et al. 2001; Langan et al. 2005; Tomson et al. 2005). As few as three tonic–clonic seizures per year signiἀcantly increase SUDEP risk, compared to no tonic–clonic seizures; risk increases further with more frequent tonic–clonic seizures. Other evidence strongly supports the position that tonic–clonic seizures are an important risk factor for epilepsy. All studies assessing seizure type report a history of tonic–clonic seizures in at least 90% of SUDEP cases. These ἀndings are consistent no matter what the study design or source population (Hirsch and Martin 1971; Terrence et al. 1975; Earnest et al. 1992; Leestma et al. 1989; Kloster and Torstein 1999; Walczak et al. 2001; Timmings 1993; Langan et al. 2005). Furthermore, studies addressing circumstances of death report tonic–clonic seizure prior to death in most cases (Terrence et al. 1975; Leestma et al. 1989; Earnest et al. 1992; Nillson 1999; Langan et al. 2000; Opeskin and Berkovic 2003). The consistency of these ἀndings indicates that tonic–clonic seizures are an important proximate cause of SUDEP. The relationship between epilepsy duration and SUDEP risk is less clear. SUDEP did not occur in studies assessing outcome in the several years after an initial seizure (Beghi et al. 2005). When risk is stratiἀed by duration of epilepsy, a clinically and statistically signiἀcant risk is noted after 10 to 30 years of epilepsy (Walczak et al. 2001; Leestma et al. 1989). One case control study found increased SUDEP risk with longer epilepsy duration (Walczak et al. 2001) while another did not (Langan et al. 2005). Age of seizure onset is generally lower in SUDEP cases than in controls (Nillson 1999; Jick et al. 1992; Kloster and Torstein 1999). This also supports the idea that duration of epilepsy is an important risk factor.

192 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 12.3â•… Expected Yearly Number of SUDEP Cases in a Hypothetical City of 6,000,000 Inhabitantsa People with Epilepsy

SUDEP Rates (patient years)

Number of SUDEP Cases

Percentage of All SUDEP Cases (%)

24,000

0.5/1000 patient years

12

50

6,000 30,000

2.0/1000 patient years

12 24

50

Well-controlled epilepsy Intractable epilepsy Total a

See Section 12.4 for details.

12.4╇SUDEP Is Not Confined to Severe Epilepsy This information relating higher SUDEP risk to increased seizure severity is leading to the impression that SUDEP is conἀned to people with severe epilepsy. Population-based medical examiner series and clinical experience clearly indicate that this is not the case. SUDEP also occurs in people with what are generally considered to be well-controlled seizures (Opeskin and Berkovic 2003). In fact, a SUDEP presenting to a random physician is probably equally likely to occur in a person with well-controlled seizures as in a person with poorly controlled seizures. This is because, on a population basis, a large majority of people with epilepsy have reasonable seizure control. A thought experiment illustrates why this is the case (Table 12.3). Consider a large city with 6 million inhabitants. Assuming an epilepsy prevalence of 0.5%, we would expect the city to contain 30,000 individuals with epilepsy. Let us further assume that 80% of the individuals with epilepsy have well-controlled seizures and a SUDEP incidence of 0.5/1000 patient years. Of the individuals with epilepsy, 20% have poorly controlled seizures and a SUDEP risk of 2.0/1000 patient years. With these assumptions (Hauser and Hesdorffer 1990, Table 2), we would expect 12 SUDEP cases per year in the 24,000 individuals with well-controlled seizures and 12 SUDEP cases in the 6000 individuals with poorly controlled seizures. Thus, a SUDEP case presenting to a random health care worker in this city is as likely to have had well-controlled seizures as poorly controlled seizures. General practitioners would be more likely to encounter the SUDEP cases whose seizures had been well-controlled because most people with well-controlled epilepsy are followed by community physicians.

12.5â•…Other Traditional Risk Factors 12.5.1╇Age and Gender Initial uncontrolled case series described SUDEP as a phenomenon found in young men with excessive alcohol use (Leestma et al. 1989; Terrence et al. 1975). This constellation of risk factors appears to have reflected the cases typically referred to medical examiners’ offices and has not been found in controlled studies. Mean age at death in most studies is between 25 and 39 years (see Tomson et al. 2005 for review). Somewhat higher ages were found in the large cohort-based studies (Walczak et al. 2001; Langan et al. 2005; Nillson 1999). Neither population-based studies (Ficker et al. 1998) nor the large case control studies found a male predominance. In fact, two controlled studies (Walczak et al. 2001; Opeskin

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193

and Berkovic 2003) found increased incidence of SUDEP among women. Controlled series have not found evidence for increased alcohol abuse among victims of SUDEP (Nilsson et al. 1999; Langan et al. 2005; Opeskin and Berkovic 2003; Kloster and Torstein 1999). However, SUDEP risk appears lower among children than adults. SUDEP incidence in four pediatric studies ranged between 0.11 and 0.43/1000 patient years (Harvey et al. 1993; Donner et al. 2001; Weber et al. 2005; Camἀeld et al. 2002). A prospective cohort study supports this: SUDEP incidence was 0/3625 patient years (0/1000) in those aged 0–19 years, 13/7792 (1.67/1000) in those aged 20–39 years, and 7/3958 patient years (1.77/1000) in those aged 40–59 years (Walczak et al. 2001). Children with the rare and severe myoclonic epilepsy of infancy are an exception; unusually high rates of SUDEP have been reported in this condition (Dravet et al. 2005). 12.5.2â•… Symptomatic Causes of Epilepsy Early series also found an apparent excess of epileptogenic lesions among SUDEP victims (Leestma et al. 1989; Terrence et al. 1975). This ἀnding also appears to be related to selection bias. Controlled clinical (Walczak et al. 2001) and medical examiner’s series (Kloster and Torstein 1999; Opeskin and Berkovic 2003) have not found this association. Controlled studies have not found either symptomatic epilepsy (Nillson 1999; Kloster and Torstein 1999) or any particular epilepsy syndrome (Walczak et al. 2001; Opeskin and Berkovic 2003) to be more common among SUDEP victims either. However, there is some evidence that mental retardation is more common among SUDEP victims (Jick et al. 1992; Walczak et al. 2001) and the inability to ambulate may confer further risk in mentally retarded people with epilepsy (McKee and Bodἀsh 2000). Nonetheless, most SUDEP cases are not afflicted with mental retardation or cerebral palsy. 12.5.3â•… Sleep, Sleep Position, and Supervision during Sleep SUDEP victims are found dead in bed in the majority of cases (Leestma et al. 1989; Terrence et al. 1975; Opeskin and Berkovic 2003; Kloster and Torstein 1999; Nashef et al. 1995), suggesting that sleep increases SUDEP risk. Most patients found dead in bed are found prone in both controlled and uncontrolled studies (Leestma et al. 1989; Kloster and Torstein 1999). Supervision at night (deἀned here as the presence in the bedroom of a responsible individual of normal intelligence), the use of a listening device, and regular checks throughout the night were associated with lower SUDEP rates in a large, retrospective, controlled study (Langan et al. 2005). These ἀndings are consistent with the idea that SUDEP related to postictal apnea is more likely to be lethal when appropriate positioning and ἀrst aid does not occur following a nocturnal seizure. Please see the chapter by Drs. Sato and Hughes discussing SUDEP and sleep in this book. 12.5.4â•… Psychotropic Drugs Antipsychotic drugs are associated with increased risk of sudden death (Ray et al. 2009) and treatment with selective serotonin reuptake inhibitors decreases SUDEP risk in an animal model of SUDEP (Tupal and Faingold 2006). Use of psychotropic medications is probably more common in persons with epilepsy than in the general population. This raises the question of whether use of psychotropic drugs affects SUDEP risk. Several controlled

194 Sudden Death in Epilepsy: Forensic and Clinical Issues

studies have found that the use of psychotropic drugs in general is not more common in SUDEP victims than in control persons with epilepsy (Tennis et al. 1995; Nilsson et al. 1999; Walczak et al. 2001; Langan et al. 2005; Opeskin and Berkovic 2003). Anxiolytic drugs speciἀcally were found to be more common in SUDEP in one study (Nilsson et al. 1999) and less common in SUDEP in another (Opeskin and Berkovic 2003). Antipsychotic use was speciἀcally examined in one study (Nillson 1999) and was not associated with SUDEP. The association between clinical use of selective serotonin reuptake inhibitors and SUDEP has not been examined.

12.6â•…A ED Use and SUDEP 12.6.1â•…A ED Compliance and SUDEP Initial medical examiner series found that most SUDEP victims had subtherapeutic AED levels (Leestma et al. 1989; Terrence et al. 1975; Kloster and Torstein 1999). This led to the conclusion that noncompliance was associated with SUDEP. Controlled medical examiner series have not consistently found subtherapeutic AED levels in SUDEP cases (George and Davis 1998; Opeskin et al. 1999). Furthermore, antiepileptic drug metabolism continues after death so postmortem AED levels may not accurately reflect compliance (see Walczak 2003 for review). Comparison of AED levels at antemortem visits in SUDEP and control patients has not found evidence of decreased noncompliance in SUDEP patients (Walczak et al. 2001; Nilsson et al. 2001; Langan et al. 2005). Overall, noncompliance with antepileptic drug treatment does not appear to be an important risk factor for SUDEP. 12.6.2â•…A ED Polytherapy and SUDEP AED polytherapy at death was noted to be common in initial studies (Leestma et al. 1989; Terrence et al. 1975; Tennis et al. 1995). This was initially thought to be a surrogate marker for severe epilepsy rather than an independent risk factor. However, two controlled studies found that treatment with more than two AEDs was associated with SUDEP, even after adjusting for the number of seizures and seizure type (Walczak et al. 2001; Nilsson et al. 1999). A third controlled study adjusting for seizure frequency and type did not ἀnd SUDEP to be associated with the number of AEDs at the time of death, but did ἀnd SUDEP to be associated with the number of AEDs ever used (Langan et al. 2005). Thus, it appears that AED polytherapy is associated with SUDEP, even after adjusting for seizure severity and frequency. The pathophysiologic implications of these ἀndings are unclear. AED polytherapy could have additive adverse effects on cardiac function (see Section 12.6.3). Alternatively, increased sedation associated with polytherapy could prolong recovery from the postictal state and cause greater susceptibility to the postictal central apnea and positional asphyxia that may play a role in SUDEP. 12.6.3â•…Individual AEDs and SUDEP This raises the question as to whether any individual AED or combination is associated with SUDEP. Carbamazepine use appears particularly likely to be associated with cardiac arrhythmia and alteration of cardiac autonomic function (see Walczak et al. 2003 for

Risk Factors for Sudden Death in Epilepsy

195

review). Consequently several reports have asked whether carbamazepine use is associated with SUDEP with mixed ἀndings. An uncontrolled series found what appeared to be a high rate of carbamazepine use in people succumbing to SUDEP (Timmings 1998). Four larger controlled series found that carbamazepine use was equally likely in SUDEP cases and in control subjects (Walczak et al. 2001; Nilsson et al. 1999; Kloster and Torstein 1999; Opeskin et al. 1999). A cohort based controlled study (Jick et al. 1992) found that carbaÂ� mazepine use was less likely in SUDEP cases. The largest SUDEP series published (Langan et al. 2005) found that SUDEP was associated with current carbamazepine use (odds ratio 2.0, 95% conἀdence interval 1.1–3.8), even after adjustment for potential confounders. This series of 154 SUDEP cases had the highest power to detect association between individual AED use and SUDEP. However, this was not a cohort-based study; cases and controls were drawn from differing sources, allowing an introduction of bias. Further analyses have asked whether carbamazepine toxicity is associated with SUDEP. Two studies have not found association between carbamazepine toxicity and SUDEP (Walczak et al. 2001; Opeskin et al. 1999). However, a more detailed analysis (Nilsson et al. 2001) found that SUDEP risk was increased more than nine-fold with toxic carbamazepine concentrations at the time of last visit, even after adjusting for confounders. Risk was further increased after adjusting for number of AED dose changes in the last year. SUDEP risk was also increased nine-fold with low carbamazepine concentrations at last visit, but only when more than one AED dose change had been made in the last year. In contrast, SUDEP risk was not increased with therapeutic carbamazepine concentrations, irrespective of how many AED dose changes had been made. The authors concluded that frequent changes of carbamazepine dose with concentrations outside therapeutic range were an independent risk factor for SUDEP after adjustment for seizure severity. This would go along with the idea that abrupt large fluctuations in carbamazepine levels exacerbate cardiac autonomic instability in people with epilepsy and increase SUDEP risk. The occurrence of SUDEP with other epilepsy treatments has not been thoroughly examined. SUDEP may be less frequent with phenytoin use than with carbamazepine use (Nilsson et al. 2001); it is not clear whether this reflects a deleterious effect of carbaÂ� mazepine or a protective effect of phenytoin. Single retrospective studies have reported that SUDEP is less common when lamotrigine (Leestma et al. 1997) or the vagal nerve stimulator (Annegers et al. 2000) is used.

12.7â•…Novel SUDEP Risk Factors: Recent Work Several risk factors have been proposed based on preliminary observations. We discuss them because they illustrate the study of SUDEP risk factors related to pathophysiologic theories, rather than standard demographic variables. In general, two major theories of SUDEP pathogenesis have been proposed (Tomson et al. 2008). One holds that severe postÂ� ictal cerebral inhibition leads to postictal central apnea, which, together with obstructive apnea, leads to arrhythmia and death. Another theory holds that the signiἀcant adrenergic stimulation associated with frequent tonic–clonic seizures results in microscopic cardiac lesions such as subendocardial ἀbrosis or contraction band necrosis. These then act as potential foci for arrhythmia, perhaps triggered by adrenergic stimulation associated with further tonic–clonic seizures. Arrhythmia risk may already be increased in this population because of the cardiac autonomic abnormalities thought to be more common in people

196 Sudden Death in Epilepsy: Forensic and Clinical Issues

with epilepsy, as previously discussed. Some literature has begun to address risk factors based on these pathophysiologic theories. 12.7.1â•…SCN1A Mutations Two cases of SUDEP have been reported in a family with generalized epilepsy with febrile seizures and with a mutation in the sodium channel gene SCN1A (Hindocha et al. 2008). Mortality and SUDEP rates are increased in severe myoclonic epilepsy of infancy—an epilepsy syndrome also caused by an SCN1A mutation (Dravet et al. 2005). SCN1A is expressed in the heart. This has led to the idea that SCN1A mutations may predispose people with epilepsy to arrhythmia and SUDEP (Nashef et al. 2007). In principle, comparing the prevalence of SCN1A mutations in SUDEP victims and persons with epilepsy controls dying of other causes could answer this question. This approach could be extended to other genes predisposing to cardiac arrhythmias (Nashef et al. 2007). 12.7.2â•…Heart Rate Variability and Cardiac Autonomic Instability Heart rate variability is an indicator of cardiac autonomic function and can be easily assessed by a standardized analysis of R–R intervals during electrocardiography. Heart rate variability changes are known to be associated with sudden death in the general population. Heart rate variability changes are more common in people with epilepsy, though it is not clear whether the epilepsy itself, use of AEDs, or conditions comorbid with epilepsy are responsible (Tomson et al. 1998; Walczak 2003). This has led to the idea that altered heart rate variability may be a marker of SUDEP risk (Yuen and Sander 2004; DeGiorgio et al. 2008). Observers have further noted that omega-3 fatty acids reduce sudden cardiac deaths in healthy subjects and may therefore help prevent SUDEP (Yuen and Sander 2004). Preliminary studies suggest that omega-3 fatty acids normalize HRV in people with epilepsy (DeGiorgio et al. 2008). A large study examining whether omega-3 fatty acids can prevent SUDEP is being planned. 12.7.3â•…A natomic and Electrophysiologic Substrates of SUDEP 12.7.3.1â•…A natomic Substrates of Postictal Apnea If postictal central and obstructive apnea are responsible for SUDEP, anatomic features associated with obstructive sleep apnea (increased body mass index, increased neck circumference, nasal obstruction, decreased pharyngeal diameter, etc.) should be more common in people with SUDEP than in persons with epilepsy controls. This information does not appear in the literature, though such data should be easy to obtain from material in medical examiner series. Similarly, a person with epilepsy will adjust spontaneously in the postictal state to maintain an open airway. One would expect such spontaneous adjustments to be less common in people with cerebral palsy or other conditions limiting movement. This idea is supported by reports that SUDEP is more common in people with developmental delay (Walczak et al. 2001) and inability to ambulate (McKee and Bodἀsh 2000). 12.7.3.2â•…A natomic Substrates of Cardiac Arrhythmia in SUDEP If cardiac arrhythmia due to microscopic cardiac lesions and the adrenergic surge associated with a tonic–clonic seizure is responsible for SUDEP, microscopic subendocardial

Risk Factors for Sudden Death in Epilepsy

197

abnormalities or conduction abnormalities should be more common in SUDEP victims than in control persons with epilepsy. Information from small, controlled series indicates that subendocardial abnormalities may be more common in persons with epilepsy than in control subjects without epilepsy (P-Codrea Tigaran et al. 2005; Natelson 1998). However, prevalence of subendocardial or conduction abnormalities does not differ between people with epilepsy dying from SUDEP and those dying of other causes (Opeskin et al. 2000). Nonetheless, these are small studies with inadequate power to exclude a potential contribution from subtle cardiac lesions, so further study is warranted. 12.7.3.3â•…Electrophysiologic Substrates of Cardiac Arrhythmia in SUDEP If the hearts of persons with epilepsy are, in fact, more susceptible to arrhythmia, one would expect nonfatal arrhythmia to be more common in persons with epilepsy than in control populations. A controlled study of 24 to 48 hours of cardiac monitoring has not found this to be the case (Blumhardt et al. 1986). Long-term electrocardiographic recordings of small numbers of people with severe epilepsy, usually lasting for many months, have found periods of asystole generally thought to require intervention in 15% (Rugg-Gunn et al. 2004). However, these studies are not controlled; the incidence of asystole during prolonged recordings in people with chronic disease (or, for that matter, in healthy young men) is not known. This amalgam of information raises the question whether people with severe epilepsy should undergo long term electrocardiographic monitoring and whether asymptomatic arrhythmias found by such monitoring should be treated. Long-term cardiographic monitoring of a larger group of persons with epilepsy is currently underway (Cooper 2008). However, this appears to be an uncontrolled study so it may be difficult to determine the clinical relevance of the information obtained.

12.8â•…The Next Steps in the Study of SUDEP Risk Factors The studies reviewed here have established a reasonably consistent risk proἀle for SUDEP. Persons with epilepsy succumbing to SUDEP suffer from generalized tonic–clonic seizures, have longer durations of epilepsy, and are often treated with multiple AEDs. Other potential risk factors such as treatment with speciἀc classes of psychotropic drugs, or treatment with speciἀc AEDs deserve further exploration. Examining these potential risk factors will be challenging for two reasons. First, SUDEP is uncommon in the general population and persistent surveillance of large groups is required for detection. Second, any risks associated with putative risk factors will require adjustment for risks known to be associated with the traditional risk factors described above. It is clear that future research should move beyond the old approach of retrospective case accumulation with convenience controls in convenience populations. Analysis of what we have called traditional risk factors together with animal studies have led to reasonably supported pathophysiologic theories (Lathers 2010, Chapter 25; Lathers and Schraeder 2010, Chapter 28; Lathers and Levin 2010, Chapter 33; Alkadhi and Alzoubi 2010, Chapter 26; Bealer et al. 2010, Chapter 38; Faingold et al. 2010, Chapter 41; Stewart 2010, Chapter 39; Goodman et al. 2010, Chapter 40). We are now in a position to study novel risk factors that support or detract from those theories. The state of knowledge is such that prospective studies validating traditional risk factors can now be undertaken. This would require periodic standardized longitudinal

198 Sudden Death in Epilepsy: Forensic and Clinical Issues

surveillance for SUDEP in multiple centers but should be feasible with a well-organized approach. With a little more information, hypothesis-based intervention studies in populations at high risk should soon be feasible as well. Much work will need to be done to increase recognition of SUDEP and set up the core infrastructure for such studies (So et al. 2009). Given what we have learned already, such an investment is quite likely to lead to more complete understanding and, ultimately, prevention of this tragic condition.

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EEG Findings in SUDEP Maromi Nei Nicole Simpkins

13

Contents 13.1 Introduction 13.2 EEG Data in Patients Who Subsequently Died due to SUDEP 13.3 EEG in SUDEP and Near-SUDEP 13.4 Conclusions References

201 201 202 205 206

13.1â•…Introduction Most of the data regarding the EEG during SUDEP are obtained from case reports from patients undergoing ambulatory EEG or video-EEG monitoring. These data are limited, but the EEG during SUDEP has generally shown a generalized tonic–clonic seizure with subsequent suppression. Ictal and interictal EEG recordings in patients with SUDEP have revealed varied ἀndings.

13.2â•…EEG Data in Patients Who Subsequently Died due to SUDEP In the majority of cases of witnessed SUDEP, a seizure is reported to precede death. In 12 of 15 witnessed cases of SUDEP, a generalized tonic–clonic seizure preceded death (Langan et al. 2000). In the other three cases in this series, either an aura occurred or the patient was thought to be in a postictal state. Since seizures usually precede death in SUDEP, this suggests that seizures are often responsible for triggering the physiologic changes that ultimately lead to SUDEP. Thus, the evaluation of the EEG and other physiologic data during seizures and interictally could yield clues regarding the pathophysiology of SUDEP. The video-EEG monitoring data in individuals who subsequently died due to SUDEP have revealed seizures of various localization and lateralization (Nei et al. 2004). In this study, video-EEG data from 21 patients who subsequently died due to SUDEP were reviewed and compared with video-EEG data from a control refractory focal epilepsy population. The majority (86%) of patients had ictal EEG recorded, in addition to interictal EEG data. Localization of seizure onset was conἀdently identiἀed as arising from the left hemisphere in 29% and from the right hemisphere in 14%. The remainder had seizures that were either nonlateralized (24%), multifocal (5%), or generalized (14%) in onset. Of these patients, 43% were thought to have temporal lobe onset for their seizures and 19% had a probable frontal lobe onset; however, these data are likely biased since the majority of patients were admitted as part of their evaluations for potential epilepsy surgery. No speciἀc lobe of onset or lateralization for seizures was more common in SUDEP than in control patients. 201

202 Sudden Death in Epilepsy: Forensic and Clinical Issues

There are also data to suggest that prolonged seizures, generalized tonic–clonic seizures, as well as seizure clusters, might increase the risk for increased autonomic stimulation during seizures and might increase the risk for cardiac arrhythmias (Nei et al. 2000, 2004). Unfortunately, there were no speciἀc EEG ἀndings that were predictive of SUDEP. Most patients with SUDEP die in their sleep. EEG data also suggest that patients with SUDEP are more likely to have a history of and/or documentation of seizures arising from sleep, as compared with control patients (Nei et al. 2004). Opherk et al. also found that in patients with refractory epilepsy (in a non-SUDEP population), there was a trend toward increased ictal-related EKG abnormalities during seizures associated with sleep, suggesting a potential speciἀc sleep-related risk on autonomic status during seizures arising at this time, which might increase risk for SUDEP. The reader is referred to the chapter on sleep and SUDEP by Drs. Sato and Hughes in this book. While it is clear that seizures can cause ictal and postictal EKG rate and repolarization abnormalities, the potential interictal effects of epileptiform abnormalities on cardiac and pulmonary function are not as clear. One study evaluated the effect of interictal epileptiform EEG discharges on the QTc interval of the EKG in patients who subsequently died due to SUDEP (Tavernor et al. 1996). In this study, the EEGs influence on EKG data from eleven patients with SUDEP were compared with data from 11 age and sex matched control patients, also with uncontrolled tonic–clonic seizures who were alive at the time of the investigation. They found that only for those with SUDEP, the QTc interval was signiἀcantly prolonged during epileptiform EEG discharges. This led to the speculation that prolonged QTc intervals might increase the likelihood for potentially lethal ventricular arrhythmias and sudden cardiac death. However, additional data are needed to conἀrm these ἀndings. No speciἀc information regarding the type or localization of the EEG epileptiform abnormalities is available from this study. Most epidemiologic studies on SUDEP have focused on seizure type, rather than speciἀc EEG ἀndings. Generalized tonic–clonic seizures increase the risk for SUDEP and these may be either primarily or secondarily generalized seizures (Nei et al. 2004).

13.3â•…EEG in SUDEP and Near-SUDEP There are few case reports of SUDEP or near SUDEP captured during EEG recording available in the literature (see Table 13.1). One case of SUDEP captured during video-EEG monitoring includes a 41-year-old woman with refractory focal epilepsy since infancy (Lee 1998). Interictally, she had independent bitemporal sharp waves, with left greater than right. During sleep, she had an unwitnessed secondarily generalized tonic–clonic seizure lasting 70 seconds, which was followed by diffuse slowing on the EEG and left temporal sharp waves for 40 seconds, then marked suppression, with overlying EKG artifact seen that failed to recover. The EKG initially showed bradycardia to 30 beats per minute (bpm), which slowly increased to 70 bpm ἀve minutes after the seizure. However, the heart rate then began to slow and stopped 18 minutes after the seizure. There was no evidence of cardiovascular nor pulmonary abnormalities at autopsy, and no evidence of asphyxia. The cause of SUDEP in this case was postulated to be cessation of brain function. McLean and Wimalaratna (2007) reported a case of a woman in her ἀfties who died following a seizure while undergoing ambulatory EEG monitoring. Interictally, she had slow and sharp wave discharges that increased in frequency during sleep. During sleep,

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203

Table 13.1â•… EEG and Seizure Data: Cases of SUDEP and Near-SUDEP Interictal EEG

Report

Death

Dasheiff and Dickinson (1986)

Yes

N/A

Bird et al. (1997)

Yes

Lee et al. (1998)

Yes

L Temp, R temp, R occipital Bitemporal sharp waves, L€>€R

McLean and Wimalaratna (2007) So et al. (2000)

Yes

Tavee and Morris (2008) Espinosa et al. (2009)

No

Slow and sharp discharge Bifrontal sharp waves

No

L temp

No

Bitemporal theta/delta

Postictal EEG

Sz Type Prior to Event

N/A

N/A

CPS

R medial temporal

R suppressed, GTC then bilateral suppression GTC Diffusely Slow; L temp sharp waves × 40 secs Diffuse EEG c/w No suppression GTC

EKG: pulse artifact at 48 bpm EKG:€brady� cardia at 30 bpm€post� ictally

Bifrontal

Diffusely slow, then suppressed

GTC

Yes: 4 GTC in 6 h

L hem, maximal temp R temp

Continuous slowing

GTC

Yes: 1 aura, 4 partial and 2 GTC No

Apnea postictally, then€brady� cardia and asystole Stridor/ resp distress€af�� ter sz ended EKG: VT, then VF

Ictal EEG

N/A

Spike-wave discharge

Diffusely slow GTC

Sz Cluster Prior to Event Yes: cluster of 2 GTC and 1 CPS within 3 h Yes: cluster of 5 GTCs in 24 h No

Notes EKG: VF



Note: sz, seizure; L, left; R, right; temp, temporal; N/A, not available; hem, hemisphere; secs, seconds; GTC, generalized tonic–clonic seizures (either primary or secondarily generalized); c/w, consistent with; CPS, complex partial seizure; bpm, beats per minute; VF, ventricular ἀbrillation; resp, respiratory; VT, ventricular tachycardia.

a 52-second seizure beginning with spike and wave discharges was captured, followed abruptly by marked suppression that failed to recover. Further details regarding localization of ictal and interictal discharges are not available. Rhythmic movement artifact was seen at the T3 electrode, with associated muscle activity that became less frequent and disappeared completely 3 minutes after seizure termination, leaving a suppressed EEG. No EKG or respiratory data were available. One case of SUDEP during intracranial EEG monitoring was reported by Bird et al. (1997). A 47-year-old man with refractory seizures since age 19 was admitted for videoEEG monitoring. He had undergone ambulatory scalp monitoring and had three complex partial seizures with secondary generalization that began with right hemispheric slow waves, but were otherwise nonlocalized. Interictally, there were complex left temporal discharges, right temporal spikes, and occasional right occipital spikes. He then underwent implantation of bilateral temporal depth electrodes and subdural electrodes of the anterior

204 Sudden Death in Epilepsy: Forensic and Clinical Issues

and posterior temporal regions for further evaluation of his seizures. The operation and immediate postoperative period were uneventful. He subsequently had four secondarily generalized seizures and died following the ἀfth seizure at 3 a .m. Electrographic onset in all ἀve seizures was in the right medial temporal lobe. The ἀfth seizure occurred during sleep and began with head version to the left followed by turning of his body, then a generalized convulsion lasting for 2.5 minutes. At the end of the convulsion, he no longer moved. The EEG showed right mesial temporal onset, with the electrographic discharge spreading to the left hemisphere after 15 seconds, and subsequent generalized discharge lasting 2.5 minutes. The right-sided ictal discharge then briefly flattened, alternating with spindling spike discharges for 16 seconds, before stopping completely, leaving a suppressed background on the right. The left hemisphere continued to show spikes for 8 more seconds, then stopped. Pulse artifact, at 46 beats per minute, was seen for another 2 minutes and then gradually decreased in amplitude (continuing at the same rate) until the heart beat stopped. There were no respiratory or EKG recordings. Postmortem examination revealed mild congestion in the lungs and normal cardiac examination. The neuropathological examination showed an acute infarct in the right temporal lobe, attributed to insertion of the depth electrodes, acute hypoxic changes in the right hippocampus, evidence of old frontal contusions bilaterally, and bilateral occipital ulegyria. Dasheiff and Dickinson (1986) reported a case of sudden unexpected death in a patient undergoing video-EEG monitoring with intracranial electrodes. The patient was a 48-yearold man with a history of prior myocardial infarction and refractory focal epilepsy who had been implanted with depth electrodes for seizure focus localization. He had two secondarily generalized tonic–clonic seizures within 1 hour of each other. After the second seizure, the patient complained of chest and left arm pain. An EKG revealed ST segment elevation and inverted T waves. One hour later, the patient complained of chest pain, then was witnessed to have a complex partial seizure, becoming cyanotic and apneic. The ἀrst available EKG revealed coarse ventricular ἀbrillation, followed by asystole. Cardiopulmonary resuscitation was ineffective. Postmortem examination revealed no acute coronary artery thromboses or pulmonary emboli but did reveal an old myocardial infarction. The EEG ἀndings were not reported. It is likely that the acute sympathetic discharge due to the cluster of seizures precipitated both the angina and ventricular arrhythmia, to which he was already predisposed, due to his underlying previous myocardial infarction. A similar mechanism has been proposed as resulting in myocardial infarction in the setting of seizure (Chin et al. 2004). It is of interest to speculate that a vasospasm mechanism such as that observed in Prinzmetal Angina could account for the ST elevation and cause infarction in the absence of atherosclerosis. A case of near SUDEP due to postictal severe laryngospasm was reported by Tavee and Morris (2008). A 42-year-old man with refractory epilepsy since age 6 was admitted for video-EEG monitoring. Interictally, he had frequent left sphenoidal electrode sharp waves and less frequent posterior temporal sharp waves. He had one simple partial seizure and 5 complex partial seizures, two of which secondarily generalized. Ictal EEG showed left hemisphere, maximal in the temporal region, ictal fast activity. During seizure six, the patient awakened from sleep with right arm and face twitching, followed by right arm extension, left arm flexion, head version to the right and a generalized convulsion. The entire seizure lasted 82 seconds. Following the seizure, he developed inspiratory stridor and marked cyanosis, eventually requiring intubation for respiratory support. The anesthesiologist noted laryngospasm at the time of intubation. It was postulated that aspiraÂ� tion€may have triggered the laryngospasm. The postictal EEG showed diffuse slowing until

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6 hours after the seizure, when he developed nonconvulsive status epilepticus, which eventually resolved. He recovered to baseline and was ultimately discharged home. So et al. (2000) reported a case of near-SUDEP due to postictal central apnea. A 20-yearold woman with refractory epilepsy since age 1, was admitted for video EEG monitoring. She had frequent generalized convulsions and complex partial seizures and also had a history of convulsive status epilepticus at age 9 when she developed mononucleosis, which culminated in cardiorespiratory arrest. There were no permanent neurologic deἀcits after this event. She had no known cardiovascular or pulmonary disorders; however, following both clusters of seizures, as well as isolated, self-limited seizures, she had postictal respiratory arrest and had required cardiopulmonary resuscitation since age 10. It had been observed that following a seizure, her pulse was initially regular and strong, but this disappeared€as the apnea continued. Outpatient interictal EEG showed bisynchronous frontal sharp waves. During the monitoring, she had a cluster of four generalized convulsions within 6€hours, lasting 55–85 seconds each. Ictal EEG showed bifrontal slow waves at onset. She had fully recovered from the ἀrst three seizures when she had a fourth seizure, lasting 56 seconds. She was noted to have apnea immediately following the seizure. The EKG remained unchanged for 10 seconds, then gradually slowed until the heart stopped 57 seconds later. Postictally, the EEG showed diffuse slowing for 20 seconds, which was followed by marked suppression. She was successfully resuscitated, and follow-up cardiac evaluation showed no evidence of cardiac or pulmonary disease. A demand cardiac pacemaker was placed. Following implantation of the pacemaker, 10–15 second periods of apnea were noted after seizures; however, she no longer required cardiopulmonary resuscitation. Recently, a case of near-SUDEP revealed a right temporal complex partial seizure with secondary generalization associated with ventricular tachycardia (Espinosa et al. 2009). A 51-year-old woman underwent video-EEG monitoring for refractory focal epilepsy. Her interictal EEG revealed bitemporal independent theta and delta activity, and a baseline EKG revealed a ἀrst-degree atrioventricular block, with a normal QTc interval. She had a typical complex partial seizure with secondary generalization, which was associated with ventricular tachycardia, then ventricular ἀbrillation, toward the end of the seizure. The patient underwent successful cardiopulmonary resuscitation and subsequent deἀbrillator implantation.

13.4â•…Conclusions The EEG data from patients with SUDEP, near-SUDEP, or subsequent SUDEP reveal a variety of interictal ἀndings, with both focal and generalized interictal epileptiform abnormalities. While the case numbers are limited, the ictal EEG recordings from patients with SUDEP or near-SUDEP have uniformly recorded a terminal generalized tonic–clonic seizure, except in one case, which reported a cluster of two secondarily generalized tonic–clonic seizures and then a complex partial seizure just prior to death. This ἀnding is consistent with epidemiologic data that generalized tonic–clonic seizures increase risk for SUDEP. The data thus far do not implicate a speciἀc seizure focus lateralization or lobe of the brain being associated with a higher risk for SUDEP. These data, while limited, also suggest that seizure clusters might also increase risk for SUDEP. The EEGs from cases of SUDEP also reveal diffuse suppression after the seizure ends. Based on this ἀnding, the possibility of primary cerebral shutdown has been proposed

206 Sudden Death in Epilepsy: Forensic and Clinical Issues

(Bird et al. 1997). The sudden cessation of cerebral activity has been suggested to be due to primary irreversible brain failure, with cardiorespiratory failure occurring as a secondary consequence. However, it is important to note that there are limited cardiorespiratory data available in these cases. Alternatively, it is possible that seizures could result in concomitant cardiopulmonary abnormalities during the ictal or postictal phase of the seizure, resulting in either anoxia or decreased cardiac output. While there can be diffuse suppression of the EEG after an uncomplicated generalized tonic–clonic seizure, anoxia or decreased cardiac output, such as related to a seizure-related arrhythmia or pulseless electrical activity, may explain the persistence of this suppression and lack of recovery of the EEG in these SUDEP cases. While a primary cerebral etiology is possible, the data thus far suggest that the seizure itself is an important trigger for a cascade of respiratory and/or cardiac abnormalities that ultimately cause death. The near-SUDEP case of Espinosa et al. (2009) and the SUDEP case of Dasheiff and Dickinson (1986) were associated with ventricular tachyarrhythmias occurring during or toward the end of a seizure. In the two SUDEP cases with EKG or pulse artifact, bradycardia was recorded, suggesting that cardiac function was affected. The respiratory status in these cases is unknown, but it is possible that respiratory compromise could have occurred during the seizure, resulting in persistent postictal suppression of the EEG and reflex bradycardia. In the So et al. (2000) case, it appears that apnea triggered the bradycardia and treatment with a cardiac pacemaker insertion has been helpful. Even though the apnea was the initial event, the more concerning life-threatening cardiorespiratory response may have been the secondary cardiac effect of bradycardia, which had been eliminated by the pacemaker. More detailed analysis of EEG data and close correlation with cardiac and pulmonary function is needed to fully interpret the EEG ἀndings obtained thus far during SUDEP. Perhaps the use of more routine pulmonary and cardiac monitoring, along with EEG recordings, may yield further insights into the pathophysiology of SUDEP. Hopefully, specialized investigation, ideally evaluating the combined neurologic, cardiac, and pulmonary data in people with epilepsy during both the ictal as well as interictal states, will identify risk factors for SUDEP and provide targets for preventative therapy.

References Bird, J. M., K. A. T. Dembny, D. Sandeman, and S. Butler. 1997. Sudden unexplained death in epilepsy: An intracranially monitored case. Epilepsia 38 (S11): S52–S56. Chin, P. S., K. R. Branch, and K. J. Becker. 2004. Myocardial infarction following brief convulsive seizures. Neurology 63 (12): 2453. Dasheiff, R. M., and L. J. Dickinson. 1986. Sudden unexpected death of epileptic patient due to cardiac arrhythmia after seizure. Arch Neurol (43): 194–196. Espinosa, P. S., J. W. Lee, U. B. Tedrow, E. Bromἀeld, and B. A. Dworetzky. 2009. Sudden unexpected near death in epilepsy (SUNDEP): Malignant ventricular arrhythmia from a partial seizure. Neurology 72: 1702–1703. Langan, Y., L. Nashef, and J. W. A. S. Sander. 2000. Sudden unexpected death in epilepsy: A series of witnessed deaths. J Neurol Neurosurg Psychiatry 68: 211–213. Lee, M. A. 1998. EEG video recording of sudden unexpected death in epilepsy. Epilepsia 39 (S6): 120–121. McClean, B. N., and S. Wimalaratna. 2007. Sudden death in epilepsy recorded in ambulatory EEG. J Neurol Neurosurg Psych 78: 1395–1397.

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Nei, M., R. T. Ho, and B. W. Abou-Khalil et al. 2004. EEG and ECG in sudden unexplained death in epilepsy. Epilepsia 45 (4): 338–345. Nei, M., R. T. Ho, and M. R. Sperling. 2000. EKG abnormalities during partial seizures in refractory epilepsy. Epilepsia 41 (5): 542–548. Opherk, C., J. Coromilas, and L. J. Hirsch. 2002. Heart rate and EKG changes in 102 seizures: Analysis of influencing factors. Epilepsy Res 52: 117–127. So, E., M. Sam, and T. Lagerlund. 2000. Postictal central apnea as a cause of SUDEP: Evidence from near-SUDEP incident. Epilepsia 41 (11): 1494–1497. Tavee, J., and H. Morris. 2008. Severe postictal laryngospasm as a potential mechanism for sudden unexpected death in epilepsy: A near-miss in an EMU. Epilepsia 49 (12): 2113–2117. Tavernor, S. J., S. W. Brown, R. M. E. Tavernor, and C. Gifford. 1996. Electrocardiograph QT lengthening associated with epileptiform EEG discharges—A role in sudden unexplained death in epilepsy? Seizure 5: 79–83.

Severity of Seizures as a Forensic Risk and Case Reports Edward H. Maa Michael P. Earnest Mark C. Spitz Jacquelyn Bainbridge

14

Contents 14.1 What Is a Severe Seizure? 14.2 Deἀnition 14.3 Epidemiology 14.4 SUDEP Risk Factors 14.5 Witnessed Cases 14.6 University of Colorado Epilepsy Monitoring Unit Case 14.7 Conclusion References

209 210 211 211 211 215 218 219

14.1â•…What Is a Severe Seizure? Seizures are a debilitating neurological condition characterized by the sudden evolution of synchronous electrical activity in the brain that can lead to loss of awareness, confusion, sudden falls, odd motor behaviors or sensations, and convulsions (Spitz 1998). Medically inexperienced, ἀrst-time witnesses of seizures are frightened or confused and often misinterpret the event as the impending death of the patient. What makes a seizure severe? The lay media implies the severity of seizures by the intense shaking, drooling, and eye rolling associated with a convulsion. The severity of a seizure in a typical medical encounter is judged by its duration and the presence of witnessed convulsion, tongue biting, and incontinence. To the patient stricken with seizures, however, each event is severe not only because of the clinical manifestation of the seizure, but also because of the psychosocial impact of the unpredictability of the seizure. The epileptologist’s approach to seizure severity is in alignment with the patient perspective but also emphasizes the likelihood of injury. This likelihood of injury is the foundation of seizure precautions and is intended as a safety recommendation because of the unpredictability of epileptic seizures. The sudden change or loss of awareness associated with seizures would not in and of itself be harmful if it only occurred in sleep. In the settings of operating heavy machinery, swimming or bathing alone, work or play at heights, tight spaces, or with open flames including cooking stoves, seizures can have devastating consequences. Even a single seizure in these settings increases the risk of death or serious injury. 209

210 Sudden Death in Epilepsy: Forensic and Clinical Issues

Unpredictability inevitably leads to anxiety. Any new neurology resident taking stroke calls can attest to many sleepless nights waiting for their ἀrst tissue plasminogen activator (tPA) candidate. New parents experience anxious and uneasy sleep, listening to the irregular breaths and sounds of a sleeping newborn infant. In much the same way, it is the overwhelming anticipation, rather than the seizure itself, that leads to chronic anxiety. In fact, of 1023 epilepsy patients who responded to an Epilepsy Foundation questionnaire, uncertainty and fear of the next seizure was rated as the worst thing about having epilepsy (Fisher et al. 2000). Fear eventually leads to restricted movements outside of the home, decreased productivity, and impaired livelihood. Psychiatric disturbances including depression and agoraphobia can be found in as many as 70%, and the risk of suicide in uncontrolled epilepsy patients is 13%, nine times that of the general population (Nowack 2006). Seizures themselves have graded severity; intuitively, the more violent the motor involvement, the more severe the seizure. This concept is manifest in the old terminology of “grand mal” and “petit mal” seizures. The imprecision of these terms from the perspective of therapeutics and modern epilepsy care ignores the fact that to the lay person, blinking and staring cannot possibly be as serious as convulsing and becoming cyanotic. The higher the frequency and longer the duration of an individual seizure, as well as the overall duration of epilepsy, add to the concept of severity, as do a number of surrogate markers including increased numbers and doses of medications, specialists, and surgeries. The ultimate marker of seizure and epilepsy severity is any seizure event that results in death. Recent sensationalized deaths in persons having a seizure emphasize the fact that uncontrolled epilepsy should not be thought of as a chronic condition that merely necessitates annual reἀlling of medications (Epilepsy Foundation 2009; Phillips 2008). Obviously, patients with persistent seizures are at increased risk of fractures, burns, and drowning, but they also exhibit increased rates of depression, anxiety, and suicide (Sperling 2004; Spitz et al. 1994). Less well known in the general medical community is that sudden unexplained death in epilepsy (SUDEP) is the most common cause of seizure-related death (Langan et al. 2000; Langan and Nashef 2003), accounting for as many as 50% of early deaths in refractory epilepsy patients (Sperling 2001).

14.2â•…Definition Sudden unexplained death in epilepsy can be established by applying the criteria developed by an expert panel (Leestma et al. 1997):

1. Diagnosis of epilepsy 2. Death occurring unexpectedly while in a reasonable state of health 3. Death occurring suddenly 4. Death occurring during normal activities and benign circumstances 5. No obvious medical cause of death determined during postmortem examination 6. Death is not the result of trauma, asphyxia from aspiration, or status epilepticus

Death from SUDEP is “deἀnite” if all conditions are satisἀed and “probable” if no postmortem data is available.

Severity of Seizures as a Forensic Risk and Case Reports

211

14.3â•…Epidemiology Fortunately, SUDEP remains relatively rare with annual incidence ἀgures ranging from 0 to 10 per 1000 patients, depending on the studied population (Tellez-Zenteno et al. 2005). Reflected in these numbers is the suggestion that seizure severity accounts for a higher incidence of SUDEP, with epilepsy surgical candidates representing the higher end of the spectrum and general population coroner’s cases representing the lower end of the spectrum. SUDEP appears to be mainly a problem in patients with refractory epilepsy. In the National General Practice Study of Epilepsy in the United Kingdom (NGPSE), there was only one conἀrmed case of SUDEP in 7147 person years. In this prospective cohort of 564 patients, 70% became seizure-free for at least 5 years of the mean 15 years of follow-up (Sander et al. 1990).

14.4â•…SUDEP Risk Factors Accumulated risk factors from descriptive cohort studies over the years include youth (Leestma et al. 1997; Opeskin and Berkovic 2003), male gender (Tennis et al. 1995), early onset of epilepsy (Kloster and Engelskjon 1999; Nilsson et al. 1999), duration of epilepsy and seizure frequency (Walczak et al. 2001; Leestma et al. 1997), poor control of seizures (Sperling et al. 1999), convulsive seizure type (Kloster and Engelskjon 1999; Birnbach et al. 1991), high antiepileptic drug number (Nilsson et al. 1999; Tennis et al. 1995; Walczak et al. 2001; Racoosin et al. 2001), frequency of antiepileptic drug changes (Nilsson et al. 1999), subtherapeutic antiepileptic drug levels (Kloster and Engelskjon 1999; Earnest et al. 1992), mental retardation (Walczaket al. 2001), concomitant use of psychotropic medications (Nilsson et al. 1999; Tennis et al. 1995), prone position (Kloster and Engelskjon 1999), and being found in bed or home (Kloster and Engelskjon 1999; Opeskin and Berkovic 2003). Despite inconsistent methodologies, patient populations, and autopsy availability, Stollberger and Finsterer (2004) and Tellez-Zenteno et al. (2005) summarized these ἀndings in their works, providing a picture of a mid to late 30s male living alone with poorly€controlled, long-standing symptomatic convulsive epilepsy, on multiple medications, found dead in bed in the prone position, often with evidence of a recent seizure.

14.5â•…Witnessed Cases The elusiveness of SUDEP’s etiology likely remains because of its predilection for unwitnessed sleep, relative rarity, and its multifactorial nature. Witnessed case reports over the years have shed some light on this devastating condition. Dasheiff and Dickinson (1986) described a 48-year-old male from the Wisconsin Epilepsy Center with a witnessed complex partial seizure who recovered, but then suffered what appeared to be a second seizure accompanied by ventricular ἀbrillation on EKG. Even though witnessed in the hospital, he was not successfully resuscitated and went on to receive an unrevealing autopsy. The authors suspected a cardiac origin of SUDEP. Later, Dasheiff (1991) described a much higher incidence of SUDEP, almost 1:100, than previously reported from their experience at the Pittsburgh Epilepsy Center. One of the seven patients he described was in the midst of transfer from the intensive care unit to

212 Sudden Death in Epilepsy: Forensic and Clinical Issues

the hospital floor after receiving a temporal lobectomy for refractory epilepsy when she suddenly expired while sitting unmonitored in bed. Efforts to resuscitate her were also fruitless and, despite another negative autopsy, the author suspected a cardiac cause as the leading etiologic hypothesis. Purves et al. (1992) reported a case of a 27-year-old woman from the British Columbia epilepsy program. She had complex partial seizures during her monitoring stay, but her last event was a secondarily generalized tonic–clonic seizure that resulted in her lying in the prone position. She was found 24 min later, cyanotic and unable to be resuscitated. Authors attributed this death to asphyxia following severe postictal depression. Bird et al. (1997) reported the ἀrst intracranially monitored case, from their experience in Bristol, England. The patient had bilateral, anterior and posterior temporal depth electrodes placed. Two days later, all medications were withdrawn and he had four typical seizures with right mesial temporal onset of electrical activity followed by blank staring, left head turn, then 2−4 min of convulsion. His ἀfth seizure occurred in sleep during which his left head turn was followed by his whole body turning to the prone position. He convulsed for 2.5 min then stopped moving and never recovered. Evidence of labored breathing or asphyxia was not seen by the authors and, unfortunately, there was no cardiac rhythm strip associated with this recording. The electroencephalogram (EEG) revealed an unusual right mesial spindling spike-discharge burst suppression activity for 16 s, followed by electrical silence. The left hemisphere showed rhythmic spike discharges for an

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Figure 14.1╇ The time stamps on each figure show the progression of time. EKG rhythm strips illustrate the lengthening between complexes and the peaking of T waves.

Severity of Seizures as a Forensic Risk and Case Reports

213

additional 8 s when they also disappeared permanently. Pulse artifact was seen for an additional 2 min, prompting the authors to downplay the cardiac arrhythmia hypothesis of SUDEP. The lack of slow wave changes on EEG was also not suggestive of cerebral anoxia. Based on the pattern of spindling spike discharges seen as the terminal event, the authors suggested that dysregulation of thalamocortical regulatory systems may not only shut off cortical activity, but may be responsible for cessation of all life functions. Lee (1998) reported a case from Calgary during which a woman’s convulsion was followed by bradycardia to a rate of 30 beats/min. A minute after seizure cessation, the EEG became silent and never recovered. Interestingly, the bradycardia resolved after 4 additional minutes, returning to a rate of 70 beats/min, until the patient ἀnally expired 18 min later. A cardiac cause was also not suspected as an explanation for the death. Finally, McLean and Wimalaratna (2007) described an ambulatory EEG case from the United Kingdom of a woman with poorly controlled epilepsy who underwent ambulatory monitoring. Her ambulatory recorder documented increasing spike frequency once she had fallen asleep, eventually coalescing into an ictal event at 08:27:18 the next morning. Reminiscent of the intracranial case, the seizure exhibited polyspike (up to 6 spikes) activity for 52 s, abruptly terminated at 08:28:14, leaving an isoelectric EEG. No cardiac rhythm information was recorded, but rhythmic movement artifact was seen in the left temporal leads associated with muscle activity. It slowed to complete cessation of activity over the next 3 min. The patient was found the next morning in her night clothes, prone on

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Figure 14.2╇ The time stamps on each figure show the progression of time. EKG rhythm strips illustrate the lengthening between complexes and the peaking of T waves.

214 Sudden Death in Epilepsy: Forensic and Clinical Issues

the floor with arm outstretched toward the telephone. The authors also could not attribute the death to hypotension or cerebral anoxia due to the lack of slow wave activity on the EEG (Neidemeyer and Da Silva 1987). They coined the phrase abrupt irreversible “cerebral electrical shutdown” to explain the primary mechanism of SUDEP. The largest case-control study of SUDEP is from the United Kingdom, where autopsies are routinely performed on suspected seizure deaths. Langan et al. (2005) published their results of 154 cases of conἀrmed SUDEP. Of the conἀrmed SUPDEP cases, 15% (23 cases) were witnessed, with the majority following a convulsive seizure and associated with breathing difficulties. In addition to previous accounts of cardiac arrhythmias, they suggest central and obstructive apneas are likely contributors to SUDEP mechanisms, based on the high frequency of labored breathing reported. In the controlled environment of epilepsy monitoring and telemetry units, cardiac cases may be enriched because nurse interventions, such as rolling patients into the recovery position, nasal cannula oxygen, as well as engaging the postictal patient in the neurological exam, may be sufficient to prevent deaths from apneic mechanisms. This argument is supported by their ἀnding that supervision was a protective factor in their study, and further supported by a study of SUDEP incidence at a residential school for children with epilepsy who were supervised at night and carefully monitored after a seizure. Of the 310 students enrolled between 1970 and 1993, there were no SUDEP deaths during term, but 14 sudden deaths while at home on vacation. Most were unwitnessed (Nashef et al. 1995).

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14.6â•…University of Colorado Epilepsy Monitoring Unit Case The patient was a 63-year-old, right-handed male with seizures beginning at age 6 or 7. His seizures began with a vague, “strange feeling,” followed quickly by a sensation of nervousness and feeling of “wanting to get away.” This lasted 30 s and was followed by lethargy and trouble with expressive speech for several minutes. These events occurred multiple times a day despite maximal medical management, and very rarely would be followed by a secondarily generalized tonic–clonic seizure lasting 1 to 2 min. His last convulsive seizure occurred more than 5 years ago, and he had no history of status epilepticus. He had failed multiple antiepileptic medications including phenobarbital, valproic acid, gabaÂ� pentin, lamotrigine, topiramate, zonisamide, and levetiracetam, and was currently being managed by phenytoin, 300 mg twice daily, and carbamazepine, 600 mg twice daily, by a community neurologist. His past medical history was signiἀcant for complex partial seizures, depression (fluoxetine, 20 mg nightly), hypertension (atenolol, 50 mg nightly), and a history of head trauma before 2 years of age during which he was unconscious for more than a week. He was the product of an uncomplicated pregnancy and birth and there was no family history of epilepsy. Physical examination was remarkable for blood pressure of 147/77 and pulse 62, II/VI systolic crescendo/decrescendo cardiac murmur at the right upper sternal border, and brisk but symmetric lower extremity reflexes with flexor plantar responses. Routine EEG revealed left temporal sharp waves. MRI scans were performed at an outside hospital and not available for review. Fp1 - F7

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Figure 14.4╇ The time stamps on each figure show the progression of time. EKG rhythm strips illustrate the lengthening between complexes and the peaking of T waves.

216 Sudden Death in Epilepsy: Forensic and Clinical Issues

He was admitted for epilepsy monitoring for potential ablative epilepsy surgery. Phenytoin and carbamazepine doses were halved on day 2. Phenytoin was discontinued on day 3, and carbamazepine was discontinued on day 4. During the latter half of day 4, the patient had two of his typical complex partial events with the second one generalizing into a mild convulsion. These events evolved out of the left temporal lobe and, of note, the patient’s postictal pulse following his convulsion was 140 beats/min. In the early morning of day 5, he had a third and ἀnal event. The seizure began typically, evolving from the left temporal region, but clinically the patient was sleeping in a prone position. His seizure generalized after 45 s, but the patient remained prone, his face hidden in his pillow. Audio and visual conἀrmation of progressively labored postictal breathing with good chest expansion was evident after the gentle convulsion ended 1 min later. One-and-a-half minutes after this, his EEG attenuated to essentially a flat baseline with only pulse artifact appreciated. Less than 30 s later, audio and visual evidence of breathing stopped as the EKG rhythm strip also terminated in electrical silence (Figures 14.1 through 14.8). The cardiac rhythm strip is particularly insightful in this tragic case, and suggests that previous cases may beneἀt from reevaluation by a multidisciplinary team. The EKG following the cessation of the convulsive seizure begins to suggest a peaked T wave (Figure 14.4 compared with Figure 14.1). In Figure 14.5, junctional escape beats are appreciated as the T wave continues to exhibit a more peaked appearance. By Figure 14.7, signiἀcant ST elevation is appreciated as the cardiac rhythm begins to slow signiἀcantly and, by Figure 14.8, cardiac electrical activity is silent. In a review of these series of rhythm strips with Fp1 - F7

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Figure 14.5╇ The time stamps on each figure show the progression of time. EKG rhythm strips illustrate the lengthening between complexes and the peaking of T waves.

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a cardiologist, the peaking of T waves followed by junctional escape beats suggests acidemic hyperkalemia (C. Long, personal communication, April 21, 2009). Not having the beneἀt of the corresponding video that clearly demonstrates the patient as being postictal with labored, facedown breathing, Long suggested the EKG showed the patient becoming acidemic, possibly by a rebreathing mechanism. Acute potassium shifts associated with respiratory acidosis are predicted (Perez et al. 1981), but whether levels associated with rebreathing are sufficient to produce cardiac disturbance are less certain (S. Linus, personal communication, May 4, 2009). Linus reviewed the postictal EKG as well, but as a nephrologist, he was much less impressed with the EKG being explained by hyperkalemia, claiming that despite the minimal peaking of the T wave, the QRS complex remained narrow throughout. Montague et al. (2008) retrospectively reviewed the frequency of EKG changes in hyperkalemia. Despite subjective corroboration of peaking of the T wave with quantitative amplitude measurements, no diagnostic threshold could be established. In fact, the EKG had such poor sensitivity and speciἀcity for hyperkalemia, they recommended against EKGs in guiding treatment of hyperkalemia in stable patients. The cardiologic and nephrologic interpretation of this rhythm strip remains unresolved, but suggests a different and broader approach to the problem of SUDEP. Could a combination of convulsion-related lactic acidosis plus respiratory acidosis from prone rebreathing be sufficient to cause a potassium-related fatal arrhythmia? Much like the ambulatory and intracranial EEG cases, there was no evidence of slow waves to suggest that hypotension or cerebral anoxia were the cause of death. Additionally, the EEG Fp1 - F7

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Figure 14.6╇ The time stamps on each figure show the progression of time. EKG rhythm strips illustrate the lengthening between complexes and the peaking of T waves.

218 Sudden Death in Epilepsy: Forensic and Clinical Issues

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Figure 14.7╇ The time stamps on each figure show the progression of time. EKG rhythm strips illustrate the lengthening between complexes and the peaking of T waves.

had become silent a full 4 min before the last EKG activity, possibly supporting McLean’s concept of “cerebral electrical shutdown.” Could hyperkalemia or respiratory acidosis contribute to this phenomenon? Or are these patient’s EKG changes wholly unrelated to the underlying mechanism of SUDEP? More questions than answers remain.

14.7â•…Conclusion Seizure severity appears to be a forensic risk for the development of SUDEP. Seizures that are convulsive, frequent, and of long duration appear to increase the risk of SUDEP to almost 1:100 per year (Tellez-Zenteno et al. 2005), but not all SUDEP deaths are preceded by convulsions. Instead complex partial seizures and recovery from complex partial seizures with death a short time later have been reported (Langan et al. 2005). The severity of a speciἀc convulsion is also not particularly helpful, as witnessed in the University of Colorado case. The patient began convulsing in a prone position and essentially never moved from the spot. The convulsion was not of an unusual duration or violent motor behavior, but appeared to be position dependent. The nexus of coroners’ (Leestma 1990) and witnessed cases of SUDEP seems to suggest that a signiἀcant number of deaths are associated with prone positioning, which really has nothing at all to do with seizure severity. As increased interest and research in SUDEP further clariἀes the pathophysiologic explanations of sudden death in epilepsy, our epidemiological concept of seizure severity

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Figure 14.8╇ The time stamps on each figure show the progression of time. EKG rhythm strips illustrate the lengthening between complexes and the peaking of T waves.

may likely play a less signiἀcant role in our approach to SUDEP understanding, education, and avoidance.

References Bird, J. M., K. A. T. Dembny, D. Sandeman, and S. Butler. 1997. Sudden unexplained death in epilepsy: An intracranially monitored case. Epilepsia 38 (s11): 52–56. Birnbach, C. D., A. J. Wilensky, and C. B. Dodril. 1991. Predictors of early mortality and sudden death in epilepsy: A multidisciplinary approach. J Epilepsy 4: 11–17. Dasheiff, R. M. 1991. Sudden unexpected death in epilepsy and its relationship to sudden cardiac death. J Clin Neurophysiol 8: 216–222. Dasheiff, R. M., and L. J. Dickinson. 1986. Sudden unexpected death following a seizure in an epileptic patient: A case report. Arch Neurol 43: 194–196. Earnest, M. P., G. E. Thomas, R. A. Eden, and K. F. Hossack. 1992. The sudden unexplained death syndrome in epilepsy: Demographic, clinical, and postmortem features. Epilepsia 33: 310–316. Epilepsy Foundation. 2009. http://www.epilepsyfoundation.org/epilepsyusa/news/Travolta.cfm (acÂ�Â� cessed February 8, 2009). Fisher, R. S., B. G. Vickrey, P. Gibson et al. 2000. The impact of epilepsy from the patient’s perspective I. Descriptions and subjective perceptions. Epilepsy Res 41 (1): 39–51. Kloster, R., and T. Engelskjon. 1999. Sudden unexpected death in epilepsy (SUDEP): A clinical perspective and a search for risk factors. J Neurol Neurosurg Psychiatry 67: 439–444. Langan, Y., and L. Nashef. 2003. Sudden unexpected death in epilepsy (SUDEP). ACNR 2 (6): 6–8.

220 Sudden Death in Epilepsy: Forensic and Clinical Issues Langan, Y., L. Nashef, and J. W. Sander. 2000. Sudden unexpected death in epilepsy: A series of witnessed deaths. J Neurol Neurosurg Psychiatry 68: 211–213. Langan, Y., L. Nashef, and J. W. Sander. 2005. Case-control study of SUDEP. Neurology 64: 1131–1133. Lee, M. A. 1998. EEG Video recording of sudden unexpected death in epilepsy (SUDEP). Epilepsia 39 (s6): 123–124. Leestma, J. E. 1990. Sudden unexpected death associated with seizures: A pathological review. In Epilepsy and Sudden Death, ed. C. M. Lathers and P. L. Schraeder, 61–88. New York, NY: Marcel Dekker. Leestma, J. E., J. F. Annegers, M. J. Brodie et al. 1997. Sudden unexplained death in epilepsy: Observations from a large clinical development program. Epilepsia 38: 47–55. McLean, B. N., and S. Wimalaratna. 2007. Sudden death in epilepsy recorded in ambulatory EEG. J Neurol Neurosurg Psychiatry 78: 1395–1397. Montague, B. T., J. R. Ouellette, and G. K. Buller. 2008. Retrospective review of the frequency of ECG changes in hyperkalemia. Clin J Am Soc Nephrol 3(2): 324–330. Nashef, L., D. R. Fish, S. Garner, J. W. Sander, and S. D. Shorvon. 1995. Sudden death in epilepsy: A study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 36: 1187–1194. Neidemeyer, E., and F. L. Da Silva. 1987. Electroencephalography, Basic Principles, Clinical Applications and Related Fields, 2nd ed., 385. Baltimore, MD: Urban and Schanarzenberg. Nilsson, L., B. Y. Farahmand, P. G. Persson et al. 1999. Risk factors for sudden unexpected death in epilepsy: A case-controlled study. Lancet 13: 888–893. Nowack, W. J. 2006. Psychiatric disorders associated with epilepsy. http://www.emedicine.medscape╉ .com/article/1186336 (accessed May 12, 2009). Opeskin, K., and S. Berkovic. 2003. Risk factors for sudden unexpected death in epilepsy: A controlled prospective study based on coroners cases. Seizure 12: 456–464. Perez, G. O., J. R. Oster, and C. A. Vaamonde. 1981. Serum potassium concentration in acidemic states. Nephron 27 (4–5): 233–243. Phillips, L. A. 2008. Death in epilepsy monitoring unit raises questions about safety policies and practice standards. Neurology Today 8 (16): 1–15. Purves, S. J., M. Wilson-Young, and V. P. Sweeney. 1992. Sudden death in epilepsy: Single case report with video-EEG documentation. Epilepsia 33 (Sl3): 123. Racoosin, J. A., J. Feeney, G. Burkhart et al. 2001. Mortality in antiepileptic drug development programs. Neurology 56: 514–519. Sander, J. W., Y. M. Hart, A. L. Johnson, and S. D. Shorvon. 1990. National General Practice Study of Epilepsy: Newly diagnosed epileptic seizures in a general population. Lancet 336: 1267–1271. Sperling, M. R. 2001. Sudden unexplained death in epilepsy. Epilepsy Curr 1 (1): 21–23. Sperling, M. R. 2004. The consequences of uncontrolled epilepsy. CNS Spectr 9: 98–101, 106–109. Sperling, M. R., H. Feldman, J. Kinman et al. 1999. Seizure control and mortality in epilepsy. Ann Neurol 46: 45–50. Spitz, M. C. 1998. Injuries and death as a consequence of seizures in people with epilepsy. Epilepsia 39: 904–907. Spitz, M. C., J. A. Towbin, D. Shantz, and L. E. Adler. 1994. Risk factors for burns as a consequence of seizures in people with epilepsy. Epilepsia 35: 764–767. Stollberger, C., and J. Finsterer. 2004. Cardiorespiratory ἀndings in sudden unexplained/unexpected death in epilepsy (SUDEP). Epilepsy Res 59: 51–60. Tellez-Zenteno. J. F., L. H. Ronquillo, and S. Weibe. 2005. Sudden unexpected death in epilepsy: Evidence-based analysis of incidence and risk factors. Epilepsy Res 65: 101–115. Tennis, P., T. B. Cole, J. F. Annegers et al. 1995. Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada. Epilepsia 36: 29–36. Walczak, T. S., I. E. Leppik, M. D’Amelio et al. 2001. Incidence and risk factors in sudden unexpected death in epilepsy: A prospective cohort study. Neurology 56: 519–525.

Intractable Epilepsy in the Setting of Malformations of Cortical Development as a Mechanism for SUDEP

15

Lara Jehi Imad Najm

Contents 15.1 Introduction 15.2 SUDEP: Epidemiology and Risk Factors 15.3 Proposed Mechanisms of SUDEP 15.3.1 Pulmonary Pathophysiology 15.3.1.1 Clinical Evidence 15.3.1.2 Experimental Evidence 15.3.2 Cardiac Pathophysiology 15.3.2.1 Clinical Evidence 15.3.2.2 Experimental Evidence 15.4 Central Autonomic and Respiratory Control 15.5 Malformations of Cortical Development and SUDEP 15.5.1 Classiἀcation of MCD 15.5.2 Neuroimaging of MCD 15.5.3 Relevance of MCD Classiἀcation and Imaging to SUDEP 15.6 Localization of MCD and SUDEP 15.6.1 Case Reports 15.6.2 Cleveland Clinic Epilepsy Center Experience 15.7 Mechanisms of Epileptogenicity in MCD and SUDEP 15.7.1 Localized Disruption of Excitatory and Inhibitory Neurotransmission 15.7.1.1 Experimental Evidence 15.7.1.2 Clinical Evidence 15.7.1.3 Relevance to SUDEP 15.7.2 Diffuse Disruption of Normal Neural Circuitry 15.7.2.1 Experimental Evidence 15.7.2.2 Clinical Evidence 15.7.2.3 Relevance to SUDEP 15.8 Conclusion References

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222 Sudden Death in Epilepsy: Forensic and Clinical Issues

15.1â•…Introduction Sudden unexpected death in epilepsy (SUDEP) is currently accepted as the most important epilepsy-related mode of death, and is the leading cause of death in chronic uncontrolled epilepsy (Jehi and Najm 2008; Tomson 2000). Despite signiἀcantly increased interest in SUDEP over the past few decades, the exact mechanisms leading to its occurrence remain unknown (Nashef et al. 2007; Pedley and Hauser 2002; Schraeder et al. 2009; Tomson et al. 2008a). Furthermore, despite higher rates of SUDEP observed in patients with structural brain abnormalities (Monte et al. 2007), little is known about how, or even if, speciἀc epilepsy etiologies and brain pathologies interact with other potential triggers leading up to sudden death in a given epilepsy patient. Speciἀcally, the role played by malformations of cortical development (MCD), a major cause of intractable epilepsy, remains unknown. This chapter will ἀrst briefly review general concepts related to SUDEP and its proposed mechanisms, outline basic concepts pertaining to intractable epilepsy in MCD, and then focus on how those two topics—intractable epilepsy in MCD and SUDEP—may be related. The discussion will be based on a review of SUDEP occurrences among a cohort of patients evaluated at Cleveland Clinic Epilepsy Center over a 15-year period, and on a review of the currently available literature.

15.2â•… SUDEP: Epidemiology and Risk Factors SUDEP is most often deἀned as the sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, and in whom postmortem examination does not reveal a structural or toxicological cause for death (Nashef et al. 2007). Estimates of its incidence range from 0.7 to 1.3 cases per 1000 patient years in large cohorts of patients with epilepsy (Nilsson et al. 1997; Tennis et al. 1995), and from 3.5 to 9.3 cases per 1000 patient years in anticonvulsant drug registries, medical device registries, and epilepsy surgery programs (Leestma et al. 1997; Nashef et al. 1995; Tomson et al. 2008b). Several potential risk factors for SUDEP have been investigated with conflicting ἀndings (Jehi and Najm 2008). Consistently identiἀed risk factors include young age, early onset of seizures, refractoriness of epilepsy, the presence of generalized tonic–clonic seizures, male sex, and being in bed at the time of death (Langan et al. 2005; Monte et al. 2007; Nashef et al. 2007; Tomson et al. 2008b). Weaker risk factors include being in the prone position at the time of death, having one or more subtherapeutic blood levels of anticonvulsant medication, having a structural brain lesion, and being asleep (Monte et al. 2007; Tomson et al. 2008b). At any rate, the current consensus is that SUDEP is primarily a seizure-related occurrence, with patients having poorly controlled epilepsy and frequent generalized tonic–clonic seizures being particularly vulnerable (Jehi and Najm 2008; Tomson et al. 2008b) (see Table 15.1).

15.3â•… Proposed Mechanisms of SUDEP 15.3.1â•… Pulmonary Pathophysiology The two major proposed respiratory mechanisms of SUDEP are central apnea and acute neurogenic pulmonary edema.

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Table 15.1â•… Summary of the General Mechanisms Thought to Contribute to SUDEP Respiratory mechanisms â•… Central apnea â•… Pulmonary edema Cardiac mechanisms â•… Arrhythmia â•… Asystole Effects of long-standing seizure disorder â•… Altered autonomic function â•… Structural heart change

15.3.1.1â•…Clinical Evidence In a prospective study of epilepsy patients undergoing a video-EEG evaluation, central apnea lasting at least 10 s was observed postictally in 40% of the recorded seizures (Nashef et al. 1996); otherwise healthy young epilepsy patients have been reported to develop central apnea immediately following complex partial seizures (Blum et al. 2000; Jehi and Najm 2008). Apnea might also represent the only ictal symptom of temporal lobe seizures, especially in children (Lee et al. 1999; Singh et al. 1993). Pulmonary edema is frequently found in SUDEP patients at autopsy (Terrence et al. 1981) and is known to occur in other neurological disorders affecting the central neurorespiratory control centers such as head trauma and subarachnoid hemorrhage. 15.3.1.2â•…Experimental Evidence In a sheep animal model of SUDEP, one third of animals died from hypoventilation and had associated pulmonary edema at autopsy (Johnston et al. 1995). DBA/2 mice are another proposed SUDEP model because they exhibit respiratory arrest after audiogenic seizures (Tupal and Faingold 2006), and where sudden death was preventable by oxygenation without any change in seizure severity (Venit et al. 2004). 15.3.2â•…Cardiac Pathophysiology The most signiἀcant and widely discussed cardiac mechanism of SUDEP is cardiac arrhythmia precipitated by seizure discharges acting via the autonomic nervous system (Jehi and Najm 2008; Nei et al. 2004; Tomson et al. 2008b). 15.3.2.1â•…Clinical Evidence A wide spectrum of cardiac arrhythmias, such as ictal asystole, atrial ἀbrillation, repolarization abnormalities, and bundle branch blocks, has been reported during seizures (Blumhardt et al. 1986; Galimberti et al. 1996; Leung et al. 2006; Nei et al. 2004; Opherk et al. 2002). Ictal cardiac arrhythmias occurred in 42% of hospitalized epilepsy patients in one study, with the most common being an irregular series of abrupt rate changes toward the end of the electroencephalographic (EEG) seizure discharge (Blumhardt et al. 1986). In another study, analysis of R–R intervals during the ἀrst 10-s period of EEG discharge showed a signiἀcant early heart rate increase in 49% of seizures and an early heart rate

224 Sudden Death in Epilepsy: Forensic and Clinical Issues

reduction in 25.5% (Galimberti et al. 1996) (Figures 15.1 and 15.2). Certain clinical seizure characteristics have been correlated with the occurrence of ictal electrocardiographic (ECG) abnormalities. While one study found that mean seizure duration was longer in patients with ECG abnormalities than in those without such changes (Nei et al. 2000), others observed that ictal ECG abnormalities occurred more often and were more severe in generalized tonic–clonic seizures relative to complex partial seizures (Nei et al. 2000, 2004; Opherk et al. 2002). Those same clinical seizure characteristics were correlated with a higher risk of SUDEP (Langan et al. 2005), suggesting an interrelation between seizure semiology, ECG abnormalities, and SUDEP. 15.3.2.2â•…Experimental Evidence Electrical brain stimulation of the limbic system and insular cortex has repeatedly been shown to provoke heart rate changes, including bradycardia, tachycardia, and asystole (Leung et al. 2006). Some studies have even suggested a lateralized influence of the insulae on cardiovascular autonomic control with intraoperative stimulation of the left posterior insula eliciting a cardioinhibitory response and hypotension, and stimulation of the right anterior insula eliciting tachycardia and hypertension (Jehi and Najm 2008). Other studies have suggested a localization-related influence of the limbic system on cardiovascular responses with stimulation of the amygdala alone being insufficient to produce the ictal

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Figure 15.1╇ Asystole documented during a left hemispheric seizure (10-s epoch) in a patient with a normal MRI, and subsequently pathologically proven malformation of cortical development. The arrow identifies movement artifact secondary to patient fall.

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EEG EMG (masseter) EMG (biceps) Pupils Electrodermogram C. H. R. B.

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Recuperation

Interictal

Figure 15.2╇ Autonomic changes during a motor seizure. Clear increases in the heart rate

(H) and blood pressure (B) correspond to a suppression in the respiratory rate (R) during the ictal phase. Autonomic changes continue well after the ictal event is finished. C, cystogram. (Reprinted From Gastaut, H., and Broughton, R., Epileptic Seizures: Electrographic Features, Diagnosis, and Treatment, Springfield, IL: Charles C Thomas Publisher, 1972: 28. With permission.)

tachycardia so commonly seen in epileptic seizures, suggesting that cortical involvement is essential for the increase in HR (Keilson et al. 1987). Such cortical stimulation-induced HR changes may explain how massive seizure-related discharges can affect the cardiac rhythm during the seizure itself. There is, however, also evidence of a baseline epilepsy-related autonomic dysfunction. A recent study showed a pronounced reduction in cardiac metaiodobenzylguanidine (MIBG) uptake in patients who had ictal asystole compared to other epileptic and nonepileptic controls, suggesting a postganglionic cardiac catecholamine disturbance. The authors then propose that epilepsy-related impaired sympathetic cardiac innervation limits adjustment and heart rate modulation and may thus increase the risk of asystole and, ultimately, SUDEP (Kerling et al. 2008).

15.4â•…Central Autonomic and Respiratory Control A tight, interconnected network exists throughout the neuraxis to control various elements of the cardiovascular autonomic system. A solid understanding of this network provides

226 Sudden Death in Epilepsy: Forensic and Clinical Issues

useful insights for consideration of a cardiac pathophysiology of SUDEP (Jehi and Najm 2008). Key components of the central cortical control of autonomic functions include the insula, the anterior cingulate gyrus, and the ventromedial prefrontal cortex. The insula represents the primary viscerosensory cortex, while the cingulate gyrus and prefrontal cortices form the premotor autonomic region. At the subcortical level, the hypothalamus provides the interface with the endocrine stimuli and triggers corresponding autonomic responses to maintain homeostasis. The amygdala, an integral component of the limbic system linking the cortical and subcortical centers, mediates the autonomic response to emotions. In addition to playing a key role in autonomic control, the insula, amygdala, cingulate gyrus, and prefrontal cortex also represent the most common foci of partial epilepsy, a concept that we will elaborate on further later and that may explain the frequent observation of autonomic changes in relation to epileptic seizures (Leung et al. 2006). Although central apnea has been observed with focal epileptiform activity alone (Lee et al. 1999), a more accepted hypothesis is that neurotransmitters mediating the brain’s own seizure-terminating mechanism could also be inhibiting respiratory centers in the brainstem and causing postictal apnea (Jehi and Najm 2008). Understanding the concepts of central autonomic pathways and respiratory control will facilitate the discussion of possible mechanisms of SUDEP in MCD. In the subsequent sections of this chapter, we will discuss how the general concepts of SUDEP discussed so far apply speciἀcally to intractable epilepsy in MCD patients.

15.5â•…Malformations of Cortical Development and SUDEP Alzheimer and Rahcke recognized the presence of aberrant cortical lamination in autopsies of patients with a history of chronic epilepsy almost a century ago. It was, however, the detailed report published by Taylor et al. (1971) that has since raised awareness of the role of misshapen dysmorphic (dysplastic) neurons in the setting of cortical architectural disorganization (both columnar and laminar) as the pathological substrate in some patients with drug-resistant epilepsy. The report identiἀed the possible role of disorientated and giant neurons (and balloon cells with eccentric nuclei) in temporal cortex resected from patients with temporal lobe epilepsy. In the past 20 years, studies showed that MCDs include a broad spectrum of architectural anomalies, such as cortical laminar disorganization, neuronal heterotopia in the subcortical white matter, the persistence of neurons in the superἀcial cortical layer (layer I of the neocortex), clustering of neurons in the gray matter, nodular heterotopia, and the presence of aberrant neurons such as giant neurons and balloon cells (Fauser et al. 2006; Lawson et al. 2005; Palmini et al. 2004; Tassi et al. 2002). The relationship between epilepsy and MCD in general, and focal cortical dysplasia (FCD) in particular, has been well established. In fact, 8–12% of cases with intractable epilepsy are attributed to MCD, whereas 14–26% of surgically treated cases have MCD (Tassi et al. 2002). 15.5.1â•…Classification of MCD MCDs are due to abnormalities in neuronal migration, proliferation, and/or differentiation that result in four distinct pathological subtypes: IA, IB, IIA, and IIB (Widdess-Walsh et al. 2005). Those various subtypes have different microscopic and imaging characteristics, as well as distinct outcomes with epilepsy surgery. Type I is characterized by a lack of

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dysmorphic neurons or balloon cells (abnormal cellular elements with a thin membrane; pale, glassy, and eosinophilic cytoplasm, eccentric nucleus, usually of increased size compared with gemistocytic astrocytes).. Type IA is characterized by patchy and isolated architectural abnormalities, mainly consisting of dyslamination and columnar disorganization, accompanied, or not, by other abnormalities of mild MCD. Type IB is characterized by architectural disorganization intermixed with giant or immature, but not dysmorphic, neurons. Most of these mild abnormalities defy in vivo imaging recognition. The only available evidence is from patients undergoing epilepsy surgery in whom such mild abnormalities were the only histopathological ἀnding. This suggests that at least some patients with type IA/B FCD can have medically refractory epilepsy (Palmini et al. 2004). Type II or Taylor-type FCD show dysmorphic neurons without (IIA) or with balloon cells (IIB) in the setting of diffuse cortical architectural disorganization. These are the focal lesions most commonly identiἀed on MRI. However, studies showed various degrees of imaging abnormalities in patients with Taylor-type FCD ranging from thickening of the cortical mantle to focal and severe fluid-attenuated inversion recovery (FLAIR) signal abnormalities (Palmini et al. 2004). Figure 15.3 illustrates the various histopathological ἀndings of those four MCD subtypes. 15.5.2â•…Neuroimaging of MCD MRI can be either normal (most often in type I), despite the use of high-resolution techniques, or may demonstrate one or more of the following characteristics: (1) focal areas of increased cortical thickness; (2) blurring of the cortex (gray)/white matter junction; (3)€ increased signal on T2-weighted proton density or FLAIR sequences (more likely to occur in balloon cell-containing lesions); and (4) extension of cortical tissue with increased FLAIR signal from the surface to the periventricular region (transmantle dysplasia) (Palmini et al. 2004; Ruggieri et al. 2004; Tassi et al. 2002; Widdess-Walsh et al. 2005). 15.5.3â•… Relevance of MCD Classification and Imaging to SUDEP Several studies have shown that MRI and histopathological ἀndings in MCD correlate with seizure outcome following resective surgery for intractable epilepsy, with better outcomes

Normal

Type I

Type IIA

Type IIB

Figure 15.3╇ Cresyl echt violet staining of sections representing normal neocortex and type I,

type IIA, and type IIB malformations of cortical development; scale bar, 100 µm. (Palmini, A. et al., Neurology, 62 (6 Suppl 3), S2–S8, 2004. With permission.)

228 Sudden Death in Epilepsy: Forensic and Clinical Issues

observed in patients with clear MRI lesions, and more severe histopathological changes (mainly type IIB), as opposed to those with normal MRI (types IA and IB) (Jeha et al. 2007; Tassi et al. 2002; Widdess-Walsh et al. 2005). The poorer outcome following surgery in nonlesional MCD cases is mainly attributed to difficulties localizing the epileptogenic focus and/or its incomplete resection due to more diffuse cytoarchitectural changes that may be invisible on MRI (Jeha et al. 2007). This is relevant in a discussion about SUDEP because persistent seizures are the main risk factor for SUDEP, as extensively discussed earlier in this chapter (Jehi and Najm 2008; Tomson 2000; Tomson et al. 2008b). In fact, it has been shown in a recent prospective study that persistent seizures speciἀcally following failed epilepsy surgery carry a signiἀcantly high risk of sudden death, estimated at 6.3 cases per 1000 patient years (Sperling et al. 2005). As such, patients with intractable epilepsy, MCD, and normal imaging may be particularly more vulnerable to SUDEP.

15.6â•…Localization of MCD and SUDEP Several studies showed a predisposition of speciἀc MCD pathological subtypes to localize to certain brain regions. In a review of 145 cases of MCD operated on for intractable epilepsy at Cleveland Clinic Epilepsy Center between 1990 and 2002, we found that pathological subtypes IIA and IIB were predominantly frontal in location and had a more severe epilepsy syndrome than patients with subtypes IA and IB. Patients with subtype IA FCD had less severe, later onset epilepsy that was predominantly located in the temporal lobe (Widdess-Walsh et al. 2005). This is similar to ἀndings of another review of 52 MCD surgical cases of intractable epilepsy where patients with architectural dysplasia alone (type IA) had lower seizure frequency than those with Taylor-type dysplasia, and the epileptogenic zone was mainly in the temporal lobe, while in patients with Taylor-type dysplasia, the epileptogenic zone was mainly extratemporal, predominantly frontal (Tassi et al. 2002). Beyond these anatomical distributions of MCD in relation to histopathology, it remains€to be shown whether MCDs have a speciἀc affinity to localize in brain regions particularly relevant in the proposed mechanisms of SUDEP, such as the insula, cingulate gyrus, orbitoÂ�frontal regions, or amygdalae. We will review now the limited available data concerning this point. 15.6.1â•…Case Reports A few case reports have indeed documented ictal cardiac or respiratory changes in patients with MCD involving brain regions thought to be part of the central autonomic control centers. Known examples include one case report of a three-and-a-half-year-old child with episodic sinus bradycardia during habitual seizures and prolonged interictal discharges due to FCD in the anterior two-thirds of the insula and the inferior frontal cortex (Seeck et al. 2003). In another case report of a 30-year-old man who was found dead on arrival to the hospital following an hour-and-a-half of complex partial seizure, post mortem examination showed bilateral occipital frontal polymicrogyria in the brain and chronic interstitial and perivascular ἀbrosis in the heart without previous vascular risk factors, a ἀnding which the authors attributed to possibly chronic repetition of seizures (Ribacoba Montero et al. 2002).

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15.6.2â•…Cleveland Clinic Epilepsy Center Experience We recently reviewed 3841 patients evaluated with prolonged video-EEG monitoring in our epilepsy monitoring unit between 1990 and 2005 and identiἀed 301 mortalities (Jehi et al., in preparation). Of 223 mortalities evaluated so far, 29 died of SUDEP, including six who had MCD. Of these six cases, four had dual pathology with associated hippocampal sclerosis affecting their mesial temporal structures (three with type IA MCD, including two in their temporal lobe, and another in his lateral temporal and inferior frontal lobes; and one with MRI-visible dysplasia affecting his posterior temporal and angular gyrus), one had posterior left temporal lobe closed lip schizencephaly, and one had a temporoparietal ictal onset zone on invasive EEG with normal imaging. Five of the above patients had epilepsy surgery (some even up to three times), but continued to have seizures postoperatively. The epileptogenic zone thus localized to the peri-insular region in all of our MCD cases with SUDEP suggests a direct anatomical disruption of baseline physiologic autonomic centers in the insula as a possible mechanism of SUDEP. Although the observation is clear, a direct relationship between the suspected anatomical location of the FCD and epileptogenicity in the insular region and SUDEP is difficult to prove. An alternative hypothesis in this group may be that the increased risk of SUDEP is simply due to continuous seizures following a failed epilepsy surgery.

15.7â•…Mechanisms of Epileptogenicity in MCD and SUDEP Multiple mechanisms of epileptogenicity in MCD have been proposed, mainly revolving around two central concepts: (1) localized disruption of excitatory and inhibitory neurotransmission and (2) diffuse disruption of normal neural circuitry. We will now elaborate on those two general principles and discuss how they might be related to SUDEP. 15.7.1â•…Localized Disruption of Excitatory and Inhibitory Neurotransmission Dysplastic lesions have a high degree of intrinsic epileptogenicity: In one study, up to 67% of patients with MCD manifested continuous or frequent rhythmic epileptogenic discharges recorded directly from their cortical dysplastic lesions during intraoperative electrocorticography, as opposed to only 2.5% of patients with intractable partial epilepsy associated with other types of structural lesions (Palmini et al. 1995). Data collected through immunocytochemical and clinical studies support an increase in excitatory amino acid neurotransmission and an overall decrease in intralesional and perilesional inhibition as a signiἀcant contributor to this high degree of intrinsic epileptogenicity (Avoli et al. 1999; Najm et al. 2004; Palmini et al. 1995, 2004). 15.7.1.1â•…Experimental Evidence Ferrer et al. (1992) ἀrst showed abnormalities in the morphology and distribution of localcircuit (inhibitory) neurons in FCD, and hypothesized they may have a pivotal role in the appearance and prolongation of electrical discharges. Since then, Najm et al. (2000) correlated signiἀcantly higher immunoreactivity of the excitatory N-methyl-d-aspartate (NMDA) receptor (NR) 2A/B in both the dysplastic somata and all their dendritic processes

230 Sudden Death in Epilepsy: Forensic and Clinical Issues

with in vivo epileptic activity recorded through subdural EEG, whereas White et al. (2001) observed reduced levels of the inhibitory gamma aminobutyric acid A (GABA-A) receptors alpha1 and alpha2 mRNA in both dysplastic neurons and giant cells compared to control neurons. Neurotransmission changes in the dysplastic cortex extend, however, beyond the classical excitatory and inhibitory NMDA and GABA systems. Trottier et al. (1996) found evidence of serotonergic hyperinnervation and altered patterns of the catecholaminergic innervation in dysplastic cortex of epilepsy patients with MCD, as opposed to tissue from patients with cryptogenic neocortical epilepsy and normal controls (Trottier et al. 1996). 15.7.1.2â•…Clinical Evidence Most patients diagnosed by imaging studies as having lesions identiἀed as type IIA/B FCD have medically intractable partial epilepsy, with frequently disabling motor and secondary generalized seizures (Fauser et al. 2006; Lawson et al. 2005; Palmini et al. 2004; Tassi et al. 2002; Widdess-Walsh et al. 2005). Many patients have a history of status epilepticus, including epilepsia partialis continua, and scalp EEG and acute electrocorticography often show continuous spiking or other highly epileptogenic patterns, attesting to some type of re-entrant excitatory circuitry unopposed by faulty inhibition (Avoli et al. 1999; Ferrer et al. 1992; Palmini et al. 1995). 15.7.1.3â•…Relevance to SUDEP It is reasonable to hypothesize that the previously discussed disturbances in excitatory versus inhibitory balance leading to epileptogenicity of dysplastic tissue may also translate to disturbances in the normal sympathetic versus parasympathetic balance if the MCD happens to involve cortical regions crucial for central autonomic control. There is however no information available currently on the status of either NMDA or GABA receptors in SUDEP victims. Data presented previously supporting a role for serotonin in the modulation of sudden death induced by audiogenic seizures in DBA/2 mice via causing respiratory arrest (Tupal and Faingold 2006) may be related to the altered serotonergic pathways described speciἀcally in MCD (Trottier et al. 1996), but further investigation is needed. 15.7.2â•…Diffuse Disruption of Normal Neural Circuitry This hypothesis is based on the concept that rather than intrinsic epileptogenicity of the dysplastic lesion itself, the main mechanism of epilepsy, in the context of MCD, is disruption of neuronal circuitry extending far beyond the lesion itself. Following this idea, focal epileptogenesis associated with MCD, as opposed with postnatally acquired lesions such as those due to tumors or trauma, is best conceptualized as a disorder of widespread and patchy disturbance of cortical networks. This developmental perspective implies that the epileptogenic region in MCD is rarely discrete, even in patients with focal dysplasia, and may include remote cortical or subcortical areas (Duchowny et al. 2000). 15.7.2.1â•…Experimental Evidence Subtle structural abnormalities are seen beyond the clearly visible dysplastic lesion in many patients with MCD. Measurements of cerebral surface area and volume reveal widespread and unusually extensive anatomic changes throughout extralesional gray and subcortical white matter in a high proportion of patients with FCD (Sisodiya et al. 1997). Similarly, prenatal damage during critical maturational stages of primates resulted in anomalous

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sulcation and reorganization at remote cortical sites in both cerebral hemispheres (Goldman 1978). Functional neuroimaging abnormalities on proton MR spectroscopy and flumazenil PET studies of benzodiazepine receptors in FCD reveal abnormal activation patterns extending far beyond the lesional boundary (Richardson et al. 1996). Ictal SPECT in tuberous sclerosis complex also shows increased blood flow in the perituberal penumbra, suggesting dysfunction beyond the tuber (Koh et al. 1999). 15.7.2.2â•…Clinical Evidence Neurological deἀcits in patients with MCD are often more extensive than expected based on the extent of the lesion visible on MRI. Besides epilepsy, patients with MCD often suffer from cognitive impairment, and are prone to attention and behavioral problems and autism. Verbal IQ scores are decreased even in patients with very focal lesions of the dominant cerebral hemisphere (Duchowny et al. 2000). These ἀndings may be attributed to dysfunction beyond the lesion itself. However, there are other factors to consider. Younger age of seizure onset and larger lesions are associated with diminished cognitive outcome. Epileptogenic activity and medication also make it difficult to separate cause from effect. However, not all patients with frequent seizures and chronic medications exhibit cognitive disturbance (Duchowny et al. 2000; Fauser et al. 2006; Lawson et al. 2005) and the extent of the MRI lesion itself does not always correlate with cognitive outcome suggesting an additional functional mechanism to the disturbances seen with MCD besides the structural disturbance visible on routine imaging. 15.7.2.3â•…Relevance to SUDEP Parallels can be drawn between the dysfunctional connectivity alluded to previously in MCD, and the disruptions in the sympathetic and parasympathetic networks felt to be contributing to SUDEP. This issue needs, however, to be further investigated.

15.8â•…Conclusion SUDEP is the leading cause of death in chronic uncontrolled epilepsy and is a devastating complication, usually occurring in young, otherwise healthy individuals with persistent seizures or poor compliance to antiepileptic medications. Despite signiἀcantly increased interest in SUDEP over the past few decades, the exact mechanisms leading to its occurrence remain unknown. On the other hand, MCD have been increasingly recognized as a common and very signiἀcant cause of epilepsy that still remains difficult to control with epilepsy surgery. As such, MCDs may provide a unique substrate for further study of SUDEP mechanisms and possible preventative interventions. A lot remains unknown though, and areas of further research may include: 1. Determination of the incidence of SUDEP in MCD speciἀcally, as compared to other epilepsy etiologies, to evaluate whether this patient population is particularly more vulnerable to sudden death. 2. Investigation of the autonomic function in patients with MCD as compared to those with other structural abnormalities and epilepsy to clarify whether strategically located MCD can lead to distant autonomic dysfunction, possibly contributing to cardiac arrhythmias hypothesized in SUDEP.

232 Sudden Death in Epilepsy: Forensic and Clinical Issues

3. Characterization of the immunocytochemical characteristics of brain tissue from patients with SUDEP and MCD, especially excitatory and inhibitory pathways, and serotonergic pathways to investigate further the potential for common mechanisms between intractable epilepsy in MCD and SUDEP.

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16

Neurogenic Cardiac Arrhythmias Howan Leung Anne Y. Y. Chan

Contents 16.1 Introduction 16.2 What Can We Learn from Electrical Brain Stimulation Studies about the Cortical Control of the Autonomic System? 16.3 What Can We Learn from Functional Magnetic Resonance Imaging Studies Demonstrating Cortical Control of the Autonomic System? 16.4 Illustrating Ictal Bradyarrhythmia and Asystole with Scalp EEG Data 16.5 Illustrating Ictal Bradyarrhythmia and Asystole with Intracranial EEG Data (Diagram 2) 16.6 Can Ictal Bradyarrhythmia Enlighten Us about the Various Mechanisms of Neurogenic Cardiac Arrhythmia? 16.7 Could There Be a Link between Ictal Bradyarrhythmia and SUDEP? 16.8 What Lies in the Future for Researchers? Acknowledgments References

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16.1╅Introduction The analysis of abnormal changes in heart rate is not only a matter of concern for cardi� ologists, but also a topic of importance among neurologists. Through the study of patients with epilepsy, which is characterized by recurrent abnormal and excessive discharge of a set of neurons in the brain (Commission on Epidemiology and Prognosis 1993), cardiac arrhythmias of neurogenic origin may be examined. In fact, it is a recognized clinical observation that during seizures there might be an increase or decrease in the rate of cardiac rhythm. Through the functional study of the brain during investigations and work-up of epilepsy patients, the cortical control of cardiac rhythmic activities may be uncovered. Blumhardt et al. (1986) analyzed the electrocardiograms (ECGs) of 26 patients with temporal lobe epilepsy and showed that ictal cardiac arrhythmias occurred in 42% of patients. Ictal bradyarrhythmia and ictal asystole, in particular, have received much attention recently because of the postulation that autonomic manifestations of seizures could be one of the mechanisms underlying sudden unexpected death in epilepsy (SUDEP), although the evidence supporting this remains fragmented. This short chapter aims to review the potential role of cardiac arrhythmia in the pathogenesis of SUDEP by examining the data pertaining to the cortical control of the autonomic system, the clinical observation of potentially life-threatening ictal bradyarrhythmia, and various proposed mechanisms for SUDEP. 235

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16.2â•…What Can We Learn from Electrical Brain Stimulation Studies about the Cortical Control of the Autonomic System? The central representation of autonomic states has long suspected, as stipulated by the James–Lange theory, that arousal and emotion were closely related (James 1894). More information about the representation of the autonomic system above the level of the brain stem was reported more than 50 years ago beginning with studies in primates and other animals (Kaada 1951). The limbic structures are thought to be the principal mediators of this function and the candidate areas include cingulate gyrus, amygdala, and insular and orbitofrontal cortex. In Kaada’s experiments, stimulation of the anterior portion of the cingulate gyrus in monkeys showed inhibition and arrest of respiration. Penἀeld and Jasper (1954) carried out experiments in humans in the 1950s and showed that stimulation of the cingulate gyrus in its anterior and inferior portion produced apnea, which could not be overcome even with a conscious effort. In addition, stimulation of the uncus and of the right anterior margin of insular cortex also produced a similar effect on respiration. The cortical influence on cardiovascular responses has been likewise demonstrated in various animal studies (Kaada 1951; Ward 1948; Burns and Wyss 1985; Chefer et al. 1997; Healy and Peck 1997) and in humans. This was demonstrated by delivering electrical stimulation to psychotic patients before bilateral fractional ablation of the cortex (Pool and Ransohoff 1949). A total of 12 patients were tested with bilateral cingulate stimulation, of which three cases had heart rate elevation, seven had heart rate reduction, and two cases showed no change. The authors did not explain what factors determined the direction of change nor whether the change in heart rate was unidirectional in any given patient. Van Buren (1961) performed electric stimulation to right orbitofrontal and right mesial temporal areas in 11 patients before pituitary surgery. The stimulation of the right orbitofrontal area was associated with a slight drop in heart rate, whereas stimulation of the right mesial temporal region produced a mixture of increase and decrease in heart rate. In an often-quoted study by Oppenheimer et al. (1992), electrical stimulation of the insular regions of ἀve epileptic patients (three with origin on the right side and two on the left side) was associated with changes in both heart rate and blood pressure. Electrical stimulation with 5 to 10 V was carried out with a pulse duration of 2 ms at 40 Hz. They found that bradycardia and depressor responses were more frequently produced than tachycardia when the left insular cortex was stimulated. The converse was noted when the right insular cortex was stimulated. Of interest, the amplitude of the bradycardia was greater on stimulation of the left posterior insular cortex compared with the left anterior insular cortex. This study was able to demonstrate that there is a left–right difference in the cortical control of heart rate (the implications of this ἀnding for SUDEP will be discussed in Section 16.7). Electrical stimulations are sometimes performed as part of the presurgical evaluation of medically refractory epilepsy, particularly in determining cortical eloquent areas and sensorimotor areas, or for the reproduction of habitual seizures. The amount of electrical stimulation given in those situations may vary from 1 to 10 mA depending on the apparatus used and the interpatient variation of parenchymal impedance. The frequency of stimulation may be higher for stimulation of eloquent areas but lower for motor areas to minimize discomfort. The duration of electrical stimulation is usually short (e.g., 40 s into the typical semiology of a complex partial seizure. However, EEG changes were only typical of cerebral hypoperfusion and no clinical predisposing factors can be identiἀed (Schuele et al. 2007).

16.5â•…Illustrating Ictal Bradyarrhythmia and Asystole with Intracranial EEG Data (Diagram 2) Ictal bradyarrhythmia captured on invasive EEG monitoring can give invaluable information, although the event is actually one that occurs rarely. Among the few reported cases (Altenmuller et al. 2004; Broglin and Bancaud 1991; Munari et al. 1995; Devinsky et al. 1997; Manitius-Robeck et al. 1998; Kahane et al. 1999; Rossetti et al. 2005), only four provided sufficient clinical information enabling correlation between ictal EEG and onset of bradyarrhythmia. In one of these reports, a patient with right hippocampal atrophy was described who underwent presurgical evaluation with placement of left temporal subdural grid and strip electrodes, right temporal subdural electrodes, and right orbitofrontal and

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frontal electrodes. Subsequent evaluations led to left temporal resective surgery rather than the right. An 8-s period of asystole took place after the onset of seizure and the intracranial recording registered a left temporal onset, although the asystole did not start until the seizure had spread to the right temporal lobe (Devinsky et al. 1997). In another case, a patient with hypothalamic hamartoma was implanted with 10 electrodes exploring the right frontal, central, and temporal cortices, two electrodes within the left frontal lobe, and one implanted within the lesion. The patient had dacrystic (i.e., crying seizures with intracranial EEG monitoring showing epileptiform activities beginning from and remaining localized in the hamartoma). An episode of ictal asystole, however, was registered with the onset of epileptiform discharges in the right frontocentral and temporal neocortical areas rather than the hypothalamic mass itself (Kahane et al. 1999). It was noteworthy that this patient was left-handed. In another report, a patient had foci of encephalomalacia in the right inferior frontal gyrus, temporal pole, and anterior parietal lobe. Invasive monitoring was carried out with bilateral temporal depth electrodes and right dorsolateral frontoparietal subdural strips. Asystole occurred in a seizure episode with left temporal seizure onset, and sharing similarity with the ἀrst case report, the actual phenomenon of asystole only occurred after an interhemispheric spread to opposite mesial structures. The proposed route of spread to the opposite side was thought to be via the anterior commissure or the corpus callosum. Although no intracranial electrode was placed in the neocortical portions of the left temporal lobe, the surface EEG showed rhythmic activity over the left lateral temporal region before involvement of the opposite mesial structure so that involvement of the left insular region before interhemispheric spread remained possible. Intracranial electrodes conἀrmed that the right frontal lobe was spared (Rossetti et al. 2005). In the last of the four reports, a patient with left temporal lobe epilepsy was implanted with left lateral and basal temporal subdural grid (x1) and strips (x2) with an additional left temporal depth electrode. Further evaluation eventually led to left temporal lobe surgery, the pathology of which was shown to be glioneuronal hamartoma. High-grade AV blocks were observed with left temporal seizure onset that was recorded before intracranial electrode placement. A left basal and anterior lateral temporal lobe seizure onset was thought to be present during the ictal cardiac event as this was subsequently inferred from the intracranial recording. Epileptic discharges were thought to be localized during the event of AV block on the basis of scalp EEG ἀndings, although the time lag from seizure onset and the placement of intracranial recording at a separate time may still raise doubts about a possible spread. Electrical stimulation to this region also reproduced AV block once, as described previously in the section about human brain stimulation studies (Altenmuller et al. 2004).

16.6â•…Can Ictal Bradyarrhythmia Enlighten Us about the Various Mechanisms of Neurogenic Cardiac Arrhythmia? Factors predisposing an epilepsy patient to ictal bradyarrhythmia remain unknown. It is tempting to suspect that certain seizure mechanisms may predispose to ictal bradyarrhythmia and there might be additional pathological factors contributing to this, such as an aberrant condition in the mediators of cortical autonomic control (e.g., the vagus nerve), concomitant antiepileptic drugs thought to be arrhythmogenic, imbalance between the

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sympathetic and parasympathetic divisions of the autonomic nervous system, and/or a cardiac substrate (i.e., underlying disease process affecting the cardiac functions). The observation of bradyarrhythmia associated with temporal and frontal lobe onset seizures may lend support to the hypothesis that activation of these regions is part of the mechanism, and in particular, the operculo–insulo–mesiotemporal–orbital complex (Mufson and Mesulam 1982). However, none of the intracranial reports of ictal bradyarrhythmia gave information about involvement of the left insular cortex as the electrodes are seldom placed in this area in clinical practice. Selection bias is also possible, given the fact that there is a preponderance of temporal and frontal epilepsies in specialized centers. The concept of recognizing a pattern of seizure spread during ictal bradyarrhythmia is important, as our analysis of intracranial EEG data showed that seizures beginning from the central autonomic network on the dominant hemisphere were present in the episodes with ictal bradycardia. In addition, a spread to the contralateral central autonomic network was frequently witnessed. The timing of onset of bradycardia in relation to seizure onset was supporting evidence for this. We suspect that the cerebral dominance may alter the “internal wiring” of the central autonomic network, hence a patient with left cerebral dominance may be observed with a left-to-right spread, and vice versa for a patient with right cerebral dominance, although in the intracranial reports there was no patient with bilateral cerebral dominance. This idea of cerebral dominance may be mirrored by the fact that language representation can be lateralized to either hemisphere or bilaterally during the patient’s developmental process. However, we did not know exactly what effect the lesions had on the mechanisms producing bradycardia, as the spreading of epileptiform discharges to the opposite hemisphere cannot be easily correlated with whether the lesion was ipsilateral or contralateral to the seizure onset using the intracranial data. In the only case with hypothalamic hamartoma, there was no seizure spread required for the process and the bradycardia was registered at the onset of seizure. In the case where the lesion was on the same side as seizure onset, no spreading was noted (Altenmuller et al. 2004). In the two cases where the lesion was contralateral to the seizure onset, spreading can be witnessed (Devinsky et al. 1997; Rossetti et al. 2005). We also suspect that the presence of a lesion may disrupt the original central autonomic network, keeping the speciἀc network required for the production of bradycardia more localized than it otherwise would be (e.g., only localized to one part of the central autonomic network, or simply one cerebral hemisphere). The inception of bradycardia may also be viewed as the indirect result of epileptiform discharges, and hence a less localization-speciἀc mechanism. In this respect, bradycardia may be viewed as a release phenomenon comparable to the release mechanisms observed in many mesial temporal seizures, such as chewing and epigastric sensation, which are also vegetative in nature. Under this precinct, the generation of the release mechanism did not have to have a one-to-one transmission relationship with the ictal epileptiform discharges. Regarding the issue of lateralization of seizures in ictal bradyarrhythmia, the basic science data as outlined above may lend support for this to occur at ἀrst glance, despite the existence of some inconsistencies. There was also an additional study investigating heart rate during a Wada test (Zamrini et al. 1990) with a total of 25 patients, using a repeatedmeasures analysis of variance design. (A Wada test is a commonly performed procedure in the presurgical evaluation of epilepsy in which intracarotid injections of amobarbital are given and the subjects tested for language and memory. The test indicates which of

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the two cerebral hemispheres is the dominant hemisphere and it may give an approximation to the effect of surgery after lobectomy.) The authors suggested that left carotid artery infusion was associated with tachycardia whereas right carotid artery infusion was noted with bradycardia. However, these subjects were not patients reported to have any ictal bradycardia. In practice, as we have seen with the observations in ictal bradycardia recorded with intracranial EEGs, the pattern of seizure spread, hand dominance, and the presence of lesion contribute to the lateralization issue, making the simplistic left/right dichotomy less likely for one to predict. Mediators of the cortical signals for the autonomic system should also be considered. The parasympathetic system and the vagus nerves are essential in this respect. The functional distribution of the efferent ἀbers of the vagi also demonstrates laterality, although it is not entirely clear how this may relate to the laterality observed in the cortical representation of cardiac autonomic control. The left vagus nerve carries fewer efferent ἀbers to the ventricle, which is why traditionally vagus nerve stimulation is performed on the left side. (Fewer efferent ἀbers may mean that electrical stimulation of the vagus nerve produces less vagal-mediated parasympathetic activation and/or bradycardia.) Using information about patients in whom vagus nerve stimulators were implanted, it was observed that neither left-sided nor right-sided vagal stimulation gave rise to frequent bradycardia or asystole (McGregor et al. 2005; Handforth et al. 1998). However, one case report during intraoperative implantation of left vagus stimulator did show persistent bradycardia and the author (Asconape et al. 1999) proposed, among other speculations, that the intensity of the vagus stimulation, or some idiosyncratic mechanism at work, may contribute to this. It was not known whether during a seizure such intensity or amplitude of vagus nerve activation can be achieved or if an ictal bradyarrhythmia occurs at all. Some authorities may view that both sympathetic and parasympathetic systems are at work during ictal bradyarrhythmia, owing to the synchronization of the cardiac autonomic neural discharge with epileptogenic activity, the so-called “lockstep” phenomenon (Lathers et al. 1983). In this theory, the effect may vary from animal to animal or patient to patient, so sometimes there might be excessive sympathetic stimulation and at other times only parasympathetic nervous system dominance, or an imbalance between the two divisions. Previous studies (Stauffer et al. 1989, 1990) and O’Rourke and Lathers (2010) reported precipitous mean arterial blood pressure changes correlating with unstable lockstep phenomenon. Four possible mechanisms through which lockstep phenomenon may be related to arrhythmia and sudden death in persons with epilepsy were postulated: (1) excessive sympathetic stimulation of a heart that is already electrically unstable due to prior damage (Jay and Leestma 1981); (2) a nonuniform discharge in the postganglionic cardiac sympathetic nerve branches (Lathers et al. 1977, 1978); (3) the parasympathetic nervous system causing sinus arrest and bradycardia during seizures (Kiok et al. 1986; Lathers and Schraeder 1982); and (4) the associated precipitous changes in blood pressure per se. A coexisting pathological cardiac substrate is, and has always been, a potential confounding factor in determining the mechanism underlying ictal bradyarrhythmia. Studies on refractory epilepsy patients showed that echocardiographic abnormalities can be found in up to 9% of patients (Tigaran 2002). Among the ἀve patients observed to have ictal asystole in one study mentioned earlier, two had underlying cardiac disease that was reported by the authors to be a history of myocardial infarction in one and a history of an aberrant complex in the other (Rocamora et al. 2003). Another school of thought proposes that long-standing epilepsy may alter the neuronal network system on the cardiac tissues. One

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study found altered postganglionic cardiac sympathetic innervation with a predominantly parasympathetic cardiac activity in patients with temporal lobe epilepsy by using MIBGSPECT (123-I metaiodobenzylguanidine single photon emission computed tomography) (Druschky et al. 2001). Others argue that there may be a common pathology that leads to both seizure and arrhythmia, such as a channelopathy (e.g., mutations of genes encoding nicotinic acetylcholine receptors) that may underlie many forms of inherited idiopathic generalized epilepsy (Hiroso et al. 2005). The potential arrhythmogenic effect of antiepileptic drugs should also be considered. It is well documented that carbamazepine can slow the AV conduction and increase the sympathetic tone in the autonomic nervous system (Isojarvi et al. 1998) and decrease heart rate variability (Persson et al. 2003). One study demonstrated that abrupt withdrawal of carbamazepine can lead to enhanced sympathetic activity in sleep (Hennessy et al. 2001). Other studies have reported conflicting results (Kenneback et al. 1992, 1997). In the clinical cases discussed above, not all patients were receiving carbamazepine when ictal bradyarrhythmia occurred. However, the contributory ἀndings for other antiepileptic drugs are not easy to decipher because most, if not all, of those patients in whom ictal bradyarrhythmia occurred had been put on multiple drugs rather than a single one. Another caveat in the discussion of ictal bradyarrhythmia is the careful ascertainment of the time sequence between the seizure event and the cardiac arrhythmia. A neurocardiogenic syncope in which the bradyarrhythmic event precedes the clinical attack will be a differential diagnosis for all patients who have ictal bradyarrhythmia.

16.7â•…Could There Be a Link between Ictal Bradyarrhythmia and SUDEP? The incidence of SUDEP varies between 1 in 200 and 1 in 1000 (Lhatoo and Sander 2002). A widely accepted deἀnition of SUDEP is “a sudden unexpected nonaccidental death in an individual with epilepsy, with or without evidence of a seizure having occurred, excluding status epilepticus, where autopsy does not reveal an anatomical or toxicological cause of death” (Nashef 1997). Another deἀnition consisting of six criteria was put forward by an expert panel in 1997 (Leestma et al. 1997). In all these deἀnitions, a “deἀnite” case can only be reached if all criteria are satisἀed, but where postmortem data are lacking, the term “probable” should be used. Many risk factors have been stratiἀed for SUDEP and on face value they may not always be consistent (Langan and Sander 1999; Kloster and Engelskjon 1999; Birnbach et al. 1991; George and Davis 1998; Opeskin and Berkovic 2003; Schnabel et al. 2000; Shields et al. 2002; Opeskin et al. 2000; Jick et al. 1992; McKee and Bodἀs 2000; Nilsson et al. 1999; Timmings 1993; Walczak et al. 2001). But on the other hand, these risk factors for SUDEP may depend on the type of controls used, and therefore may be regarded as complementary (Tellez-Zenteno et al. 2005). For instance, in the studies in which non-SUDEP deaths were used as controls, seizure preceding death, subtherapeutic drug levels, and patient-found-in-bed were considered the most consistent factors (Kloster and Engelskjon 1999; Birnbach et al. 1991; George and Davis 1998; Opeskin and Berkovic 2003; Schnabel et al. 2000; Shields et al. 2002; Opeskin et al. 2000). These studies may be clinically useful in terms of ascertaining the peri-SUDEP circumstances of the patients. In studies that used persons living with epilepsy as controls, the main risk factors were high seizure frequency, high number of antiepileptic drugs, youth (but not children), and

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long duration of epilepsy (Jick et al. 1992; McKee and Bodἀsh 2000; Nilsson et al. 1999; Timmings 1993; Walczak et al. 2001). These studies may be better in terms of determining enduring, long-term factors affecting SUDEP. Although risk factors located in epidemiological studies may not offer detailed mechanistic explanations for the mechanism of SUDEP, they may nonetheless provide lines of thinking to support or refute proposed mechanisms of SUDEP. Central to this issue is that seizures do have an important role to play in SUDEP. Research into the pathogenic mechanism of SUDEP has proposed several paradigms: (1) cortical control of autonomic system, in terms of ictal bradyarrhythmia; (2) primary cardiac disease; (3) arrhythmogenic side effects of antiepileptic drugs; and (4) respiratory€mechanisms (e.g., the contribution of peri-ictal apnea and hypoxia in generalized tonic–clonic seizures is well recognized and pulmonary edema to varying extent has been reported in patients with SUDEP), mainly with retrospective ἀndings, particularly autopsy cases (Stöllberger and Finsterer 2004, Lathers and Schraeder 2010). It is not difficult for one to decipher the overlap between the mechanisms underlying ictal bradyarrhythmia and SUDEP in this regard owing to the suggestion that the cortical control of the autonomic system is a prevailing underlying explanation. The discussions about the pathogenic mechanisms of ictal bradyarrhythmia may very well apply to SUDEP, but this is made on the assumption that ictal bradyarrhythmia actually occurs during a SUDEP episode. Epidemiological data suggesting that a seizure may occur shortly before SUDEP bear witness to the possibility of ictal bradyarrhythmia having taken place. In fact, in the study in which the highest ἀgure was quoted, signs of seizures starting the ἀnal event were observed in 67% of SUDEP patients, all due to generalized motor seizures (Kloster and Engelskjon 1999). If the patient was found to have SUDEP in bed or during sleep, then it may well be possible that during such times the patient was in a physiological state that predisposed the patient to SUDEP, such as reduced sympathetic tone to counteract ictal bradyarrhythmia or increased autonomic instability leading to extreme fluctuations in heart rate. More discussion regarding sleep and SUDEP will be given in another chapter in this book (Chapter 23; Hughes and Sato 2010). However, in our analysis of patients with ictal bradyarrhythmia (both scalp and intracranial EEG data), there was insufficient information to indicate whether ictal bradyarrhythmia may occur more often during sleep. Another useful clinical method would be to look for the characteristics in a cohort with both SUDEP and ictal arrhythmia. In one recent study (Nei et al. 2004) involving 21 patients with deἀnite and probable SUDEP, ictal cardiac repolarization and rhythm abnormalities were found to occur in 56% of cases, although only 16 out of the 21 patients had continuous ECG data recorded with video EEG and the analysis was understandably performed in retrospect. The rhythm abnormalities may range from atrial ἀbrillation, through ventricular premature depolarizations, to junctional escape. No overt ictal asystole and no association with laterality were found. Authors from this study stipulated that seizures from sleep can cause sudden and extreme fluctuations in autonomic tone, which can trigger lethal cardiac arrhythmia, including bradycardia. In one recent SUDEP review, the association between cardiac dysfunction and SUDEP was not substantiated (Tellez-Zenteno et al. 2005). Thus, we may see that the clinical data were not in perfect agreement with the mechanistic explanation of SUDEP using ictal bradyarrhythmia alone, and there is a possibility that individual variability can be important and different patients may have different mechanisms (Lathers 1982, 2008). Intrinsic cardiac diseases among SUDEP cases were suspected often by virtue of autopsy analyses. These were made on histological grounds such as focal myocarditis or

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hypertrophic or dilative cardiomyopathy or other problems in the conduction system (Cohle et al. 2002) although the quality of specimen analysis might be less than desirable due to the advanced stage of death. Speciἀc ion channel and preexcitation syndromes were also suspected by researchers, and, for instance, the long QT syndromes may be due to mutations of sodium and potassium cardiac ion channels and the short QT syndrome may be due to missense mutation in the potassium ion channel IKrHERG (de la Grandmaison 2006). Such pathology may, however, not be readily demonstrable at autopsy, making retrospective analysis of this theory rather difficult (Davies 1999). There was speculation that such genetic mutation may underlie both an epilepsy syndrome and a cardiac syndrome although the exact disease entity remains unknown (Hiroso et al. 2005). Moreover, these entities may comprise theoretically both tachycardia and bradycardia syndrome. Epidemiological studies did not identify as yet intrinsic cardiac disease as a risk factor (Tellez-Zenteno et al. 2005) and cardiac enzymes (such as troponin T) during seizure were previously shown not to be elevated ictally (Woodruff et al. 2003). Therefore, the contribution of an intrinsic cardiac disease to SUDEP, with or without direct reference to ictal bradyarrhythmia, remains unknown from a clinical point of view. The speciἀc association of carbamazepine with SUDEP has been previously investigated. An audit of an epilepsy clinic in Wales showed that carbamazepine was used in higher proportion among the 14 SUDEP patients than among the general epilepsy patients attending the clinic (Timmings 1998). However, confounding with other variables had not been removed. In a Norwegian study, carbamazepine was also shown to be in small excess among the SUDEP cases but polytherapy precluded worthwhile analysis (Kloster and Engelskjon 1999). The arrhythmogenic properties of carbamazepine had been already discussed, but once again, the contribution of carbamazepine to SUDEP with or without a linkage to ictal bradyarrhythmia is still open to debate. Please see a separate chapter in this book regarding the risk of SUDEP with pharmaceutical drugs (Chapter 51; Tomson 2010). Respiratory mechanisms have been reported to be compromised during an ictal event using polysomnography in 20 of 47 clinical seizures according to one study (Nashef et al. 1996). Central apnea was most often observed but obstructive apnea was also present. What is more, bradycardia was shown to be associated with apnea during the same time. In two reports featuring witnessed SUDEP cases, seizure associated respiratory embarrassment was a prominent observation (Nashef et al. 1998; Langan et al. 2000). The relationship between ictal bradyarrhythmia and ictal apnea lies at the proposition that either may be mediated by a similar set of central autonomic networks as suggested by previous electrical stimulation studies (Penἀeld and Jasper 1954). However, apnea due to noncentral influence may not be explained by this. In studies examining the risk factors for SUDEP, the proportion of patients found dead in a prone position ranged from 42% to 71% (Kloster and Engelskjon 1999; Nashef et al. 1996; Earnest et al. 1992). It was postulated that in such a position ventilation may be easily compromised, such as bringing about collapse of upper airways, particularly if seizure had happened. Pathological examination of SUDEP cases also revealed the common occurrence of pulmonary edema in the autopsy that pointed toward the involvement of apnea in peri-SUDEP circumstances (Black and Graham 2002). In the only case of SUDEP occurring in an intracranially monitored patient, the death occurred during a seizure with right mesial temporal onset with the EEG becoming flat after 16 s in the right hemisphere. The left hemisphere showed spike discharges for a further 8 s before ceasing suddenly as well. However, there was no respiratory or ECG recording

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although pulse artifact was found for a further 120 s at a rate of 46 s. During the event the patient was lying face down although no apparent evidence of asphyxia was noted. Bird et al. (1997) proposed that the mechanism of SUDEP in this case was entirely cerebrogenic. Therefore, the mechanism underlying SUDEP may be a multifactorial one, with contribution of seizure playing a major role, and with the central influence of cardiac and respiratory functions giving rise to potentially life-threatening events, with or without extra predisposition from intrinsically altered physiological parameters such as a cardiac substrate (Amlie 1997), or drugs, together with certain peri-SUDEP events, such as a prone position or during sleep, which ultimately brings about the demise of the patient.

16.8â•…What Lies in the Future for Researchers? We have reexamined the biological plausibility of the cortical control of the autonomic system in the explanation of ictal bradyarrhythmia. Although the evidence from scientiἀc studies is in keeping with this general notion, further analysis to allow for a clear dissection of the mechanism is not readily available, such as the left-right paradigm. Further extrapolation of ictal bradyarrhythmia to a mechanistic explanation for SUDEP has remained elusive. The missing links are (1) clinical evidence of common factors shared by ictal bradyarrhythmic patients and SUDEP patients, (2) evidence of arrhythmia from epidemiological studies as a risk factor for SUDEP, and (3) ascertaining the importance of ictal bradyarrhythmia in SUDEP with regard to other proposed mechanisms including apnea and intrinsic cardiac abnormalities. It may well be possible that SUDEP has an underlying mechanism attributable to multiple causes rather than a single, unifying factor. From the seizure mechanistic perspective, and also based on data from electrical stimulation and functional imaging studies, it might be logical to speciἀcally examine cases in which intracranial EEG monitoring of the left insular region took place. However, there is ethical concern in putting an intracranial electrode near the insular region simply to look for seizure spread rather than origin. In addition, in individual patients with intracranial recording showing seizure onset from the insular region, the presence of lesion may alter the normal physiological location of the autonomic cortical pathways. From the clinical point of view, it would be logical to look again at the underlying seizure mechanism and location of seizure onset and spread in each and every case of SUDEP. Given the increasing utilization of presurgical work-up for refractory epilepsy patients, the number of SUDEP cases with previous intracranial recording may be increasingly found. Comparison of SUDEP cohorts with ictal bradyarrhythmia patients and exploration of other alternative mechanisms for SUDEP may be potential areas for further research.

Acknowledgments We thank the research team at the Division of Neurology, Department of Medicine and Therapeutics, Chinese University of Hong Kong. We are grateful to Professor Lawrence K. S. Wong, the chair professor in Neurology at the Chinese University of Hong Kong, for guidance over our research interests over the years. We are also most indebted to our collaborators at the Department of Epileptology, University of Bonn, Germany, and to Professor Christian Elger for his most kind and generous offers of training opportunities

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during our visits to the University of Bonn. We are grateful to Drs. Vincent Ip and Lisa Au for proofreading the manuscript.

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252 Sudden Death in Epilepsy: Forensic and Clinical Issues Woodruff, B. K., J. W. Britton, S. Tigaran, G. D. Gascino, M. F. Burritt, J. P. McConnell, J. Ravkilde et al. 2003. Cardiac troponin levels following monitored epileptic seizures. Neurology 60: 1690–1692. Zamrini, E. Y., K. J. Meador, D. W. Loring, F. T. Nichols, G. P. Lee, W. O. Tomson. 1990. Unilateral cerebral inactivation produces differential left/right heart rate responses. Neurology 40: 1408–1411.

17

Stress and SUDEP Claire M. Lathers Paul L. Schraeder

Contents 17.1 Introduction 17.2 Stress-Related Risk Factors 17.3 Positive Life Events as a Stress: A Case Report of SUDEP References

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17.1â•…Introduction Heart–brain interactions function during normal daily routine actions and during times of stress. The occurrence of stress itself is a powerful change initiator and may trigger transient ischemia and acute coronary syndrome in some persons (Pickworth et al. 1990; Lathers and Schraeder 2006; Lathers et al. 2008; Soufer and Burg 2007). These individuals are at increased risk for recurrent cardiac events and early death. Psychosocial stress can become an acute trigger of myocardial infarction in patients with preexisting coronary artery disease. Stress, via actions on the central and autonomic nervous systems, may produce a cascade of physiologic responses in individuals at risk that may lead to myocardial ischemia, ventricular ἀbrillation, plaque rupture, or coronary thrombosis (Krantz et al. 1996). Use of simultaneous single-photon emission computed tomography imaging with technetium99m tetrofosmin myocardial perfusion imaging and transthoracic echocardiography was done at rest and during mental stress induced in patients with stable coronary artery disease (Shah et al. 2006). It was concluded that C-reactive protein levels may be a risk marker for mental stress-induced myocardial ischemia. The role of C-reactive protein levels in stress associated with interictal and ictal seizure activity and the development of cardiac arrhythmias and/or death is unknown and should be examined. Nevertheless, today we still do not understand the pathophysiology of mental stress-induced ischemia, what diagnostic tests are needed to identify susceptible persons, nor how to develop risk stratiἀcation algorithms to be applied in the clinical workplace. Research is needed to understand the brain–heart relationship during the occurrence of mental stress that underlies the cognitive and emotional aspects of mental stress as the distinct patterns of brain activity occurring during mental stress trigger silent myocardial ischemia (Soufer and Burg 2007). Cardiac function itself may be adversely changed during an episode of acute emotional stress (Ziegelstein 2007). Left ventricular contractile dysfunction, myocardial ischemia, and/or cardiac arrhythmias have been demonstrated to be triggered by acute emotional stress. These events may be transient but have damaging and/or fatal consequences. The understanding of the anatomical substrate and physiological pathways involved in this heart–brain interaction are not clear, but new data obtained with functional neuroimaging suggest asymmetric brain activity are important in making the heart more susceptible 253

254 Sudden Death in Epilepsy: Forensic and Clinical Issues

to ventricular arrhythmias. Lateralization of cerebral activity during emotional stress may stimulate the heart asymmetrically and produce areas of inhomogeneous repolarization that create electrical instability and facilitate development of cardiac arrhythmias. Ziegelstein (2007) states that patients with ischemic heart disease, who do survive an episode of sudden cardiac death in the setting of acute emotional stress, should be treated with a beta blocker. Nonpharmacologic methods to manage the effects of stress in persons with or without coronary artery disease include social support, relaxation therapy, yoga, meditation, controlled slow breathing, and biofeedback. Clues for effective treatment of mental and emotional stress associated with heart– brain interactions exist. As early as 1993, the pathophysiologic effects of mental stress appear to involve alterations in both myocardial oxygen demand and supply (Merz et al. 1993). Intense negative emotion, such as hostility, and heightened cardiovascular reactivity are associated with occurrence of this type of ischemia. Thus, if persons at risk are taught to recognize these factors, interventional training may help protect them from unwanted consequences. Using traditional anti-ischemic therapy, such as beta blockers and vasodilators, has been shown to reduce mental stress–triggered ischemia in coronary artery disease. Both behavioral and psychosocial interventions, such as decreasing environmental stress via use of social support, alteration of stress perception by behavioral training, and altered physiologic reaction to stress through physical training were discussed as therapeutic options. Posttraumatic stress disorder, a psychiatric disorder that develops after a psychological trauma generally triggered by a situation perceived by the person experiencing the event as one that deeply threatens his/her life or integrity, is thought to be triggered by complex neurobiological changes. Kozaric-Kovacic (2008) reports that selective serotonin-reuptake inhibitors are the ἀrst line of treatment for posttraumatic stress disorders. These agents are more effective than noradrenalin-reuptake inhibitors or tricyclic antidepressants. Antipsychotic drugs, especially the atypical ones, are effective in posttraumatic stress disorder patients with psychotic characteristics or refractoriness to other drugs, reducing the overall overreaction to stress. Monoamine oxidase inhibitors have not been clearly identiἀed as beneἀcial. Serotonin agonists and antagonists, new antidepressants that are dual inhibitors of serotonin and noradrenaline reuptake, anticonvulsants, and opiate antagonists may be used. Additional rigorous clinical trials are needed to establish use, efficacy, tolerability, and safety in treating this pharmacotherapeutic disorder. The occurrence of acute postictal psychiatric symptoms are well recognized, but, fortunately, relatively uncommon, and most likely manifest after partial complex seizures. These symptoms may mimic anxiety, depression, or an acute psychotic disorder (Kanner et al. 1996). Violent behavior can also be an uncommon postictal manifestation. When such episodes of€ violence occur, they are not well organized, planned, or speciἀcally directed. Directed aggression is rare, but when postictal aggressive behavior—whether undirected or seemingly directed—does occur, the patient can be at risk for an aggressive police response including total body restraints. Mendez (1998) described a patient with directed postictal aggression.

17.2â•…Stress-Related Risk Factors The mechanisms involved in emotion-associated seizure activation are not known but multiple factors may explain the role of emotion. These factors include activation of neural networks, sleep deprivation, noncompliance, alcohol use, and hyperventilation. Increased

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risk of seizure recurrence is also associated with use of antidepressants and/or neuroleptics, drugs that may lower the seizure threshold. Poor seizure control is a major risk factor for SUDEP (Dominian et al. 1963; Mattson 1991; Nashef et al. 1995; Sperling et al. 1999). Acute stress caused by emotions such as fear may cause sudden death in persons with coronary heart disease. Chronic stress also contributes to development of long-term coronary disease (Ackerman et al. 2001). Stress management in standard cardiac rehabilitation programs is important. The distinction between type A versus type B personalities as risk correlates is overly simplistic. Psychosocial factors of depression, hostility, social isolation, anxiety, anger, and other stresses are related to increased cardiac death and illness in all groups with coronary heart disease (Buselli and Stuart 1999) and these psychosocial risk factors may beneἀt from a biopsychosocial model of intervention. Death can result from acute stress related to disasters. Sudden deaths related to atherosclerotic coronary artery disease increased ἀvefold on the day of the Los Angeles earthquake in 1994 (Leor et al. 1996). Acute mental stress induced experimentally may be associated with ST-segment deviation and wall-

Heart –Brain Int erplay : A 53-Year-Old Wo man Reco v ering fro m Mit ral Valv e Repair Anxiety, panic, fatigue, and depression can have a profound adverse effect on physical well-being. This case illustrates how these adverse psychological symptoms interfered with recovery from mitral valve surgery. A 53-year-old woman had an uncomplicated mitral valve repair, after which she refused to use the incentive spirometer, ambulate, or even sit in a chair. She experienced unexplained episodes of shortness of breath and tachycardia. At 4 weeks after operation, the ejection fraction, which was 50% pre-op, remained at 40%. She was complaining of more post-op pain and fatigue than was usual for this type of successful surgery. The patient experienced tearful episodes, and reluctantly was interviewed by a psychiatrist. While the initial diagnosis was adjustment disorder with anxious features, subsequent evaluation established a diagnosis of depression. Ultimately, the patient agreed to take an SSRI, citalopram. After several weeks of treatment, she had a profound improvement in her mental and physical states, with she and her family concurring that she had returned to her “old self” (Callahan et al. 2008). Discussio n This case illustrates how postoperative cardiac rehabilitation can be signiἀcantly affected by an adverse psychological state. Although the pathophysiological mechanism of sudden death in epilepsy (SUDEP) is not established, acute cardiac dysfunction is thought to be a major factor. Cardiologists have long known about the physical risks of adverse mental states in cardiac patients including unexpected sudden cardiac death. The role of stress and other psychological disturbances require consideration as possible risk factors associated with SUDEP. However, in contrast to the interest cardiologists have manifested in psychogenic risks associated with cardiac sudden death, little research has been undertaken on the subject of psychological issues relative to the risk of SUDEP.

256 Sudden Death in Epilepsy: Forensic and Clinical Issues

motion abnormalities (Rozanski et al. 1988). Mental stress may be a greater risk factor than eÂ�xercise-induced ischemia in increasing the rate of fatal and nonfatal cardiac events (Jiang et al. 1996). Psychosocial stress management treatment in a cardiac rehabilitation program does reduce cardiac related mortality and morbidity (Linden et al. 1996). Distress at the family level and/or stress at work are strong predictors for developing stress-related disorders and need intervention (Anderberg 2001). Management of stress factors in coronary artery disease may also help to decrease the risk of sudden death. While depression and stress are major risk factors in sudden cardiac death, it is not known if the same risks apply to SUDEP. Having epilepsy in and of itself is stress-producing and stress does increase the frequency of seizures. The uncertainty of when a seizure can occur, the consequences of having a seizure on employment status and driving privileges are stress-producing circumstances. Both depression and anxiety are symptoms associated with epilepsy (Trimble and Perez 1980; Blumer 1992). Earnest et al. (1992) suggested there was a role for acutely stressful circumstances as a possible contributor near the time of death in a case control study of the metropolitan Denver area. The strong interest of cardiologists in adverse emotional states as a risk of sudden cardiac death implies that there is a need to investigate this issue more thoroughly in persons with epilepsy. Activation of stress-responsive systems during depressive episodes may contribute to metabolic risk factors and imbalance of the autonomic heart regulation (Blumer 1992; Linden et al. 1996; Deuschle and Lederbogen 2002). Clearly, cerebral activity can have a profound effect upon the autonomic regulation of cardiac function. Lathers et al. (1977, 1978) found that nonuniform postganglionic cardiac sympathetic neural discharge is capable of triggering cardiac arrhythmias in the manner described by Han and Moe (1964) (i.e., nonuniform cardiac repolarization). These authors noted that the aberrant nonuniform neural discharge was associated with cardiac arrhythmias triggered by abrupt coronary occlusion of the left anterior descending coronary artery to produce cardiac ischemia mimicking events occurring in the sudden death heart attack victim. The nonuniform postganglionic cardiac sympathetic neural activity also occurs with cardiac changes associated with ouabain-induced toxicity characterized by cardiac arrhythmias and death. In both animal models the potentially damaging role of adrenal catecholamines in the production of arrhythmias and death was discussed. Synchronization of brain electrical activity with both cardiac sympathetic and vagal neural discharge was also identiἀed by those working in Dr. Lathers’ laboratory using the cat model (Lathers et al. 1987; O’Rourke and Lathers 1990; Dodd-O and Lathers 1990; Stauffer et al. 1989; Lathers et al. 2010). This autonomic neural discharge synchronized with cerebral ictal and interictal discharges was termed the lockstep phenomenon and was hypothesized to be one mechanism contributing to the development of cardiac arrhythmias and/or sudden death associated with both interictal and ictal discharges in persons with epilepsy found dead in a sudden, unexpected manner. Subsequently, Davis and Natelson (1993) focused on brain–heart interactions and the neurocardiology of arrhythmia and sudden cardiac death, with an emphasis on the nervous system direction of the events leading to cardiac damage associated with raising catecholamine levels in experimental and clinical entities of stroke, epilepsy, and environmental stress. Autonomic sympathetic and parasympathetic cardiac neuronal dysfunctions are associated with interictal as well as ictal epileptiform discharges and with cardiac arrhythmias (Lathers and Schraeder 1982). Both types of epileptogenic activity are associated with temporal lobe epilepsy, autonomic dysregulation, and predominant sympathetic overactivity

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Case Repo rt o f Po st ict al Ag g ressi v e Behav io r A 37-year-old man had complex partial seizures, consisting of an olfactory aura followed by alteration of consciousness, since age ἀve, with occasional tonic–clonic seizures. He also had a history of depression and bipolar affective disorder. During the postictal period, at times he would feel a sense of being threatened and having been harmed, and would focus his aggressive response by attacking any individual in his immediate environment, often resulting in physical injury to that person. The patient’s postictal confusion would remit usually after one hour, but the fear of harm and sense of being threatened would last for 24 hours, after which he felt great remorse. He had been charged with aggravated assault several times. His MRI was unremarkable, but sleep-deprived EEG manifested left anterior temporal spikes and sharp waves. The aggressive postictal episodes ended with control of his seizures resulting from the addition of carbamazepine to his original regimen of valproic acid and sertraline. Discussio n by M endez The author describes aggressive acts as direct consequence of seizures, occurring directly during seizures or postictally (Mendez 1998). He also emphasizes that postÂ� ictal violence is most commonly resistive behavior during the postictal delirium and is associated with attempts at restraint. He also discussed the observation that seemingly violent automatisms such as flailing or spitting can occur during complex partial seizures, and that secondary violent automatisms can be behavioral responses to ictal fear, hallucinations, or other disagreeable seizure related experiences. Discussio n by L at hers and Schraeder Another issue to consider in relationship to the occurrence of putative ictal or postictal violent behavior is that of the possible induction of an excited delirium syndrome when attempts are made to restrain the behavior of an individual who is manifesting actual or seemingly violent behavior. As deἀned by DiMaio and DiMaio (2006), excited delirium syndrome “involves the sudden death of an individual, during or following an episode of excited delirium, in which an autopsy fails to reveal evidence of sufficient trauma or natural disease to explain the death. In virtually all cases, the episode of excited delirium is terminated by a struggle with police or medical personnel, and the use of physical restraint. Typically, within a few to several minutes following cessation of the struggle, the individual is noted to be in cardiopulmonary arrest. Attempts at resuscitation are usually unsuccessful.” During the state of delirium, there are varying transient disturbances of consciousness and cognition with disorientation, disorganized and inconsistent thought processes, inability to distinguish reality from hallucinations, speech disturbance, and disorientation to time, place, and person. Deaths occur most commonly in individuals who have abused stimulants such as cocaine and methamphetamine, but also in persons with endogenous mental disease who have not used these drugs. The majority of deaths occur between the ages of 17 and 35. Although the mechanism of death in these individuals is not deἀned, DiMaio and DiMaio (2006) concluded that stimulation of the sympathetic nervous system causes release of norepinephrine at the synapses and in combination

258 Sudden Death in Epilepsy: Forensic and Clinical Issues

with epinephrine into the bloodstream from the adrenals. This response then results in subsequent increase in myocyte activity and oxygen demand in combination with decreased myocardial blood flow secondary to coronary artery constriction. We need to be aware of the potential for induction of this potentially fatal state of agitation when attempts are made to restrain persons with epilepsy who manifest ictal or postictal agitation or seemingly violent behavior. This is a highly stressful state and in combination with the history of epilepsy could be contributory to the occurrence of SUDEP in these individuals. Since both ictal and postictal states are self limited, it is imperative for family members, police, and emergency care personnel to understand that watchful observation to keep the affected individual out of harm’s way, rather than the high-risk intervention of physical restraint, is the most appropriate intervention.

(Hilz et al. 2002). Surgical treatment for temporal lobe epilepsy reduced sympathetic cardiomodulation and decreased baroreflex sensitivity (i.e., decreased the influence of sympathetically mediated tachyarrhythmias and excessive bradycardiac counterregulation). These factors are thought to contribute to the risk of SUDEP and thus the temporal lobe surgery itself appears to be one method to reduce and/or eliminate some risk factors associated with SUDEP (Hilz et al. 2002; Burgerman et al. 1995). Parasympathetic nervous system activity also regulates cardiac rhythm (Richter 1957; Talman 1985). Stimulation of the vagus nerve or application of acetylcholine to the SA node slows or abolishes depolarization of sinus node ἀbers (Schwartz et al. 1976; West et al. 1956). Decreased depolarization and shifts of membrane threshold potentials change the SA node rate, causing sinus bradycardia. A similar mechanism occurs in the AV node (Kralios and Millar 1981). ECG changes and cardiac muscle necrosis result from stimulation of the efferent limb of the sympathetic nervous system and by stimulation of the aortic arch and carotid baroreceptors regulated by the autonomic nervous system reflex activity (Pavlov 1951; Samuels 1997; Zavodskaya et al. 1980; Natelson et al. 1998). Sympathetic stimulation causes a sudden release of norepinephrine from cardiac nerve endings into the heart muscle. This leads to microscopic changes in the form of cardiac myocyte necrosis, cardiac dysfunction, and arrhythmias (Schwartz et al. 1976; West et al. 1956). Stimulation of cardiac sympathetic nerves accelerates sinoatrial depolarizations and shortens the cycle length of ἀring of the sinus node. Natelson et al. (1998) found pathologic changes in the form of irreversible perivascular and interstitial ἀbrosis and myocyte vacuolization in hearts of persons with epilepsy who died suddenly. These lesions occurred mostly in the subendocardium. Thus, it is possible they also resulted from sympathetic nerve catecholamine release with consequent cardiac arrhythmias and repolarization changes that predispose a patient to a form of cardiac damage known as myoἀbrillar degeneration or contraction band necrosis and possible sudden death. This lesion is associated with four types of etiologies: stress plus or minus steroids, catecholamine infusion, nervous system stimulation, and reperfusion. Sympathetic overactivity, with secondary catecholamine toxicity, is the common factor in all four etiologies. Samuels (1997) concludes that all forms of sudden death are based on the anatomic connection between the nervous system and the heart and lungs.

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Exposure of rats to stress initially resulted in structural changes of stereotypical cardiac contraction bands, regardless of the type of stress factor, and differed only in severity. At a later stage, contractures were gradually replaced by cytolytic injuries and also did not depend on the type of stress. In the case of early predominance of myocytolysis in combination with excessive contracture injuries that led to rapid death, a genetically determined predisposition was proposed as an explanation (Zavodskaya et al. 1980). Since emotional stressors impact on the autonomic nervous system, this ensures that psychogenic factors are important in leading to cardiac dysrhythmias and to coronary and noncoronary sudden death syndromes in humans and other species (Bohus and Korte 2000). There is a causal relationship among depression, stress, and increased cardiac mortality. Depression may be a state of prolonged negative arousal or mental stress associated with a measurably higher risk of fatal cardiac events. Stress may also result in histopathological changes in a previously normal heart while genetically determined and/or acquired dysfunction of the opioidegic, GABAegic, cholinergic, adenosinergic, and other transmitter/modulator systems may interact to predispose to arrhythmias and sudden death (Tulner and den Boer 2000). The influence of psychological factors on autonomic, neuroendocrine, and immune systems is complex and exerts adverse effects on cardiac function. The amygdala is involved in integration of autonomic responses to emotional stimuli (Cechetto 2000). There is a common pattern of sympathetic representation in the medial prefrontal cortex, insular cortex, ventromedial temporal lobe, and ventral hippocampal region (Westerhaus and Loewy 2001). The ventromedial temporal lobe regions studied included the central, basomedial posterior, and lateral amygdaloid transition area and posterior medial cortical amygdaloid nucleus. This latter anatomical substrate for sympathetic control is of considerable theoretical importance. The amygdala has an important role in expression of emotional behaviors while it integrates autonomic responses to emotional stimuli under conditions of fear and anxiety. The amygdala is important in cardiovascular control within the limbic system, having reciprocal connections with the insular cortex and direct projections to other autonomic control centers in the hypothalamus, pons, and medulla. Other important brain–heart connections exist. Limbic cortex activity associated with an emotionally charged stimulus occurs with cardiac neural changes, resulting in intense autonomic stimulation of both sympathetic and parasympathetic neurons. This, in turn, may result in sudden stress-related death. It is assumed that the hypothalamic and brainstem structures are involved secondarily and that stress activates the hypothalamic–pituitary– adrenal axis. Prolactin levels are elevated after seizures and are used as an indicator that a seizure has actually occurred. The prolactin level is most consistently elevated after generalized tonic–clonic and complex partial seizures, and less predictably after a simple partial seizure. Frontal lobe, absence, myoclonic, and akinetic seizures are not generally associated with elevation of the prolactin level (Pritchard 1997). This observation raised the possibility of the frequent occurrence of a stress response during and after a seizure as a risk factor for SUDEP. An alternative explanation is that the hypothalamic-pituitary axis is directly simulated by the epileptiform activity. In either case, the occurrence of acute autonomic and/or neuroendocrine dysfunction appears to put the patient at risk. Elevated prolactin levels at necropsy were examined as a marker of antemortem stress (Jones and Hallworth 1999), but postmortem prolactin values differed according to the cause of death, with higher values in postoperative deaths and in the chronically ill.

260 Sudden Death in Epilepsy: Forensic and Clinical Issues

In the study of Wannamaker and Booker (1998), patients with epilepsy have identiἀed the common stressors of fear, worry, frustration, and anger as trigger factors. The seizure event usually does not occur immediately in association with the stressor. Animal models suggest that injured populations of neurons surround and interact with an epileptogenic focus. This may cause the focus to function independently when heightened brain excitability triggers neuronal activity in this network. As discussed by Homan (1998), patients often associate increased stress with increased seizure activity. Interventions to reduce stress include the use of behavioral techniques such as biofeedback, relaxation, and desensitization, and pharmacological agents such as psychotherapeutic or benzodiazepine drugs. Physical stress associated with elevated body temperatures induced by infection also triggers seizures and antipyretic drugs are recommended for prophylactic use. Adjunctive management of the patient with seizure and stress results in improvement in the control of seizures and overall quality of life (Moffett and Scott 1984; Fenwick 1995). Education of patients about the importance of drug compliance and stress management techniques ultimately will decrease the need for high therapeutic antiepileptic drug levels while decreasing the occurrence of dose-related side effects. This will also result in an improved lifestyle. Physicians must individualize recommendations for intervention and use referrals to a clinical psychologist with expertise in stress reduction. Both internal and external stressors must be decreased. Treatment with tranquilizers, antidepressants, or neuroleptics is used with counseling. The long-acting anxiolytics clorazepate and clonazepam are relatively effective as antiepileptic drugs in selected patients. Paranoia, thought disorder, hallucinations, and extreme agitation require concurrent psychiatric consultation in addition to treatment with neuroleptics. Care must be exerted when managing the patient since a rapid change in the levels of neuoroleptics, high doses, or induction of drowsiness may worsen the occurrence of seizures. Reduction in agitation, thought disorder, and hallucinations usually exerts a calming effect and contributes to lowering the stress level and to restoring the patient’s sense of well-being (Lathers and Schraeder 2006). As can be concluded from the above discussion, most life events that may be implicated as risk factors for sudden death result in psychological responses that are regarded as negative. The following brief case history raises the possibility that, at least in some persons with epilepsy, an intensely positive event may also be a risk factor for SUDEP.

17.3â•…Positive Life Events as a Stress: A Case Report of SUDEP Many diseases that can affect autonomic balance exhibit patterns of temporal variation during circadian, seasonal, reproductive, and life span cycles that remain unexplained. Termination of organisms during senescence, achieved by emergence of autonomic imbalance and other systemic dysfunction has been examined from a Darwinian perspective. This variation in autonomic balance and disease symptoms of epilepsy has yet to be carefully studied. Cardiac neural control may be estimated by frequency domain characterization of R–R interval variations and this technique is a clinical tool to examine the role of autonomic dysfunction in the pathophysiology of sudden cardiac death (Molgaard et al. 1994). Simultaneous examination of the quality of life and changes in heart rate variability of patients immediately after acute myocardial infarction showed that survivors exhibited heart rate variability within the ἀrst 3 days that was signiἀcantly higher than nonsurvivors and had developed a clear circadian pattern after 3 weeks (Kummell et al. 1993). The authors

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SUDEP AFT ER RECEIVING V ERY GOO D NEWS An 18-year-old black female high school student had a history of infrequent (less than once yearly) generalized tonic–clonic seizures that were controlled with moderate doses of carbamazepine with therapeutic blood levels. She was an outstanding student, and during her senior year was offered admission to an Ivy League school with a full scholarship. Her social circumstances were modest in that her father worked as a municipal trash collector and she was the ἀrst family member to go to college. Shortly thereafter, her distraught parents notiἀed her neurologist (PLS) that their daughter was found dead in bed. As no postmortem was performed, and no other cause of death was evident, the diagnosis of probable SUDEP was applied. This case may demonstrate that intensely positive surprise life events can produce as much of a stress as negative events. concluded circadian patterns of heart rate and heart rate variability may be assessed meaningfully immediately post acute myocardial infarction and may ἀnd common expression in changes in sympathovagal balance. Future studies of persons with epilepsy who may be at risk for SUDEP could examine sympathovagal balance using 24-hour ambulatory BP monitoring to examine circadian blood pressure variation, power spectral analysis of R–R interval oscillation to measure autonomic function, and measurement of QTc-d and QTc intervals to monitor cardiac depolarization time. These techniques were employed in a 1-year study designed to examine sympathovagal balance, nighttime blood pressure and QT intervals (Esposito et al. 2003). Sustained weight loss eliminated the diastolic night time drop in blood pressure and sympathetic overactivity detected in normotensive obese women. This weight loss may reduce the cardiovascular risk in obese women. One could speculate that as the blood pressure falls during sleep, there may be, in some persons with epilepsy and autonomic dysfunction, an increased sympathetic discharge that results in the triggering of cardiac arrhythmias and/or sudden death. A study of the role of sympathovagal interaction in diurnal variations of QT interval suggested that although change in sympathovagal balance was responsible for diurnal variation in QT interval, the enhanced sympathetic activity in the day was a major determinate of the phenomenon (Murakawa et al. 1992). Examination of heart rate variability circadian patterns and effect on the QT interval dispersion in healthy subjects (Bilan et al. 2005) was studied. Multiple regression analysis revealed relations between mean QTd and R–R as well as mean QTd and high frequency after adjustment for periods, correlations were only observed during morning hours. The authors concluded that sympathovagal balance, as reflected in heart rate variability, and not the tone of both autonomic components that affects QTd variability. These data suggest that in persons with epilepsy, the sympathovagal balance, as reflected in heart rate variability, should be examined for changes in QTd variability as a risk factor for sudden death during both awake and sleep cycles. In Brugada syndrome, ventricular ἀbrillation occurs mainly during sleep, and Brugada ECG signs are intensiἀed by parasympathomimetic drugs (Mizumaki et al. 2004). Spontaneous augmentation of ST elevation in daily life was demonstrated along with an increase in vagal activity. The ST elevation was increased more in those patients with Brugada syndrome related ventricular ἀbrillation than in those without ventricular ἀbrillation under similar vagal tone. It may be that some patients with epilepsy at certain

262 Sudden Death in Epilepsy: Forensic and Clinical Issues

times exhibit a sympathovagal balance that is dominated by the parasympathetic nervous system and these patients may die in asystole. Most of the time, we consider stress to be associated only with adverse or negative circumstances. However, unexpected good news can also be a stress in a positive sense, especially if it is the fulἀllment of a heretofore seemingly out-of-reach quest. An explanation of why such an association could occur is speculative. However, while it is common knowledge that negative live events such as death, divorce, loss of a job, and so forth, can result in an increase in sympathetic parameters such as heart rate and blood pressure, relief from an adverse circumstance or the occurrence of a positive life event can result in more prominence of parasympathetic parameters such as decreased heart rate and blood pressure (see discussion above). One could speculate that in individuals who have the potential for an excessive parasympathetic response, the intervention of epileptiform discharges could augment this tendency to the point of asystole. Thus, when information about a SUDEP victim’s circumstances prior to the demise is solicited, one should consider eliciting the possibility of an intensely positive event as a risk factor.

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18

Genetics of Sudden Death in Epilepsy Neeti Ghali Lina Nashef

Contents 18.1 The Genetics of Epilepsy 18.2 Mortality in Speciἀc Syndromes 18.2.1 15q Inversion/Duplicaton [inv dup(15)] 18.2.2 Rett Syndrome 18.2.3 Other Examples of Syndromes with Multisystem Involvement 18.2.4 SCN1A-Related Disorders 18.3 SUDEP and Idiopathic Epilepsy 18.4 SUDEP in Genetic Epilepsies: How Does It Occur? 18.5 Genetic Susceptibility to SCD and SIDS 18.6 Conclusion References

267 269 269 270 270 271 272 275 276 278 278

18.1â•… The Genetics of Epilepsy Idiopathic epilepsies account for a substantial proportion of all epilepsies and are considered to be largely genetically determined (Steinlein 2008). The inheritance of these epilepsies may be Mendelian, whereby a single identiἀed mutation results in epilepsy and/or febrile seizures. However, there is often interfamilial and intrafamilial variability in the clinical phenotype, suggesting an effect of other genetic variants. The inheritance is more often non-Mendelian or complex, whereby the phenotype is thought to be determined by several more minor genetic defects as well as environmental effects. Epilepsies inherited in a complex or multifactorial manner will arise when a chance combination of certain susceptibility alleles come together with sufficient effect in the individual to push neuronal hyperexcitability over the seizure threshold (Mulley et al. 2005), but where each susceptibility allele alone is insufficient to cause seizures. Susceptibility genes with minor effect have hitherto been much harder to identify, and most genes conἀrmed to be implicated in idiopathic epilepsy have thus far been Mendelian. Almost all mutations identiἀed in idiopathic Mendelian epilepsies, mostly in large pedigrees, are known to be in ion channel genes or genes interacting with ion channel genes (see Table 18.1). While the broad phenotype is largely determined by a mutation in a major gene, other genes with minor effects as well as environmental factors may modulate its expression. The consequences of these modiἀer effects are twofold: incomplete penetrance, whereby not all carriers of the mutation are clinically affected, and variable phenotypic expression, whereby within a family, factors such as age of onset, type, severity and frequency of seizures, response to antiepileptic drug (AED) treatment, and duration of 267

268 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 18.1â•… Genes Found to Be Factors in Epilepsy Monogenic Epilepsies

Gene

Reference

Benign familial neonatal–infantile seizures

KCNQ2 KCNQ3 SCN2A

GEFS+, SMEI, FS

SCN1A SCN1B GABRG2 GABRG2 CLCN2 GABRA1 LGI1

Singh et al. 1998 Charlier et al. 1998 Heron et al. 2002; Striano et al. 2006 Claes et al. 2001; Escayg et al. 2000 Wallace et al. 1998 Harkin et al. 2002 Baulac et al. 2001 Haug et al. 2003 Cossette et al. 2002 Kalachikov et al. 2002

CHRNA4 CHRNB2 CHRNA2

Steinlein et al. 1995 De Fusco et al. 2000 Aridon et al. 2006

Benign familial neonatal seizures

GEFS+ GEFS+, SMEI, FS Absence epilepsy and FS IGE JME Autosomal dominant lateral temporal lobe epilepsy Autosomal dominant nocturnal frontal lobe epilepsy

Note: GEFS+, generalized epilepsy with febrile seizures plus; SMEI, severe myoclonic epilepsy of infancy; FS, febrile seizures; IGE, idiopathic generalized epilepsy; JME, juvenile myoclonic epilepsy.

the epileptic disorder may be different. Mechanisms for incomplete penetrance are largely unknown. Some believe that if there are mutations in more than one ion channel gene, the individual will have a more severe phenotype (Kearney et al. 2006). However, of interest is an animal study whereby mutations in two different ion channel genes that would individually result in opposing excitability defects resulted in nullifying the epilepsy phenotype in mice (Glasscock et al. 2007). In addition, there may be some genotype–phenotype correlation with interfamilial variability, whereby the severity of the disease relates to the type of mutation in a speciἀc gene; a nonsense mutation resulting in a stop codon, for example, may lead to a more severe phenotype. For all these reasons, it can sometimes be difficult to distinguish between monogenic epilepsies and those inherited in a complex manner. Genetic mutations may also result in symptomatic epilepsies as a result of a cortical malformation (e.g., a mutation in the GPR56 gene results in bilateral frontoparietal polymicrogyria that often presents with seizures). Mutations in the MECP2 gene result in Rett syndrome, an X-linked syndrome presenting with seizures, ataxia, and severe learning difficulties. Epilepsy in the context of learning difficulties may be a result of singlegene disorders such as Rett syndrome or due to a chromosomal abnormality such as 1p36 microdeletion syndrome, ring 20 and ring 14 syndromes, or other chromosomal aberrations such as inversion-duplication 15. The genes responsible for the epilepsy in these chromosomal syndromes are at present largely unknown. The development of higher resolution chromosomal studies such as comparative genomic hybridization using arrays may help delineate this and identify further epilepsy genes. With the advent of array technology, submicroscopic deletions and duplications are now being identiἀed. Microdeletions of 15q13.3 have been reported to be associated with epilepsy and learning difficulties (Sharp et al. 2008). Furthermore, microdeletions of 15q13.3 have been associated with idiopathic generalized epilepsy (IGE) (Helbig et al. 2009). Genomic imbalances in these regions in the form of microduplications have been found to be associated with autistic spectrum

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disorder (Miller et al. 2009) and schizophrenia (International Schizophrenia Consortium 2008). In both single-gene disorders and chromosomal disorders, the epilepsy may not always be a consistent feature of a syndrome and the phenotype and severity often varies. In some genetic syndromes, there may be an underlying brain abnormality, whereas in others, the brain appears developmentally normal. A classiἀcation of diseases frequently associated with epileptic seizures or syndromes is available in Engel’s (2001) proposed diagnostic scheme. A United Kingdom Workshop in 2006 concluded that although epilepsy genetics has advanced signiἀcantly over the past decade, this is merely the beginning. Truly characterizing the full extent of genomic variation related to multifactorial or complex epilepsy remains very much in the future (Sisodiya et al. 2007). It was noted, however, that an impact on clinical practice has already been observed. For example, as a result of the identiἀcation of SCN1A mutations in Mendelian families with a phenotype of generalized epilepsy with€ febrile seizures plus (GEFS+), sporadic cases of Dravet syndrome or severe€ myoÂ� clonic€epilepsy of infancy (SMEI) were also found to carry SCN1A mutations. These cases have been shown to respond well to stiripentol, which is considered to enhance central GABA transmission by increasing duration of channel opening (Quilichini et al. 2006) and a meta-analysis has shown signiἀcant improvement in seizure control (Kassai et al. 2008). It is hoped that this beneἀcial effect will translate into improved developmental outcome in what is currently a disorder with an extremely poor prognosis and demonstrates the key role of research into basic science for these disorders (Mullen and Scheffer 2009).

18.2â•… Mortality in Specific Syndromes A family history of an increased risk of sudden death, where looked for, has generally not been reported in sudden unexpected death in epilepsy (SUDEP) cohorts or in a case control study of SUDEP (Nashef et al. 1998; Langan et al. 2005). However, this should not be taken to exclude the possibility of a familial tendency in a subgroup. Most epidemiological studies include all epilepsies and not only those with a likely genetic basis. Studies may not be designed to identify increased risk of syncope, sudden infant death syndrome (SIDS), or sudden cardiac death (SCD), particularly if inheritance is complex or if penetrance is reduced. Data are also very limited when it comes to mortality studies in epilepsy in speciἀc syndromes, and much of what is discussed below does not have a ἀrm basis. Nevertheless, there is a suggestion that mortality rates may differ between epileptic syndromes over and above that expected from the severity of the epilepsy, as in the examples below. 18.2.1â•… 15q Inversion/Duplicaton [inv dup(15)] This chromosomal anomaly is caused by the presence of a supernumerary chromosome 15 and results in tetrasomy of the 15q11-q13 region. This region is also involved in both Angelman and Prader–Willi syndromes and overlaps with recently reported microdeletions and microduplications referred to above. Inv dup(15) syndrome is characterized by hypotonia, minor dysmorphic features, moderate to severe learning difficulties, autistic spectrum disorder, and seizures. Seizure types include spasms, atypical absences, and tonic and atonic seizures. The electroencephalograph (EEG) shows atypical hypsarhythmia, with large amplitude diffuse slow spike waves and/or multifocal abnormalities. Case

270 Sudden Death in Epilepsy: Forensic and Clinical Issues

reports indicate a variable phenotype. Mosaic inv dup (15) has been identiἀed in a healthy child (Loitzsch and Bartsch 2006), while a child with mild generalized epilepsy and a developmental disorder was found to have a large inv dup (15) (Chifari et al. 2002). Most case reports describe a phenotype where seizures are a signiἀcant and consistent problem. The IDEAS support group for inv dup (15) (Isodicentric 15 Exchange, Advocacy & Support) released a physician advisory update alerting of the risk of sudden, unexpected death in this group of patients, suggesting that the risk is in the order of 1% per year (IsoDicentric 15 Exchange, Advocacy & Support 2009). Six cases are reported on the Web site and the€mechÂ� anism is unknown in all cases with each individual dying in bed during the night, presumably while asleep. According to the Web site, “Five of the six young people had recognized seizure disorders. One had no recent seizures, and the remaining three had seizures that were described as well controlled at the time of death, and one had not had a seizure for more than a month.” While caution is required in assuming an increased risk without the data being published in a peer-reviewed publication, it is clear that the advisory clinicians felt there was cause for concern. At the time of writing, two sudden unexpected deaths in individuals with Inv dup(15) syndrome have been published (Hogart et al. 2009). Further studies on this rare chromosomal anomaly need to be carried out to conἀrm if there is a higher-than-expected rate of sudden unexpected death in these patients. 18.2.2â•…Rett Syndrome Epilepsy is a manifestation of Rett syndrome with partial and generalized seizures being reported in 50% to 90% of cases. Sudden death with no preceding symptoms is a recognized problem associated with Rett syndrome and seizures may be a partial explanation although the precise etiology is not always understood (Byard 2006). Sudden death has been reported in 22% to 26% of cases compared to 2.3% in the general population of the same age (Byard 2006). Several studies have been carried out demonstrating a prolongation of QTc interval in patients with Rett syndrome, the pathogenesis of which is unknown (Acampa and Guideri 2006). Brainstem dysfunction resulting in cardiac autonomic dysregulation is also described as being characterized by disturbed breathing and heart rate during sleep. Some studies have demonstrated labile breathing patterns and a reduction in cardiac vagal tone, indicating brainstem immaturity (Julu et al. 2001). Other support for autonomic dysregulation stems from the observation of decreased heart rate variability and sinus bradycardia (Axelrod et al. 2006). Therefore, the increase in sudden death may partly be related to the autonomic disturbance as well as perhaps to the seizures (Byard 2006). Defective autonomic nervous system control and cardiac arrhythmias relate more to functional problems than any defects demonstrated at postmortem (Byard, 2006). The pathophysiology of sudden death in Rett syndrome is an example where a single gene mutation may result in increased susceptibility to sudden death by a number of different mechanisms. 18.2.3â•…Other Examples of Syndromes with Multisystem Involvement There are other examples of syndromes with multisystem involvement, including epilepsy and increased mortality. Lafora disease, an inherited progressive myoclonic epilepsy characterized by intractable epilepsy in association with progressive neurological and cognitive deἀcit due to a mutation in the EPM2A gene on chromosome 6q24 is also associated with

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premature death from a variety of causes, including sudden death (Wick and Byard 2006). The same applies to the mitochondrial mutation 3243A>G resulting in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), which increases the risk of death among carriers and their ἀrst-degree maternal relatives. Death was due to a variety of causes including metabolic disturbances, cardiac involvement, status epilepticus, and sudden death associated with epilepsy or diabetes (Majamaa-Voltti et al. 2008). These examples emphasize the need for mortality studies in speciἀc syndromes and the limitations of “all inclusive” mortality studies in epilepsy. 18.2.4â•… SCN1A-Related Disorders The vast majority of mutations identiἀed in the SCN1A gene have been in sporadic cases of SMEI. SMEI is characterized by normal early development followed by the onset of feversensitive and refractory epilepsy with GTCS or unilateral seizures beginning within the ἀrst year of life. Most mutations identiἀed are nonsense mutations although some are missense mutations. Approximately 5% to 10% of families with GEFS+, an idiopathic familial epilepsy syndrome characterized by febrile seizures extending beyond 6 years with or without afebrile seizures, have also been shown to have SCN1A missense mutations (Marini et al. 2007), although other genes (GABRG2, SCN1B) are also implicated (Helbig et al. 2008). In addition, SCN1A mutations have been identiἀed in familial hemiplegic migraine. Mortality rates in SMEI are observed to be higher than in some other epilepsies, somewhere in the order of 15% versus 5% (Kassai et al. 2008), although controlled prospective studies have not been carried out and would require multicenter collaboration due to the rarity of SMEI. In Dravet’s series of 63 patients with a clinical diagnosis of SMEI and a mean age at follow-up of 11 years 4 months, 10 died, 2 of whom were sudden unexplained deaths. One death was unclassiἀed, while other causes of death included drowning, accidents, infection, and status epilepticus. In a Japanese series of clinically diagnosed SMEI or borderline SMEI, 12 of 85 patients died. Seven patients died from status epilepticus, one from severe infection, and one by accidental drowning. Three died suddenly of unknown causes (Oguni et al. 2001). In a further study of clinical cases of SMEI, two patients died; one from an unknown cause (Caraballo and Fejerman 2006). Accurate person years of follow-up are generally not provided to allow for incidence of sudden death, standardized mortality rates, and conἀdence intervals to be calculated. Mortality rates in GEFS+ families have not been reported to be higher than expected from patients with epilepsy, although this has not been systematically examined. We described a family with GEFS+ and a novel SCN1A mutation with two SUDEP cases (Hindocha et al. 2008) in individuals with more severe epilepsy. Although DNA samples were unavailable from the SUDEP cases to conἀrm their carrier status of the SCN1A mutation, their epilepsy phenotype was consistent with the familial diagnosis of GEFS+. To exclude as far as possible an alternative cause for the sudden death in these individuals, a ἀrst-degree relative of each SUDEP case was screened for the most common cardiac channelopathy mutations with negative results. SUDEP incidence in this family was found to be 7/1000 (95% conἀdence interval, 1–25), compared with an incidence of less than 1/1000, in population-based epilepsy cohorts. The wide conἀdence intervals suggest that the two deaths could still have occurred by chance. Nevertheless, the two SUDEP cases occurred in individuals with uncontrolled epilepsy and there was no other family history of sudden premature death. These two cases raise the possibility of an increased genetic predisposition to sudden death in people with

272 Sudden Death in Epilepsy: Forensic and Clinical Issues

SCN1A mutations in the setting of uncontrolled seizures. Possible mechanisms are discussed below. While initial characterization of ion channels presumed that these proteins were more localized to a speciἀc tissue, it is being increasingly recognized that this is not the case. Tissues are now thought to be mosaic for these proteins, composed of many isoforms, each expressed in different proportions (Haufe et al. 2007). Although SCN1A may primarily be expressed in the brain, several studies have shown that Nav1.1 (SCN1A gene product) is present in various regions of the heart in rat and mouse (Rogart et al. 1989; Dhar et al. 2001; Marionneau et al. 2005), in rabbit neonate (Baruscotti et al. 1997), and in dog (Haufe et al. 2005). There is good evidence for a role for Nav1.1 in pacemaker function of the sinoatrial (SA) node, but a lack of expression in atrial muscle (Tellez et al. 2006). In mice, Nav1.1 (but not Nav1.5, a SCN5A gene product) was detected in the SA node, and moreover, when brain-type Na+ channels were selectively blocked, signiἀcantly reduced spontaneous heart rate and greater heart rate variability were observed (Maier et al. 2003). A role for Nav1.1 in pacemaker activity in the mouse SA node (Lei et al. 2004) and rat SA node (Du et al. 2007) was conἀrmed in other studies. In contrast, evidence for a role for Nav1.1 in ventricular function is contradictory. Nav1.1 has been detected in mouse ventricular myocytes (Maier et al. 2002) and when brain-type Na+ channels are blocked, ventricular function is reduced, suggesting a role in excitation-contraction coupling (Maier et al. 2002). However, another similar study in rat ventricular myocytes demonstrated no reduction in ventricular function (Brette and Orchard 2006). SCN1A mutations may also result in dysfunction in the brainstem, resulting in alteration in autonomic function and thereby theoretically predisposing to sudden death. SCN1A mutations have been identiἀed in familial hemiplegic migraine. The pathophysiology of migraine implicates the brainstem, whereby brain imaging studies have established reproducible changes in the brain (Goadsby 2007; Goadsby and Hargreaves 2008). In addition, a study describing a missense mutation in a case of SMEI has suggested possible dysfunction of the brainstem in this disorder (Kimura et al. 2005). Two brothers with SMEI were found to have a missense mutation and their father, also a carrier of the mutation, had experienced two simple FSs before the age of 4. Both siblings had a deranged sleep-wake cycle after late infancy, postulated to be due to the dysfunction of aminergic neurons in the brainstem. Studies in rat models have also shown good expression of SCN1A in the brainstem (Gong et al. 1999).

18.3â•… SUDEP and Idiopathic Epilepsy Although most SUDEP cases are associated with more intractable and usually focal or symptomatic epilepsies, cases with IGEs with a history of generalized tonic seizures are nevertheless well represented in SUDEP cohorts. This was evident in an early study by one of the authors (L.N.) where 9 of 26 SUDEP cases were classiἀed as having idiopathic primary generalized epilepsy (see Chapter 58, this book). This cohort was largely identiἀed through the self-help group Epilepsy Bereaved and not through specialized services. Of these IGE cases, one had reportedly never been treated, and one had reportedly discontinued medication independently. Another, with juvenile myoclonic epilepsy in remission€on valproic acid, had been independently considering medication reduction, but it is not known if this had taken place. Two others had only ever been treated with carbamazepine or phenytoin.

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Two, both with a positive photoparoxysmal response, were found dead near visual display units, in one case a computer game was on and the person was found dead with a bitten tongue; the other was watching a video at the time of death. One had discontinued medication, while the other had only had a small number of convulsions in similar settings previously, and as already referred to, had never been treated (Nashef et al. 1998). In Langan et al.’s (2005) case control study, no association was found with syndromic diagnosis, but information on this variable was incomplete. In Nilsson et al.’s (1999) study, no increase in risk was associated with any particular type of epilepsy, but a lowered risk was associated with localization-related symptomatic epilepsy compared with generalized idiopathic epilepsy, especially among men, but numbers were small and conἀdence intervals wide. Genton and Gelisse (2001) reported three cases of premature death in juvenile myoÂ� clonic epilepsy. The report was useful in both highlighting this as a potential problem€and in providing person years of follow-up. Among 170 consecutive juvenile myoclonic epilepsy cases, three female patients died prematurely without autopsy being performed. One case had anorexia nervosa and died from severe aspiration pneumonia after provoked vomiting. The second had a history of psychosis and a case of IGE in her family. She had uncontrolled epilepsy and was found, aged 16, cyanotic and unconscious one morning “in the toilets of her institution” and died before resuscitation. The third had uncontrolled epilepsy, was also on neuroleptics, had a borderline personality disorder, a history of alcoholism, and low compliance. She was found dead at home at the age of 42 years. The authors concluded that severe mental disorders were risk factors for unexpected death in juvenile myoclonic epilepsy with a death ratio, if only two of these three cases are considered, of 0.9/1000. Aurlien et al. (2007) reported on four consecutive female SUDEP cases aged 25, 16, 37, and 24 years with idiopathic epilepsy treated with lamotrigine monotherapy. One case was unclassiἀed (auras suggested focal epilepsy but MRI was normal and EEG showed bilateral synchronous epileptogenic activity) and the other three were idiopathic generalized (one juvenile myoclonic epilepsy with photosensitivity, another with concomitant diabetes). The authors considered four possible explanations for this observation: an insufficient effect of lamotrigine leading to fatal seizures, a direct effect of lamotrigine on vital functions, such as cardiac rhythmicity (given that lamotrigine inhibits the cardiac rapid delayed rectiἀer potassium ion current (Ikr)), a combination of drug-induced effects and seizures, or coincidence. It is interesting that although they had not systematically identiἀed all SUDEP cases in their area during this period, these four cases were the only ones they were aware of among their outpatients and represented all SUDEP patients reported by the department pathologist. Also of interest was the control of the epilepsy. Seizure frequency on last outpatient hospital visit in cases 1 through 4, respectively, was: 1.5 simple partial seizures/ month; seizure free for 6 months; seizure free for 7 months; two seizures during the last week (previously seizure-free for 3 months). At autopsy, case 1 did not have AED levels performed, case 2 did not have detectable blood concentration of lamotrigine (previously 7 µmol/l), case 3 had a level of 15 µmol/l, previously 24.4, and one case had a lower postmortem lamotrigine (3.2 µmol/l) compared with the last antemortem level (27.5 µmol/l) when on combination therapy with carbamazepine. The authors considered the possibility that “there may be subgroups of patients with idiopathic epilepsy and generalized tonic– clonic seizures treated with lamotrigine that are at an increased risk of SUDEP.” They cited reports of a greater risk of drug-induced torsade in females, who also have an increased prevalence of symptoms of congenital long QT syndrome (LQTS) and an increase in episodes of supraventricular tachycardia in the perimenstrual period in susceptible patients.

274 Sudden Death in Epilepsy: Forensic and Clinical Issues

These careful observations yet again highlight the importance of mortality studies in speciἀc syndromes and suggest a greater risk of SUDEP in those with idiopathic epilepsy, even when the epilepsy is not severe. Which of the possible explanations suggested by the authors are true remain unknown. Note that a limited number of other studies (Timmings 1998; Langan et al. 2005; for review, see Rugg-Gunn and Nashef 2009) suggested that carbamazepine might also increase risk to a small extent again through an effect on cardiac function. In Aurlien et al.’s (2007) series, there is also possible selection bias in terms of preferential prescribing of lamotrigine to females with idiopathic epilepsy of childbearing age, whereas valproate, although particularly effective, may have been avoided because of potential teratogenicity. Theoretically, a particular AED or AED combination could have a detrimental effect by either increasing risk of sudden death through a variety of mechanisms or by giving insufficient protection for the seizure disorder. One angle that has not been explored but perhaps suggested by absent or lower levels in some of these cases (not withstanding reservations about postmortem blood levels), is a possible differential SUDEP risk associated with AED withdrawal, through an effect on seizure severity or autonomic function. This potential AED factor may have relevance if there is nonadherence to treatment or abrupt withdrawal. It is generally considered, for example, that the full effect of starting and stopping valproate in IGE cases is not all immediate with a delayed effect often observed. Thus, it is possible that effective control may be lost less quickly with valproate than when some other drugs are omitted. The same group (Aurlien et al. 2009) published a later follow up report on case 1 when autopsy DNA sequencing of LQTS-associated genes revealed a novel missense mutation in the SCN5A gene coding for the cardiac sodium channel, voltage-gated, type V alpha subunit. They discussed whether the mutation may explain both the epilepsy and the sudden death and the possible effect of lamotrigine on cardiac ion channel function. This is a particularly interesting report as it provides evidence in support of the same genetic mutation giving rise to both epilepsy and susceptibility to cardiac death. We have studied a small pedigree of an otherwise well young woman with juvenile myoclonic epilepsy who died suddenly while on lamotrigine, having been previously fully controlled on valproate, but who changed medication because of weight gain and potential teratogenicity, and whose control was not as good on lamotrigine as it had been on valproate. As can be seen in Figure 18.1, her mother had undiagnosed blackouts and her brother died of SIDS. LQT channel mutation screen in this pedigree, however, was negative. The pedigree raises the possibility of wider overlap presentations, as yet unexplored. Two other individuals with idiopathic epilepsy and cardiac arrhythmias have also so far been negative on screening for the most common LQTS and Brugada syndrome (BS) gene mutations (70% and 20%, respectively). Recently, it has been demonstrated that individuals with mutations in KCNH2 seen in LQTS are more likely to have a personal history of seizures than other subtypes of LQTS, raising the possibility that the KCNH2-encoded potassium channel could confer susceptibility to seizures (Johnson et al. 2009). Also of particular interest is the SCN1B gene previously implicated in GEFS+, absence epilepsy and temporal lobe epilepsy, and now in BS (Watanabe et al. 2008). This is discussed in more detail below. In our view, the available, though limited, evidence raises the possibility that in idiopathic epilepsy, with a history of generalized tonic clonic seizures, SUDEP may occur more often than in other syndromes with comparable epilepsy severity. At present, this is only a

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• Age of seizure onset—15 years 1.1

1.2

1.3 1.4 Late-onset epilepsy

II.I

III.1

II.2 Syncopal episodes

III.2

Seizures/epilepsy

III.3 III.4 SUDEP SIDS

• Myoclonic jerks and rare generalized tonic–clonic seizure • Idiopathic uncontrolled epilepsy at time of death • Found dead in bed • Clear bite mark on tip and left side of tongue found at postmortem supporting probability of epileptic seizure

DNA screened for the most common LQTS and BS gene mutations (account for 75% of all LQTS and BS). Mutations in these genes have been excluded as far as possible, as a cause of the sudden death.

Figure 18.1╇ SUDEP case study.

suggestion, but it needs to be explored further. AED choices may be particularly important in this subgroup as suggested by Aurlien et al. (2007). It is important in this context, however, to stress the potential for misdiagnosis of LQT as epilepsy, and to emphasize the need for clinicians to be constantly vigilant in ensuring diagnostic accuracy and in screening for alternative or concomitant diagnosis in those diagnosed with epilepsy.

18.4â•… SUDEP in Genetic Epilepsies: How Does It Occur? In SUDEP, different risk factors and mechanisms may operate with a ἀnal common pathway of cardiorespiratory compromise. Respiratory compromise and hypoxia occur frequently in seizures, particularly if convulsive, and the severity may be influenced by position and airway during postictal coma, particularly in the absence of someone capable of giving assistance. Cardiac changes occur during seizures and although sinus tachycardia is most commonly observed during seizures, ictal sinus arrest also occurs as do rare malignant dysrhythmias. Functional cardiac changes such as apical ballooning may also occur (Stöllberger and Finsterer 2004). In discussing genetic predisposition, an increased susceptibility to sudden death may be due to cardiac mechanisms, reflecting underlying processes common to neurological and cardiac functions, autonomic function, or brainstem control of respiration. Etiological factors underlying SUDEP are likely to be heterogeneous, in much the same way as in sudden unexpected death (SUD) and SIDS (see below). Given the association between intractable epilepsy and SUDEP, one can postulate that in some cases of idiopathic epilepsy a primarily “neuronal” mutation, if it can also cause a predisposition to cardiac arrhythmias, may manifest as sudden death in persons in whom the epilepsy is uncontrolled. In others there may be an unrelated coexisting “mild” susceptibility to SCD that would manifest itself in the presence of uncontrolled seizures (Nashef et al. 2007). In our 2007 review, we discussed the possibility of overlap between susceptibility to SCD and idiopathic epilepsy and that further genetic and epidemiological studies are needed (Nashef et al. 2007). However, at the time there was no bridging evidence to

276 Sudden Death in Epilepsy: Forensic and Clinical Issues

support this hypothesis. Since then there have been reports as above, which suggest that ion channel gene mutations already known to have more than a single pathological role, as demonstrated, for example, by LQTS with deafness, can cause both epilepsy and LQTS or other inherited susceptibility to cardiac dysrhythmias, although such reports are currently uncommon. Animal models provide evidence in support of this hypothesis as in the case of the Ca2+ release channel ryanodine receptor 2 (RyR2) required for excitation-Â�contraction coupling in the heart- and expressed in the brain. Mutations in RyR2, which result in “leaky” RyR2 channels, have been linked to exercise-induced SCD and catecholaminergic polymorphic ventricular tachycardia. Mice heterozygous for the R2474S mutation in Ryr2 exhibited spontaneous generalized tonic–clonic seizures (without cardiac arrhythmias), exercise-induced ventricular arrhythmias, and SCD (Lehnart et al. 2008). Treatment with a compound inhibiting the channel leak prevented cardiac arrhythmias and raised the seizure threshold. The authors proposed that this was a combined neurocardiac disorder.

18.5â•… Genetic Susceptibility to SCD and SIDS In considering possible genetic predisposition to SUDEP, it may useful to briefly review the evidence of genetic susceptibility to SCD and SIDS. At least 4% of sudden deaths are unexplained at autopsy and on average a quarter of these may be due to inherited cardiac disease (Behr et al. 2008). These ἀgures will vary according to age group (Rodriguez-Calvo et al. 2008). Diagnosis is crucial as close relatives may be at potential risk of also having a fatal cardiac event. While the genetic causes of SCD also include structural abnormalities (e.g., inherited cardiomyopathies), a proportion (Saenen and Vrints 2008) are a result of primary arrhythmogenic disorders, also known as cardiac channelopathies, such as LQTS, short QT syndrome, BS, and catecholaminergic polymorphic ventricular tachycardia. Most cases of LQTS and BS are inherited from a parent who may or may not show clinical symptoms (Morales et al. 2008). In a study of autopsies in cases of patients aged 5 to 35 years who died suddenly from cardiac causes, 29% were arrhythmia-related SCD (Puranik et al. 2005). Of the cardiac cases, SCD in a ἀrst-degree relative was reported in only 4.5% of cases with a low yield of signiἀcant positive family history from these cases. The diagnostic yield of investigating relatives of individuals who had died suddenly with no explanation has also been examined. In one study (Tan et al. 2005), 43 families with one sudden unexpected death victim who had died under the age of 40 were investigated. Seven of the 43 families studied (16%) were found clinically to have LQTS or BS, diagnoses that were conἀrmed with molecular techniques in four of these seven families (9%). A slightly larger study showed that 21 of 57 families (37%) were clinically identiἀed to have either deἀnite or probable LQTS or BS. Molecular conἀrmation was made in six of the 57 families (11%) (Behr et al. 2008). Once molecular conἀrmation is achieved, testing may be offered to appropriate relatives. One study suggests that clinical evaluation alone is no longer appropriate to exclude a diagnosis of LQTS, as penetrance may be very low (around 25%) (Priori et al. 1998). Congenital LQTS is mostly inherited in an autosomal dominant fashion (RomanoWard syndrome) and up until now, mutations in 12 genes have been identiἀed to result in LQTS (KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, and α-1-syntrophin) (Van Norstrand and Ackerman 2009). All of these genes are expressed primarily in cardiac tissue and most of these genes encode an ion

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channel protein. Those that do not have been found to affect the sodium or potassium channel (Rodriguez-Calvo et al. 2008). BS is characterized by episodes of VF and in approximately 20% of cases a positive family history of unexplained sudden death is present (Miura et al. 2008). BS is genetically heterogeneous and mutations in the sodium channel gene SCN5A account for 20% to 30% of cases (Van Norstrand and Ackerman 2009). More recently, a mutation in SCN1B, primarily a neuronal voltage-gated sodium channel and implicated in GEFS+ (Wallace et al. 1998; Singh et al. 1999) but also expressed in the heart, has been implicated in BS (Watanabe et al. 2008). This is an exciting discovery, as it is an example of a gene having a pathological effect on the heart and the brain. Mutations in SCN1B have been previously reported in a family with early onset absence epilepsy without the occurrence of febrile seizures (Audenaert et al. 2003) and temporal lobe epilepsy even without febrile seizures (Scheffer et al. 2007). Cardiac abnormalities have not been commented on in these families. β1-null mice exhibit a severe seizure disorder and premature death (Chen et al. 2004). In addition, these mice exhibit bradycardia and prolonged rate-corrected QT intervals (Lopez-Santiago et al. 2007). These changes suggest that this protein has a possible role in the heart. Other genes such as CACNA1C, CACNB2b, and GPD1-L, known to modulate sodium channel function, are also implicated in BS. Since the advent of genome-wide association studies, research examining genetic susceptibility to various disorders has developed signiἀcantly. Single nucleotide polymorphisms (SNPs) in the LQT genes have been identiἀed as demonstrating a genetic propensity to developing increased QT interval/cardiac arrhythmias/SCD, not related to a single gene defect but because of multiple low-risk alleles (Pfeufer et al. 2005; Gouas et al. 2005). However, replication data at present is lacking (Schulze-Bahr 2006). Of interest in this context is the variant allele (S1103Y) of the cardiac sodium channel gene SCN5A, which (1) has a subtle effect on risk in African Americans (13% of whom are carriers), manifesting if there are additional acquired risk factors, with most carriers never having an arrhythmia (Splawski et al. 2002), (2) has a strong effect on risk in Caucasians where it is very rare (Chen et al. 2002), and (3) is associated, if homozygous, with SIDS in AfricanAmericans (Plant et al. 2006). Using similar techniques, genetic susceptibility to SIDS has been examined (WeeseMayer et al. 2007). Around 5% to 10% of SIDS cases (9.5% by Arnestad et al. 2007) are linked to ion channelopathies (Tester and Ackerman 2005). From an 18-year study (Schwartz et al. 1998), an increase in the QT interval in the ἀrst week of life was established in individuals who went on to die from SIDS. SNPs in common cardiac channel genes may confer risk to sudden death at any age including infancy, even prenatally. Several studies have identiἀed differences between infants with SIDS and control infants with gene polymorphisms in SCN5A (Plant et al. 2006). Further research has identiἀed other genetic factors predisposing to SIDS. For example, decreased serotonin (5HT) receptor binding in the 5HT pathways of the medulla has been identiἀed in a small number of SIDS cases (Paterson et al. 2006; see Paterson’s chapter 5). In addition, association between the serotonin transporter gene (5-HTT) and SIDS has been demonstrated (Opdal and Rognum, 2004), suggesting that serotonin may play a regulatory role in SIDS. Of interest in this context is the protective effect of fluoxetine, a selective serotonin reuptake inhibitor, in reducing ictal respiratory arrest in DBA/2 mice with audiogenic seizures at doses that did not reduce seizure severity (Tupal and Faingold 2006). Polymorphisms in genes involved in inflammatory and infectious processes such as interleukin-10 (IL-10) gene have been shown to be associated with both SIDS and infectious

278 Sudden Death in Epilepsy: Forensic and Clinical Issues

death (Korachi et al. 2004) such as pneumonia and Epstein-Barr virus (Weese-Mayer et al. 2007). In addition, genes pertinent to the development of the autonomic nervous system are also being studied because of reports of autonomic dysregulation in SIDS victims and polymorphisms have been found to be associated in several genes (PHOX2a, RET, ECE1, TLX3, EN1) (Weese-Mayer et al. 2004).

18.6â•… Conclusion While genetic predisposition may be less prominent than the severity of the epilepsy, treatment-related factors, and supervision in many cases of SUDEP, it is still a potentially very important area requiring further research, particularly in idiopathic epilepsy. Future research in this area should include epidemiological studies looking at mortality in speciἀc syndromes, as well as studies of possible overlap of epilepsy and syncope in idiopathic epilepsy and in LQT cohorts. Clinicians need to be more aware, not only of the potential for misdiagnosis but also for potential clinical overlap. There is also an urgent need to collect DNA and clinical details in SUDEP cases, initially to carry out screening for genetic mutations in selected cases, but also to carry out sufficiently powered association studies. This is a difficult but not insurmountable task; one possible source is DNA from dried blood spots from Guthrie cards taken from newborns in the United Kingdom. These are stored for many years and can be retrospectively retrieved to carry out molecular studies (Skinner et al. 2004).

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Cardiac Channelopathies and Sudden Death Benito Herreros

19

Contents 19.1 Introduction 19.1.1 Sudden Cardiac Death in Subjects with a Structurally Normal Heart 19.1.2 Ion Channels and Channelopathies 19.1.3 The Cardiac Action Potential 19.1.4 Inherited Primary Arrhythmia Syndromes 19.2 Long QT Syndrome 19.2.1 Clinical Manifestations 19.2.2 Genetic Background and Pathophysiology 19.2.3 Risk Stratiἀcation and Management 19.3 Brugada Syndrome 19.3.1 Clinical Manifestations 19.3.2 Genetic Background and Pathophysiology 19.3.3 Risk Stratiἀcation and Management 19.4 Catecholaminergic Polymorphic Ventricular Tachycardia 19.4.1 Clinical Manifestations 19.4.2 Genetic Background and Pathophysiology 19.4.3 Management 19.5 Short QT Syndrome 19.5.1 Clinical Manifestations 19.5.2 Genetic Background and Pathophysiology 19.5.3 Management 19.6 Considerations about Cardiac Channelopathies, Epilepsy, and SUDEP 19.6.1 Brugada ECG and Epilepsy 19.6.2 LQT and Epilepsy 19.6.3 The Hypothesis of a Common Channelopathy 19.6.4 SUDEP and Channelopathies References

285 286 286 287 287 289 289 290 291 291 292 293 294 295 295 295 296 296 296 297 297 297 298 298 299 299 299

19.1â•…Introduction Cardiac channelopathies are genetically determined diseases that may cause sudden arrhythmic death in young subjects with a structurally normal heart. Abnormal cellular electrophysiology related to dysfunctional ion channels is the underlying substrate. Some types of idiopathic epilepsy are also caused by ion channel dysfunction in the neuronal cell membrane. This shared pathophysiologic mechanism lets us hypothesize about an arrhythmic cause for some cases of sudden death in epilepsy. In this chapter, cardiac 285

286 Sudden Death in Epilepsy: Forensic and Clinical Issues

channelopathies related to sudden death are reviewed and data supporting a potential relationship with epilepsy are exposed in the last section. 19.1.1â•… Sudden Cardiac Death in Subjects with a Structurally Normal Heart Sudden cardiac death (SCD) is deἀned as a natural death from cardiac causes, heralded by abrupt loss of consciousness within 1 hour of the onset of an acute change in cardiovascular status. Preexisting heart disease may or may not be present, but the time and mode of death are unexpected. It is likely that ventricular ἀbrillation (VF), or ventricular tachycardia (VT) deteriorating to VF, is the initiating event in most cardiac arrests (Myerburg and Castellanos 2008). These arrhythmias most often occur in the presence of a cardiac structural abnormality that is responsible for disturbances in impulse initiation and conduction. Ischemic heart disease is the most common cause, followed by other structural heart diseases such as hypertrophic, dilated, or arrhythmogenic right ventricular cardiomyopathy, but malignant arrhythmias leading to SCD can also happen in some patients with a structurally normal heart. In several postmortem series of cardiac arrest victims, no structural abnormality was found in 5% to 8% of cases (Priori et al. 2003). This occurrence used to be designated as “idiopathic VF.” The etiology of SCD in these cases may be a primary electrical disorder of a genetic basis (and thus can be inherited) that predisposes to rhythm alteration. In fact, SCD without structural heart disease is proportionally more common at younger ages, in contrast with the adult age, in which the main cause of SCD, by far, is coronary artery disease (Myerburg 2001) (Table 19.1). During the past 15 years, with the help of molecular biology, the substrate of idiopathic VF has been better deἀned and genetically determined abnormalities of proteins that control the electrical activity of the heart have been demonstrated to cause cardiac arrest in the structurally intact heart (Priori et al. 2008). 19.1.2â•…Ion Channels and Channelopathies Each normal heartbeat is initiated by a pulse of electrical excitation that begins in a group of specialized pacemaker cells and subsequently spreads throughout the heart. This electrical impulse is made possible by the electrochemical gradient that exists across the cell membrane of the cardiomyocyte. At rest, the electrochemical potential inside the cell is negative with respect to the outside due to energy-consuming processes, such as the Na+/K+ ATPase, which maintain the ionic gradients. The resting cell membrane is relatively permeable to K+, but much less so to Na+ and Ca2+. During electrical excitation, the membrane becomes permeable to Na+ ions and the electrochemical gradient reverses (depolarization). Next, Ca2+ ions move into the cell to activate the contractile process. Finally, the negative

Table 19.1â•… Etiology of Sudden Cardiac Death Coronary artery disease Cardiomyopathies Valvular, inflammatory, and inἀltrative cardiac diseases Normal hearts/idiopathic VF

80% 10%–15% ±5% ?%

Source: Myerburg, R.J., J Cardiovasc Electrophysiol, 12, 369–381, 2001. With permission.

Cardiac Channelopathies and Sudden Death

287

membrane potential is restored, mainly due to the efflux of K+, and thus the wave of depolarization is self-limiting (Marbán 2002). All these changes in permeability are accomplished by the opening and closing of ion channels that are speciἀc for the individual ions. Ion channels are transmembrane proteins that allow the passage of ions from the interior of the cell to outside and vice versa (Figure 19.1). The movements of ions are passive down their respective concentration gradients. Some channels are tissue-speciἀc (e.g., Na+ channels have several isoforms with different expression in the heart, skeletal muscle, central, or peripheral nervous system), whereas others are widely distributed throughout the body. Ion channels are basic to the processes of electrical signaling and excitation essential to the functioning of the heart. Furthermore, for the normal function of any given ion channel, not only its protein subunits (alpha, beta), but also multiple other gene products with various functions (e.g., phosphorylation, assembly, posttranslational modiἀcation, anchoring units) are necessary. Mutation in any of these genes can cause ion channel dysfunction, or channelopathy, which may provoke cardiac arrhythmias and SCD as the most severe clinical expression (Roden et al. 2002). This chapter reviews the most common inherited arrhythmogenic diseases that may cause sudden death in subjects with a structurally normal heart. As most of them are due to dysfunction of ion channels participating in the cardiomyocyte excitation, it is important to review the cardiac action potential and its involved ionic currents. These are summarized in Figure 19.1. 19.1.3â•… The Cardiac Action Potential The cardiac action potential is a graphic representation of the stereotypical voltage changes against time, which follow one another when an appropriate voltage stimulus reaches the cardiomyocyte (Figure 19.1). Thus, the action potential is a reflection of the electrical activity of a single cardiac cell. A sharp depolarizing upstroke (phase 0) is the result of rapid inflow of Na+ ions through voltage-dependent Na+ channels. Phase 1 reflects the activation of a transient outward current (Ito), mostly carried by K+, which produces a notch or early repolarization soon after the initial depolarizing upstroke. During the plateau (phase 2), the net influx of Ca2+ is balanced by the efflux of K+ through several K+ channels (IKr, IKs, IK1, Ito). Phase 3 is the downslope after the plateau, representing the late depolarization, due to the chemical forces, that favors the efflux of K+ predominating over the electrostatic forces that would favor its influx through the same channels. Phase 4 represents the resting potential, during which there tends to be a net diffusion (efflux) of K+ in the direction of its concentration gradient through IK1 channels (Berne and Levy 1992). 19.1.4â•…Inherited Primary Arrhythmia Syndromes A number of genes are associated with inherited arrhythmia syndromes that predispose to sudden death in individuals with a structurally normal heart (Table 19.2). Studies in large cohorts suggest that cardiac channelopathies could be responsible for 35% of sudden deaths in the young and in 9% of cases of sudden infant death syndrome (SIDS) (Schwartz and Crotti 2007). Recently, some authors have proposed a classiἀcation of inherited primary arrhythmia syndromes according to their pathophysiologic basis; that is, into Na+ channelopathies, K+ channelopathies, and so forth (Lehnart et al. 2007; Wilde 2008). This chapter uses the traditional clinical nomenclature to review the four main inherited arrhythmia

288 Sudden Death in Epilepsy: Forensic and Clinical Issues

(a)

Na+

K+ (b)

K+

Ca2+

Na+

Ca2+

Probable gene SCN5A

INa ICa, L

CACNA1c

INa/Ca

NCX1

0

IK1

KCNJ2

It01

KCND

It02

?

IKr

KCNH2/KCNE2

IKs

KCNQ1/KCNE1

IKp

KCNK?

Figure 19.1╇ Ion channels underlie cardiac excitability. (a) The key ion channels (and an elec-

trogenic transporter) in cardiac cells. K+ channels mediate K+ efflux from the cell; Na+ channels and Ca 2+ channels mediate Na+ and Ca 2+ influx, respectively. The Na+/Ca 2+ exchanger transports three Na+ ions for each Ca 2+ ion across the surface membrane. (b) Ionic currents and genes underlying the cardiac action potential. Top, depolarizing currents as functions of time, and their corresponding genes; center, a ventricular action potential; bottom, repolarizing currents and their corresponding genes. (From Marbán, E., Nature, 415, 213–218, 2002. With permission.)

Cardiac Channelopathies and Sudden Death

289

Table 19.2â•… Genes Involved in Arrhythmogenic Cardiac Channelopathies Related to SCD Syndrome

Subtype

Long QT syndrome

LQT1 LQT2 LQT3 LQT4

KCNQ1 KCNH2 SCN5A ANK2

IKs K+ channel α subunit IKr K+ channel α subunit Na+ channel α subunit Anchoring protein ankyrin B

LQT5 LQT6 LQT7 LQT8 LQT9 LQT10 LQT11

KCNE1 KCNE2 KCNJ2 CACNA1c CAV3 SCN4B AKAP9

Brugada syndrome

BrS1 BrS2

SCN5A GPD1L

Catecholaminergic VT

CPVT1 CPVT2 SQT1 SQT2 SQT3

RyR2 CASQ2 KCNH2 KCNQ1 KCNJ2

IKs K+ channel β subunit IKr K+ channel β subunit IK1 K+ channel α subunit ICa,L Ca2+ channel α subunit Caveolin 3 Na+ channel β4 subunit Yotiao (A-kinase anchoring protein) Na+ channel α subunit Glycerol-3-P dehydrogenase 1 like protein Cardiac ryanodine receptor Cardiac calsequestrin IKr K+ channel α subunit IKs K+ channel α subunit IK1 K+ channel α subunit

Short QT syndrome

Gene

Protein

Effect IKs loss of function IKr loss of function INa gain of function Reduction of several ionic currents IKs loss of function IKr loss of function IK1 loss of function ICa,L gain of function INa gain of function INa gain of function IKs loss of function INa loss of function INa loss of function Citoplasmic Ca2+ overload Citoplasmic Ca2+ overload IKr gain of function IKs gain of function IK1 gain of function

syndromes which, to the moment, have been shown to be responsible for sudden death: long QT syndrome (LQTS), Brugada syndrome (BrS), short QT syndrome (SQTS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). There are other inherited arrhythmic syndromes not necessarily linked to SCD that are responsible for atrial arrhythmias, sick sinus syndrome, and progressive cardiac conduction disease (PCCD).

19.2â•… Long QT Syndrome The congenital form of the LQTS is characterized by prolongation of the QT interval on the ECG and susceptibility to malignant ventricular arrhythmias. Two major forms have been described: one inherited as an autosomal dominant trait (Romano–Ward syndrome), and the other (more rare) transmitted as an autosomal recessive trait (Jervell and Lange– Nielsen syndrome) with associated neurosensorial deafness in affected individuals. 19.2.1â•… Clinical Manifestations The characteristic ECG in LQTS shows a prolonged QT interval, often with T-wave morphological abnormalities, and occasionally polymorphic VT of the torsades de pointes type. Clinical manifestations are recurrent syncope or fainting and sudden death, often precipitated by stress (fear, loud noise, sudden awakening), but they can also occur at rest (Schwartz et al. 2001). Typical onset of symptoms occurs in the ἀrst two decades of life. In the neonatal period, LQTS can be responsible for a certain number of SIDS (Arnestad et al.

290 Sudden Death in Epilepsy: Forensic and Clinical Issues

2007). Since the clinical presentation varies greatly, ranging from asymptomatic mutation carriers with normal QT interval to typical cases with marked QT prolongation and recurrent syncope, diagnostic criteria have been developed with a scoring system that allows classiἀcation of patients into categories of low, intermediate, or high probability of having LQTS (Schwartz et al. 1993). With the advent of the DNA diagnosis, these scoring systems have been shown to have less sensitivity than measurement of QTc alone (Napolitano et al. 2003; Hofman et al. 2007) for the detection of mutation carriers. Furthermore, an important proportion of mutation carriers have a normal QT interval (Priori et al. 2003), so molecular diagnosis has become part of the routine clinical management of LQTS. 19.2.2â•… Genetic Background and Pathophysiology At the time of writing, 11 genes have been proven to be or are thought to be associated with LQTS (Lehnart et al. 2007) (Table 19.2). However, LQT1, LQT2, and LQT3 variants account for more than 90% of all genotyped LQTS patients, whereas the remaining genes are responsible for a minority of cases (Priori et al. 2008). Most of these genes encode cardiac ion channels subunits. If not, they modulate ionic currents. In patients with LQT1, there is loss of function of the IKs potassium channel due to a mutation in the gene KCNQ1, which encodes the alpha subunit of IKs channel. The result is a reduced K+ outward current in phases 2 and 3 of the action potential, leading to an abnormal repolarization and reduced rate-dependent shortening of the action potential (Roden et al. 2002). Mutations in KCNQ1 resulting in IKs loss of function accounts for 40% to 50% of all genotyped LQT mutations (Splawski et al. 2000; Tester et al. 2005). The same channel IKs exhibits loss of function in patients with LQT5, but is due to mutation in gene KCNE1, which encodes its beta subunit. This variant is much less frequent than LQT1, but it is noteworthy that both genes KCNQ1 and KCNE1 are also expressed in the inner ear, where K+ channel function contributes to production of endolymph. That is the reason why mutations in both genes may cause the Jervell and Lange–Nielsen syndrome (LQT and bilateral deafness) in homozygous subjects (Neyroud et al. 1997; Schulze-Bahr et al. 1997). Patients with LQT2 exhibit loss of function of the IKr potassium channel due to a mutation in gene KCNH2, which encodes the alpha subunit of IKr channel. These mutations represent 35% to 45% of the genotyped LQTS mutations. The beta subunit of IKr channel is encoded by KCNE2, whose mutations are the substrate for the rarer LQT6 (Abbot et al. 1999). Whereas K+ channels mutations involved in LQTS produce a loss of function effect, a gain of function mutation in SCN5A encoding the alpha subunit of the cardiac Na+ channel is the substrate for the variant LQT3. As a consequence, persistent inward Na+ current during phase 2 (plateau) prolongs the action potential. LQT3 accounts for 2% to 8% of all LQTS patients (Splawski et al. 2000; Tester et al. 2005). Overall, penetrance of LQTS is 60%, but it is not the same for speciἀc variants. In LQT1 the proportion of mutation carriers without QTc prolongation is as high as 36%, in LQT2 it is 19%, and in LQT3 it is 10% (Priori et al. 2003). There are some speciἀc phenotypic features in the different variants. Patients with LQT1 have increased risk of developing VT during exercise (75%, especially swimming) or emotional stress (15%). IKs current is activated by fast heart rates and by catecholamines, so under these circumstances, LQT1 patients cannot shorten their QT interval appropriately. Accordingly, beta blocker therapy should be most effective in LQT1 patients (Schwartz et al. 2001). The ECG in LQT1 is characterized by long T wave duration (Figure 19.2). In LQT2 patients, cardiac events

Cardiac Channelopathies and Sudden Death LQT3

LQT2

291 LQT1

II aVF

V5

Figure 19.2╇ Electrocardiographic distinctive features in long QT syndrome variants. Left

panel: note the long ST segment with late onset of T wave in an LQT3 patient. Center panel: low amplitude T waves in an LQT2 patient. Right panel: early onset of broad-based T waves in an LQT1 patient. (Modified from Moss, A. J. et al., Circulation, 92 (10), 2929–2934, 1995. With permission.)

are often triggered by emotions, sudden loud noises, and acute arousal (37%). They are also at€risk during sleep or at rest (63%) but not during exercise. Their ECGs show small (low-amplitude), notched, or biphasic T waves (Figure 19.2). Finally, LQT3 patients suffer cardiac events usually at night, sleep, or rest (80%), and occasionally with emotions (15%) or during exercise (5%) (Schwartz et al. 2001). Typical ECG in LQT3 shows a flat, long ST segment with late onset of a narrow, peaked T wave (Figure 19.2). 19.2.3â•…Risk Stratification and Management Highest risk patients are those who have QTc ≥ 500 ms. Other ECG markers of bad prognosis are T wave alternans and torsades de pointes VT. Those who have survived after a cardiac arrest, and those who have recurrent syncope despite beta blockers, usually receive an implantable cardioverter deἀbrillator (ICD) (Zareba et al. 2003). On the other hand, the increasing knowledge of clinical evolution in genotyped patients has demonstrated that the different LQTS variants have distinct prognoses. LQT2 and LQT3 patients have a lower event-free survival than LQT1. Gender has influence in LQT2 (higher risk in females) and LQT3 patients (higher risk in males), but not in LQT1 (Priori et al. 2003). Once a diagnosis of LQTS has been made, lifestyle modiἀcation is recommended Â�(e.€g., avoidance of swimming among LQT1 patients, no use of loud alarm clocks in LQT2, prohibition of drugs with QT prolonging effects). Experts recommend beta blocker therapy in all symptomatic patients and in asymptomatic patients younger than 40 years with a clearly prolonged QTc (in which risk for SCD if untreated is around 13%) (Priori et al. 2003). Implantation of a deἀbrillator is recommended after a resuscitated cardiac arrest and in those patients who experience syncope or VT under beta blocker therapy (Zipes et al. 2006). Also, the recognition of the speciἀc arrhythmic risk of the different LQTS variants will probably have an increasing impact on clinical management.

19.3â•… Brugada Syndrome BrS is characterized by an ST segment elevation in the right precordial ECG leads and a high incidence of SCD in patients with structurally normal hearts. Sudden death is

292 Sudden Death in Epilepsy: Forensic and Clinical Issues

provoked by ventricular arrhythmias (polymorphic VT leading to ventricular ἀbrillation) that can also produce syncope when they are self-limited. Inheritance of BrS occurs via an autosomal dominant mode of transmission. 19.3.1â•… Clinical Manifestations Characteristic Brugada ECG shows a coved ST segment elevation ≥2 mm followed by a negative T wave in more than one right precordial lead (V1–V3, Figure 19.3). This is the only accepted diagnostic pattern (the so-called type 1), although two more ECG types have been described: type 2 has a saddleback ST elevation with a J point ≥ 2 mm, a trough ≥ 1 mm, and a positive/biphasic T wave; and in type 3, ST elevation is 10% from baseline (cardioinhibitory response), or both (mixed response). Most patients with vasovagal syncope have a mixed response. In general, tilt table testing is reserved for patients with recurrent syncope or a single high-risk syncope episode when there is no evidence of structural heart disease or when other causes of syncope have been excluded. In patients with a single episode of uncomplicated syncope where the clinical picture is typical for neurally mediated reflex syncope, tilt table testing is unnecessary. Furthermore, tilt table testing is not useful in establishing the diagnosis of neurally mediated reflex syncope with a speciἀc trigger (e.g., micturation) (Brignole et al. 2001; Schnipper and Kapoor 2001; Grubb 2005).

Figure 21.2╇ Retrieved episode data of syncopal event in a patient with unexplained syncope in

whom an implantable loop recorder was inserted for a prolonged monitoring of cardiac rhythm. The tracing shows an initial three beats of sinus rhythm followed by a premature ventricular complex and a sinus beat before the onset of a rapid ventricular tachycardia at 176 beats/min (mean cycle length of 340 ms).

320 Sudden Death in Epilepsy: Forensic and Clinical Issues

21.3.6â•… Electrophysiologic Testing The electrophysiology study is an invasive study in which electrode-tipped catheters are placed in the heart in speciἀc locations and stimulation protocols are performed to assess the cardiac electrical system. In general, electrophysiology study is indicated when syncope is associated with structural heart disease. The role of electrophysiology study in recurrent unexplained syncope with negative tilt table test and no structural heart disease is not ἀrmly established. In patients with unexplained syncope and structural heart disease (e.g., prior myocardial infarction) induction of ventricular tachycardia indicates a poor prognosis (up to 30% mortality in 3 years) (Gouello et al. 1992). Ventricular tachycardia is the most common abnormality revealed by electrophysiology study. Since recent guidelines recommend implantable cardioverter deἀbrillator implantation for primary prevention of ventricular arrhythmia in patients with severe left ventricular systolic dysfunction (ejection fraction 100 ms), and/or (2) block below the His conduction system (Gouello et al. 1992). 21.3.7â•… Miscellaneous Tests Transient ischemic attacks from carotid atherosclerosis do not cause loss of consciousness. Therefore, carotid ultrasonography is not indicated in the evaluation of syncope. Blood tests rarely assist in the diagnosis of syncope, unless a metabolic etiology is strongly suspected (e.g., hypoglycemia). Brain imaging with computerized tomography (CT) and magnetic resonance imaging (MRI) are usually unnecessary and only yields a diagnosis when there is a focal neurologic deἀcit or a witnessed seizure. If there are no signs and symptoms of seizure, electroencephalography is not useful in the diagnosis of syncope (Britton 2004). Simultaneous electroencephalography and electrocardiography (especially with video monitoring) may help to diagnose frequent episodes that cannot be distinguished as syncope or seizure (Britton 2004). Myocardial ischemia is an unlikely cause of syncope, especially in the absence of angina or exertional symptoms. Therefore, stress testing and cardiac catheterization should be reserved for patients with syncope associated with exertion when the suspicion for coronary artery disease is high.

21.4â•… Syncope and Epilepsy There are reports of patients with recurrent syncope who develop cardiac asystole, transient AV block, and severe sinus bradycardia (heart rate 55% of time in seconds) while the cat was under the influence of PTZ, this phenomenon was not found in any cat during the control period. Epileptogenic activity induced by PTZ is an experimental model of primary generalized epilepsy. The method of action of this drug, however, is uncertain (Stone 1972). There are three proposed methods of action of PTZ, which would allow the LSP to express itself: (1) spatial and temporal summation of neuronal discharges in a subcortical center producing a stimulus strong enough to overcome the cortical and ganglionic threshold (Hahn 1960); (2) increased synaptic recruitment, resulting in the ampliἀcation of subcortical stimuli along their path so that, upon reaching the cortex and sympathetic ganglion, they are capable of causing these neurons to discharge; and (3) increased irritability of all neurons so that subcortical impulses could stimulate cortical and ganglionic neurons (Hahn 1960). In each case, PTZ effectively creates a hyperirritable state of epileptogenic electrical activity present in the central and autonomic nervous systems. Although phenobarbital can act to minimize this irritability, the effect of this pharmacological agent in this study eventually was overcome by increased epileptogenic activity. The 2.8-s repeated ECoG interval, a type of latency period between the end of one spike and the beginning of another associated spike, appeared to convey a stabilizing effect on the presence of LSP. When this repeated ECoG interval was present, LSP was present a signiἀcantly greater percentage of time than when LSP was absent. When the repeated ECoG interval was not present, LSP was much less common and the distinct ECoG spikes often degenerated into prolonged ictal activity. Our analysis minimized the degree of association between the repeated ECoG interval and the presence of LSP. Our deἀnition of a repeated ECoG interval excludes periods when two or more additional ECoG spikes are contained within the 2.8-s interval, even if these additional ECoG spikes are time locked to sympathetic spikes. A more liberal deἀnition would result in a more frequent association between LSP and repeated ECoG interval. The mean proportion of each minute during which LSP was present was directly proportional to the time interval elapsed following the administration of PTZ. The direct relationship reflects the fact that the episodes of epileptogenic activity, and particularly prolonged ictal activity, are most frequently observed shortly after PTZ is administered. Similarly, the incidence of precipitous blood pressure change was signiἀcantly greater (p€10-s duration. For each cat, the mean numbers of episodes for the two durations were calculated for the control and for each dose of PTZ and timolol. Means were calculated by combining the ECoG data from all cats. To determine if there were any statistically signiἀcant differences among the means, data were analyzed by a Friedman rank ANOVA followed by a Bonferroni-corrected Wilcoxon post hoc tests. The following time points were analyzed: control; PTZ 10 and 20 mg; and timolol 10 μg, 100 μg, 500 μg, and 1 mg/kg. 34.2.2â•… Seizure Studies in Anesthetized Pigs Domestic swine weighing 13–20 kg were anesthetized with ketamine (20 mg/kg i.v.) and alpha-chloralose (80 mg/kg i.v.). Animals were prepared as described by Spivey et al. (1987). After a 10-min equilibration period, seizure activity was induced by PTZ (100 mg/ kg i.v.). Sixty seconds after the onset of epileptogenic activity, the animals were treated with no drug (control group) or propranolol 2.5 mg/kg i.v. Seizure activity was monitored for 20€min. Plasma levels of propranolol were determined by drawing blood samples (8 mL) at 1, 2, 5, 10, 15, and 20 min after propranolol. The samples were centrifuged at 1000 g for min and the plasma (3 mL) was stored frozen at −20°C. The concentrations of propranolol in plasma were determined by a modiἀcation of the method of Albani et al. (1982). The procedure involves reverse-phase high-pressure liquid chromatographic resolution with fluorometric detection of propranolol and an internal standard, Carvedilol (1-(4-carbazolyloxy)-3-[2(2-methoxyphenoxy)ethylamino]-2-propranol).

34.3â•…Results 34.3.1â•…Data Obtained in Anesthetized Cats A one-factor repeated-measures ANOVA revealed that the increase in the control blood pressure of 103 ± 13 to 149 ± 13 mm Hg minutes after intracerebroventricular PTZ was signiἀcant, whereas the mean heart rate increase from 159 ± 17 to 162 ± 10 bpm 3 min after

554 Sudden Death in Epilepsy: Forensic and Clinical Issues Table 34.1â•… Sequence in Which Incidence of the Epileptiform Activity and an Increase in Mean Arterial Blood Pressure and Heart Rate Occurred after Intracerebroventricular PTZa Precededb

Same time

Proceededc

No change

0 0 1 0

2 1 1 1

0 1 0 0

BP 5 HRd 5 BPe 11 HRe 12 d

a b

c

d e

Incidence indicates the number of cats of the 13 studied. Preceded indicates that the increase in blood pressure or heart rate occurred before the onset of epileptiform activity elicited by PTZ. Proceeded indicates that the increase in blood pressure or heart rate occurred after the onset of epileptiform activity elicited by PTZ. Seven cats receiving only PTZ; the ECoG activity was not recorded in the eighth cat. Thirteen cats receiving PTZ and timolol.

PTZ and to 175 ± 14 bpm 15 min after PTZ was not signiἀcant. The PTZ-induced increase in blood pressure and heart rate preceded the initiation of epileptiform activity in most of these cats (Table 34.1). This trend was also observed in the 13 cats receiving PTZ and then timolol (Table 34.2). During the occurrence of PTZ-induced epileptiform activity, premature ventricular contractions of 3–8 min were observed in three of the eight cats. Data obtained from one cat are illustrated in Figure 34.1. In panel a (control), the cerebral activity present was that associated with the induction of anesthesia. With the intracerebroventricular administration of 10 mg PTZ (panel b), there was induction of epileptiform activity, a slight increase in blood pressure, and a slight decrease in heart rate. When timolol (10 μg/kg i.c.v.) was administered (panel c), the epileptiform activity was diminished, although the blood pressure and heart rate values were still elevated above control. The intracerebroventricular administration of PTZ increased both the mean arterial blood pressure and the heart rate in six cats receiving only PTZ and timolol; no other pharmacological agents were administered (data not shown). When timolol was given to the six Table 34.2â•… Incidence of the Sequence in Which Suppression of Intracerebroventricular PTZ-Induced Epileptiform Activity and a Decrease in Mean Arterial Blood Pressure and Heart Rate Occurred after Timolola Partial Suppression Compared to Control

Total Suppression Compared to Control

Total Suppression Compared to Mean of Previous 5-min Interval

No No Precededb Same Proceededc Preceded Same Proceeded Change Preceded Same Proceeded Change BP 1 HR 0 a b

c

d

0 0

12 13

11 12

0 0

1 0

1 1

7 2

0 1

4 6d

2 5d

Incidence indicates the number of cats of the 13 studied. Preceded indicates that the decrease in blood pressure or heart rate occurred before the partial or total suppression of epileptiform activity. Proceeded indicates that the decrease in blood pressure or heart rate occurred after the partial or total suppression of epileptiform activity. Includes same cat, hippocampus no change; both left and right cortex proceeded total suppression of epileptogenic activity.

Electroencephalogram (µV)

Antiepileptic Activity of Beta-Blocking Agents

Mean arterial blood 200 pressure 1000 (mm Hg) Electrocardiogram (Lead II)

(a)

(b)

555

(c)

L. motor cortex R. motor cortex R. hippocampus 108

123

143

122

113

130

1s Control

1s PTZ 10 mg i.c.v.

Timolol 10 µg/kg i.c.v.

Figure 34.1╇ Effect of timolol on the ECoG and cardiovascular parameters associated with

intracerebroventricular PTZ-induced epileptiform activity in one cat. Represented in all three panels are ECoGs from the left and right motor cortex and right hippocampus, as well as mean arterial blood pressure, and electrocardiogram from top to bottom, respectively. (Reproduced from Lathers, C. M., et al., Epilepsy Res, 4, 42–54, 1989b. With permission.)

cats after the administration of PTZ, the mean arterial blood pressure and heart rate values began to decrease. Similar data were obtained when PTZ and timolol were administered to cats that had previously received other agents (n = 7 cats). In the cats receiving other pharmacological agents before the administration of PTZ, the blood pressure, heart rate, and ECoG activity had returned to baseline values before the administration to PTZ. No signiἀcant effect of previous drugs or interaction between previous drug and time was found. The lack of a signiἀcant effect indicated that the two groups of animals responded the same ways to the drug injections over time and permitted combination of the two groups for purposes of analysis (n = 13 cats; Figure 34.2). Thus, the administration of PTZ increased both mean arterial blood pressure and heart rate. When timolol was given intracerebroventricularly, the mean arterial blood pressure and heart rate values began to decrease. In the two-way ANOVA, both main effects and the interaction were signiἀcant for the heart rate. A comparison of the two experimental groups (PTZ i.c.v. and PTZ–timolol, n = 13 cats) at each experimental time showed that the timolol group was lower in the control period, sharply rising to a nonsigniἀcant difference after the second dose of PTZ and after the ἀrst and second doses of timolol. At higher doses of timolol, the timolol group was consistently signiἀcantly lower in heart rate than the group receiving only PTZ. Experimental times within groups, done as separate one-way repeated-measures ANOVAs, due to the different variances, showed no signiἀcant difference across time in the heart rate for the cats receiving no timolol and a sharp rise followed by a fall (Tukey HSD) in the cats receiving PTZ and increasing doses of timolol. The two-way ANOVA revealed that the group main effects on blood pressure were not signiἀcant. The time effect and the interactions were signiἀcant. When the experimental groups were compared at each experimental time, no differences were found until the two highest doses of timolol. The data in the control group were steady at the time equivalent to that when timolol would have been administered to the animals in the experimental group, whereas the timolol group exhibited a rapid fall in blood pressure. Consequently,

556 Sudden Death in Epilepsy: Forensic and Clinical Issues 180

11 11

160

11

140

Mean arterial blood pressure (mean ± SE mm Hg)

10

11

N = 13 cats

11 12 12 12

120

12 12

100 12

80

11 12 12 12 12

60

12

12 12

40

12

8

8

20 –10

6

2

Control

14

18

22

26

30

34

38

42

20 mg PTZ, i.c.v.

100 µg/kg 1 mg/kg 10 mg/kg Timolol, i.c.v. Timolol, i.c.v. Timolol, i.v. 10 µg/kg 500 µg/kg 5 mg/kg 20 mg/kg Timolol, i.c.v. Timolol, i.c.v. Timolol, i.v. Timolol, i.v.

10 mg PTZ, i.c.v.

(a)

10

Time (min)

180

Heart rate (beats/min) mean ± SE

N = 13 cats 160

11

11

11 1110

11

140

12

12 12

120

12 11

100

12 12 12 11 12 12 11 1212 12 8 8

80 –10 Control

2

6

10

20 mg PTZ, i.c.v.

10 mg PTZ, i.c.v.

14

18

22

26

30

34

38

42

100 µg/kg 1 mg/kg 10 mg/kg Timolol, i.c.v. Timolol, i.c.v. Timolol, i.v. 10 µg/kg 500 µg/kg 5 mg/kg 20 mg/kg Timolol, i.c.v. Timolol, i.c.v. Timolol, i.v. Timolol, i.v.

Time (min)

(b)

Figure 34.2╇ The effect of timolol on mean arterial blood pressure and heart rate changes

induced by PTZ administered intracerebroventricularly in 13 cats. In the upper graph, the mean arterial blood pressure is graphed as a function of time. The lower graph depicts the mean heart rate. The arrows along the abscissa indicate the administration of PTZ intracerebroventricularly and timolol intracerebroventricularly or intravenously. (Reproduced from Lathers, C.€M., et€al., Epilepsy Res, 4, 42–54, 1989b. With permission.)

Antiepileptic Activity of Beta-Blocking Agents

557

the latter group was signiἀcantly lower. Experimental times within each group showed no signiἀcant effect of time course on blood pressure in those cats receiving only PTZ, whereas in the cats receiving both PTZ and timolol, the PTZ increased the blood pressure and timolol reversed the effect of PTZ. In the two cats receiving the same doses of timolol at time intervals other than 5 min (i.e., 10 or 15 min), timolol suppressed the epileptogenic discharges and decreased the blood pressure and heart rate. In the one cat in which all doses of timolol were given every 15 min but no epileptogenic activity occurred since PTZ was not given, both the heart rate and blood pressure values were decreased, but the magnitude of the decrease was much less than that observed in the cats given PTZ. Although PTZ induced both interictal and ictal epileptiform discharges in all cats, most epileptiform activity exhibited durations of ≤10 s, that is, interictal and brief ictal activity (Table 34.3 and Figure 34.3). The dashed curve in Figure 34.3 depicts the epileptiform activity with a duration of ≤10 s obtained in the left cortex of the cats receiving only PTZ and no timolol. The mean number of episodes of epileptiform activity remained approximately the same for the 45-min period, the time equivalent to the entire experimental duration in the cats receiving both PTZ and increasing doses of timolol. The mean number of episodes of epileptiform activity lasting 10 s (seconds/minute; mean ± SE) Experimental Groups

Left Cortex

Right Cortex

Right Hippocampus

Control PTZ, 10 mg i.c.v. PTZ, 20 mg i.c.v. Timolol, 10 μg/kg i.c.v. Timolol, 100 μg/kg i.c.v. Timolol, 500 μg/kg i.c.v. Timolol, 1 mg/kg i.c.v. Timolol, 5 mg/kg i.v. Timolol, 10 mg/kg i.v.

0 0 0.31 ± 0.31b 0.50 ± 0.50b 0 0 0 0 0

0 0 0.54 ± 0.54b 0.45 ± 0.45b 0 0 0 0 0

0 1.21 ± 1.21b 1.00 ± 0.65 5.51 ± 4.63 4.22 ± 4.22b 0 4.62 ± 4.62b 0.89 ± 0.89b 0

a

Source: Lathers, C. M., et al., Epilepsy Res, 4, 42–54, 1989b. With permission. Deἀned as the mean ± SE for the 13 cats in which a mean 10-min control period was obtained. b Mean ± SE was calculated by averaging 12 zeros and 1 number, resulting in an SE value that is the same as the mean. a

558 Sudden Death in Epilepsy: Forensic and Clinical Issues 22

}

Left cortex Right cortex Cats received PTZ and timolol Hippocampus Left cortex in cats receiving PTZ only

Mean number of episodes epileptiform activity lasting ≤10 s (episodes/min; mean ± SE)

20 18 16 14 12 10 8 6 4 2 0

Control

5

10

15

20

25

30

35

30

45

PTZ PTZ Timolol Timolol Timolol Timolol Timolol Timolol Timolol 10 100 500 1 5 10 25 10 20 mg/kg mg/kg µg/kg µg/kg µg/kg mg/kg mg/kg mg/kg mg/kg

50

55

60

Figure 34.3╇ Epileptiform activity with a duration of ≤10 s obtained in cats treated with PTZ and timolol. For purposes of comparison, data obtained in cats receiving only PTZ are shown for the comparable experimental duration. The control values obtained in the cats receiving both PTZ and timolol are means obtained in the 10-min period before the first dose of PTZ. (Reproduced from Lathers, C. M., et al., Epilepsy Res, 4, 42–54, 1989b. With permission.)

mean times to total suppression of epileptiform activity in the left and right cortices and the hippocampus were 26 ± 2, 26 ± 2, and 27 ± 2 min, respectively. In six cats, the time to total suppression of epileptiform activity was the same in only three brain regions. In six of the other seven cats, the dose of timolol producing total suppression of epileptiform activity was the same for all three brain areas; the times to suppression varied by only a few seconds. In one cat the epileptiform activity was suppressed in the left and right cortices at a dose of 5 mg timolol, whereas a dose of 10 mg was required to elicit total suppression in the hippocampus. The administration of timolol decreased the duration of all types of epileptiform activity, that is, prolonged ictal (>10 s), brief ictal, and interictal (Table 34.3). Table 34.4 Number of Cats and Dose of Timolol Inducing Total Suppression of Epileptiform Activitya Number of Cats Doses of Timolol (mg)

1

5

10

20

Left cortex Right cortex Hippocampus

2 2 2

3 3 2

1 1 2

6 5 7

a

Epileptiform activity was not induced by PTZ in the left and right cortex of one cat and in the right cortex of a second animal.

Antiepileptic Activity of Beta-Blocking Agents

559

The Friedman ANOVAs were signiἀcant (p ≤ 0.0001) for all three areas of the brain. The Wilcoxon post hoc tests revealed the expected PTZ-induced increase in epileptiform activity from control. In the 10 cats receiving 20 mg PTZ, this dose was not different from control (for any of the three areas), although the means were higher than for 10 mg PTZ. In fact, none of the Bonferroni-corrected Wilcoxon tests were signiἀcant between 20 mg PTZ and any other dose, for any area. The ἀrst dose of timolol elicited slightly (not signiἀcant) higher rates of prolonged and brief ictal and interictal activity than 20 mg PTZ, after which a steady decrease in epileptiform activity occurred, becoming signiἀcant (one-tailed) by the dose of 1 mg/kg i.c.v. timolol. This trend occurred in all three areas of the brain. None of the Friedman ANOVAs or duration more than 10 s approached signiἀcance; this was anticipated because many subjects had no prolonged ictal episodes at any dose. Table 34.2 shows the sequence in which the mean arterial blood pressure and heart rate were depressed by timolol in relation to the time when timolol partially or totally suppressed the epileptiform activity. In 12 of 13 cats, the epileptiform activity was partially suppressed before the fall in mean arterial blood pressure, that is, the fall in this parameter followed partial suppression induced by 10 μg timolol. The heart rate decreased in all 13 cats after the epileptiform activity was partially suppressed by this dose of timolol. In almost all of the cats, the decrease in the mean arterial blood pressure and heart rate preceded total suppression of epileptogenic activity when the cardiovascular parameters were compared to control values. When mean arterial blood pressure and heart rate values at the time of total suppression of epileptogenic activity were compared to blood pressure and heart rate values in the preceding 5-min interval, in most cats (7/13) the blood pressure decreased before total suppression of the epileptiform activity by timolol. However, the decrease in the mean heart rate followed total suppression of epileptogenic activity in six cats. In ἀve cats, the heart rate did not change immediately before or after the occurrence of total suppression of epileptiform activity. 34.3.2â•…Data Obtained in Anesthetized Pigs A transient increase (16.3–50.0%) in the mean arterial blood pressure occurred after the PTZ administration. The elevated blood pressure gradually declined to the basal level within 10 min after PTZ. Intravenously administered propranolol signiἀcantly reduced this transient pressor response and returned the elevated blood pressure to the basal level at 2 min after drug infusion (Figure 34.4). There was no signiἀcant change in the basal heart rate after PTZ administration. However, a marked bradycardia was observed at 1 min after intravenous propranolol administration. Propranolol produced a maximal decrease of 32–38% in the basal heart rate; the bradycardia persisted throughout the experiment (Figure 34.5). Epileptogenic activity induced by PTZ was associated with the occurrence of premature ventricular contractions in some pigs, similar to those observed in anesthetized cats when administered PTZ. Figure 34.4 illustrates the duration of seizure activity elicited by PTZ over an experimental period of 20 min. The seizure activity was continuous from t = 0 to 1 min for both groups. Intravenous propranolol produced a signiἀcant reduction in the duration of seizure activity 1 min after drug infusion; the seizure durations (second per minute interval) were 36.3 ± 4.8 and 12.3 ± 5.1 for the control and intravenous groups, respectively. Animals treated with intravenous propranolol had reduced duration of seizure activity throughout the entire experiment when compared to the control animals.

560 Sudden Death in Epilepsy: Forensic and Clinical Issues

Duration of seizure activity (s/min interval)

60 50 40 30 20 10 0

0

5 Propranolol (2.5 mg/kg)

10 Time (min)

15

20

PTZ (100 mg/kg, i.v.)

Figure 34.4╇ The effect of intravenous propranolol (2.5 mg/kg) on seizure activity induced by PTZ (100 mg/kg i.v.) in pigs (n = 5–6). PTZ was given to induce seizure activity. Propranolol was administered 60 s after the onset of seizure activity. The seizure activity at time zero was determined from the seizure duration of 0- to 1-min interval. A significant suppression of seizure activity was observed at 1 min after propranolol administration. (Modified and reproduced from Lathers, C. M., et al., Epilepsia, 30, 473–479, 1989a. With permission.)

Propranolol µg/ml plasma

10.0

1.0

0.1

0

2

4

6

8

10

12

14

16

18

20

Minutes after the dose

Figure 34.5╇ Propranolol plasma concentrations versus time in pigs administered propranolol 2.5 mg/kg i.v. Values are means ± SD (n = 6).

Antiepileptic Activity of Beta-Blocking Agents

561

Plasma propranolol concentrations were determined from 1 to 20 min after the intravenous administration of 2.5 mg/kg. After a rapid fall from 6.04 ± 1.43 μg/mL at minute 1 to 1.69 ± 0.31 μg/mL at minute 5, a steady decline in plasma concentration was observed up to 20 min, with a mean half-life of 23.3 ± 4.8 min (Figure 34.5). The brevity of the experiment precluded the determination of further kinetic parameters.

34.4â•…Discussion Previous studies have shown that PTZ administered intravenously induced epileptiform activity associated with cardiac arrhythmias and changes in the mean arterial blood pressure and heart rate (Carnel et al. 1985; Lathers and Schraeder 1982; Lathers et al. 1984; Schraeder and Lathers 1983). The present study demonstrated that the central administration of PTZ produced similar effects within seconds of its intracerebroventricular injection. These data support the conclusion that the intravenous administration of PTZ has little direct effect on the heart in eliciting cardiac arrhythmias and that such arrhythmias are associated with the epileptiform discharges induced by PTZ. The central administration of timolol decreased mean arterial blood pressure and heart rate. In another study, timolol administered intravenously to anesthetized cats also decreased the mean arterial blood pressure and heart rate (Lathers 1980) and exhibited an antiarrhythmic action against ouabain-induced arrhythmias. Lathers et al. (1986) demonstrated that chronic oral dosing with timolol for 1 or 2 weeks increased the time, although not signiἀcantly, to arrhythmia induced by acute permanent occlusion of the left anterior descending coronary artery. In the present study, increasing doses of timolol administered intracerebroventricularly and intravenously not only signiἀcantly decreased the elevation of mean arterial blood pressure and heart rate but also decreased and subsequently abolished the incidence of cardiac arrhythmias associated with the epileptiform activity. Epileptiform activity elicited in the present study with a duration less than or equal to 10 s includes both interictal and brief ictal discharges. PTZ-induced bilateral interictal spike activity is indicative of increased cortical excitability often evident in the EEG records of epileptic individuals. PTZ-induced generalized asynchronous clonic movements followed by a tonic convulsion in which limb movements are flexion followed by extension are analogous to the brief ictal discharges. Motor activity characterized by forelimb clonus is analogous to the prolonged ictal activity, that is, duration greater than 10€s. In the animal model using the cat and intracerebroventricular injection of PTZ, most of the epileptiform activity elicited was interictal and/or brief ictal activity. It has been hypothesized that the cardiac arrhythmias associated with interictal activity could be one potential mechanism for sudden unexplained death in epileptic persons (Carnel et al. 1985; Lathers and Schraeder 1982; Lathers et al. 1984; Schraeder and Lathers 1983). That timolol either partially or totally abolishes the epileptiform activity in the shorter duration category suggests that it may be a useful therapeutic agent to suppress the interictal discharges associated with cardiac arrhythmias. The administration of PTZ elicited epileptiform activity that was followed by increases in blood pressure, heart rate, and cardiac arrhythmias. Exactly how these changes develop is unknown, but this laboratory (Kraras et al. 1987; Suter and Lathers 1984) has proposed a possible mechanism to explain how epileptogenic activity and autonomic dysfunction may occur in epileptic patients, resulting in fatal cardiovascular changes. PTZ, trauma,

562 Sudden Death in Epilepsy: Forensic and Clinical Issues

inhibition of prostaglandin transport across the blood–brain barrier, or altered synthesis or metabolism of central enkephalins may lead to increased central levels of PGE2 and/or enkephalins. The consequence of this is thought to be inhibition of central GABA release, epileptogenic activity, increased blood pressure and heart rate, increased sympathetic and parasympathetic central neural outflow, impaired or imbalanced cardiac sympathetic and parasympathetic discharge, and a resultant arrhythmia and/or death. In the present study, the central intracerebroventricular administration of timolol partially suppressed the epileptiform activity and subsequently decreased the blood pressure and heart rate values elevated by PTZ. It may be that timolol is interfering with the central actions of PGE2 or enkephalins to reverse their known capabilities to induce epileptiform activity (see Chapter 18). Additional experimental studies are required to verify this suggestion. Additional mechanisms to explain the anticonvulsant and antiarrhythmic actions of timolol are discussed later. It has been theorized that pharmacological agents capable of suppressing epileptiform activity and the sympathetic component of cardiac arrhythmias may be the best regimens to prevent interictal activity and the associated cardiac arrhythmias that may contribute to the production of sudden unexplained death in the epileptic person (Carnel et al. 1985; Lathers and Schraeder 1982; Lathers et al. 1984; Schraeder and Lathers 1983). The data obtained in the present study indicate that in the experimental setting the pharmacologic agent timolol possesses components of both of these capabilities. Blockade of cardiac beta receptors, a cardiac neurodepressant effect, and/or membrane depressant actions of betablocking agents are thought to contribute to the antiarrhythmic action of beta-blocking agents (Lathers and Spivey 1987). PTZ has been used to induce seizure activity in humans (Franz 1980; Van Buren 1958), study seizure mechanisms (Faingold and Berry 1973; Krall et al. 1978; Langeluddeke 1936; Swinyard 1972), examine autonomic dysfunction associated with epileptogenic activity (Lathers and Schraeder 1982; Onuma 1957; Orihara 1952; Schraeder and Lathers 1983; Van Buren 1958; Van Buren and Ajmone-Marsan 1960), and screen anticonvulsant agents (Carnel et al. 1985; Faingold and Berry 1973; Lathers et al. 1984). Because it is accepted that PTZ is a convulsive model and that many drugs capable of suppressing the PTZ-induced epileptiform activity are anticonvulsant agents, the results of this study suggest that timolol exhibited an anticonvulsant action. Although the data indicate that timolol can reverse the effects of PTZ on the brain, this does not necessarily mean that timolol has intrinsic “anticonvulsant” properties separate from an ability to reverse the effects of PTZ. To answer this question, additional studies must be done to determine whether timolol will protect against seizures induced in other experimental models of epilepsy. In particular, it would be important to evaluate the capability of timolol to suppress interictal discharges and cardiac arrhythmias elicited in other in vivo experimental models not involving PTZ. If timolol also suppresses both the interictal discharges and the arrhythmias in these experimental models, this would provide additional evidence to support the possibility that timolol may be an effective agent to use in epileptic patients to prevent sudden unexplained death. The concept that beta-blocking agents may possess anticonvulsant action is not new (Bose et al. 1963; Conway et al. 1978; Papanicolaou et al. 1982). The studies of Dashputra et al. (1985), Jaeger et al. (1979), Murmann et al. (1966), and Tocco et al. (1980) demonstrated that propranolol possesses anticonvulsant actions. Mueller and Dunwiddie (1983) showed that timolol selectively blocked the proconvulsant activity of 2-fluoro-norepinephrine and 1-isoproterenol in in vitro hippocampal slice preparations superfused with penicillin and

Antiepileptic Activity of Beta-Blocking Agents

563

elevated levels of potassium. Louis et al. (1982) reported that propranolol or timolol (0.25 μg/kg i.c.v.) produced an anticonvulsant action when PTZ was used to induce convulsions in rats. The anticonvulsant action of timolol reported here for the data obtained in swine is similar to the anticonvulsant action of diazepam when used in the same experimental model (Lathers et al. 1987; Spivey et al. 1987). The anticonvulsant action of beta-blocking agents is commonly ascribed to a membranestabilizing effect, although exceptions have been reported (Lints and Nyquist-Battie 1985). Other proposed anticonvulsant mechanisms include decreased central serotonergic (Conway et al. 1978) and monoamine oxidase activity (Bose et al. 1963). An additional possible antiepileptic mechanism of the beta-blocking agents may include beta-Â�adrenoceptor blockade, especially beta2 receptors in the central nervous system (Papanicolaou et al. 1982). Although norepinephrine is generally believed to be anticonvulsant, studies suggest that norepinephrine may exacerbate seizure activity via activation of beta receptors. The state of abnormal seizure susceptibility, but not severity, in genetically epilepsy-prone rats may be determined by norepinephrine deἀcits in the hypothalamus/thalamus (Dailey and Jobe 1986). Both severity and susceptibility can be determined by norepinephrine deἀcits in the telencephalon, midbrain, and pons medulla, whereas seizure severity but not susceptibility may be determined by norepinephrine abnormalities in the cerebellum. Noradrenergic effects may not be uniform throughout the hippocampus; thus, selective activation of alpha or beta receptors by norepinephrine in the brain areas such as the hippocampus might produce either anticonvulsant or proconvulsant effects, respectively (Mueller and Dunwiddie 1983). Beta-blocking agents can increase norepinephrine concentration in cerebral spinal fluid (Tackett et al. 1981) and potentiate the effects of exogenously administered norepinephrine on vas deferens contraction (Patil et al. 1968). If a similar action occurred in this study, the establishment of beta blockade with timolol would increase the central norepinephrine concentration. The increased norepinephrine activity at the central postsynaptic alpha1 receptor sites may account for the anticonvulsant effects of beta-blocking agents (Goldman et al. 1987). Thus, the protective mechanism for timolol against seizures induced by PTZ may be due to a selective blockade of seizure-inducing beta receptors, allowing available norepinephrine to stimulate the central alpha1 receptors that exert an anticonvulsant action. In addition to the possibility that the central alpha1 receptors may be involved in the anticonvulsant action of beta-blocking agents, the role of central postsynaptic alpha2 receptors must be evaluated. Activation of alpha2 receptors decreases the excitability of CA1 pyramidal neurons (Mueller et al. 1982). Clonidine and 1-m-norepinephrine are more selective for alpha2 than for alpha1 receptors and inhibit epileptiform activity at low concentrations; the alpha1 agonist 1-phenylephrine was ineffective at much higher concentrations. These data suggest that central postsynaptic alpha 2 receptors may play a greater role than the alpha1 receptors in the anticonvulsant action of timolol observed in the present study. Deἀnitive experiments will have to be done to conἀrm this possibility.

34.5â•… Summary The experiments in this study were designed to explore the ability of beta-blocking agents to suppress seizures induced by PTZ in two species: the cat and the pig. Cats were anesthetized with alpha-chloralose and PTZ (10–20 mg i.c.v.) was administered to elicit epileptiform

564 Sudden Death in Epilepsy: Forensic and Clinical Issues

activity, including both interictal and ictal discharges. Various doses of timolol (10, 100, 500 μg/kg i.c.v. and 1, 5, 10, and/or 20 mg/kg i.v.) were then administered at 5-min intervals to determine whether it suppressed the epileptiform activity. Mean arterial blood pressure increased after the administration of PTZ and was associated with the development of epileptiform activity. Heart rate also was increased after PTZ. All doses of timolol caused a decrease in the blood pressure and heart rate elevated by PTZ. The administration of timolol also suppressed the epileptiform activity. Similar ἀndings were obtained in cats that received the same doses of timolol administered at different time intervals. The data indicate that the central administration of timolol reverses the epileptiform activity of PTZ on the brain and suppresses the associated increases in blood pressure and heart rate. Domestic swine (13–20 kg) were prepared for recordings of arterial blood pressure, ECG, and electrocortical activity. Seizure activity was induced by PTZ (100 mg/kg i.v.). Sixty seconds after the onset of seizure activity, the animals received either no drug (control) or propranolol (2.5 mg/kg i.v.). A transient increase in the mean arterial blood pressure was observed after PTZ administration. Intravenous propranolol signiἀcantly suppressed the seizure duration (second per minute interval) at 1 min after drug administration; seizure duration control, 36.3 ± 4.8; i.v. propranolol, 12.3 ± 5.1. Intravenous propranolol also produced a maximal decrease of 32–38% in the basal heart rate and reduced the transient increase in mean arterial blood pressure elicited by PTZ, with no signiἀcant effect on the basal mean arterial blood pressure. Plasma propranolol levels were found to be 6.07 ± 1.43 μg/mL at 1 min after administration, falling to 1.10 ± 0.27 μg/mg over the following 19 min of the experiment. The data demonstrate that propranolol possesses anticonvulsant activity against PTZ-induced seizures in both the pig and in the cat.

Acknowledgments The study was funded by a grant from the Epilepsy Foundation of America and from the Ben Franklin Partnership Fund, a program of the Commonwealth of Pennsylvania. The authors would like to thank Valerie Farris, Larry Pratt, and Michele Spino for technical help and also for typing the manuscript, and Dr. Edward Gracely for statistical analyses.

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566 Sudden Death in Epilepsy: Forensic and Clinical Issues Louis, W. J., J. Papanicolaou, R. J. Summers, and F. J. E. Vajda. 1982. Role of central beta adrenoceptors in the control of pentylenetetrazol-induced convulsions in rats. Br J Pharmacol 75: 441–446. Lown, B., and R. L. Verrier. 1978. Neural factors and sudden death. In Perspectives in Cardiovascular Research, vol. 2, Neural Mechanisms in Cardiac Arrhythmias, ed. P. J. Schwartz, A. M. Brown, A. Malliani, and A. Zanchetti, 87–88. New York, NY: Raven Press. Mueller, A. L., and T. V. Dunwiddie. 1983. Anticonvulsant and proconvulsant actions of alpha- and beta-noradrenergic agonists on epileptiform activity in rat hippocampus in vitro. Epilepsia 24: 51–64. Mueller, A. L., B. J. Hoffer, and T. V. Dunwiddie. 1981. Noradrenergic responses in rat hippocampus: Evidence for mediation by alpha and beta receptors in the in vitro slice. Brain Res 214: 113–126. Murmann, W., L. Almirante, and M. Saccani-Gueli. 1966. Central nervous system effects of four beta-adrenergic receptor blocking agents. J Pharm Pharmacol 18: 317–318. Onuma, T. 1957. Relationships of the predisposition to convulsions with the action potentials of the autonomic nerves and the brain: II. Changes in action potential of the autonomic nerves and the brain under conditions for increasing the predisposition to convulsions. Tohoku J Exp Med 65: 121–129. Orihara, O. 1952. Comparative observations of the action potential of autonomic nerve with EEC. Tohoku J Exp Med 57: 43–54. Papanicolaou, J., F. J. Vajda, R. J. Summers, and W. J. Louis. 1982. Role of beta-adrenoreceptors in the anticonvulsant effect of propranolol on leptazol-induced convulsions in rats. J Pharm Pharmacol 34: 124–125. Patil, P. N., A. Tye, C. May, S. Hetey, and S. Miyagi. 1968. Steric aspects of adrenergic drugs: XI. Interactions of dibenamine and beta adrenergic blockers. J Pharmacol Exp Ther 163: 309–319. Randall, W. C., J. X. Thomas, D. E. Euler, and G. J. Rozanski. 1978. Cardiac dysrhythmias associated with autonomic nervous system imbalance in the conscious dog. In Perspectives in Cardiovascular Research, vol. 2, Neural Mechanisms in Cardiac Arrhythmias, ed. P. J. Schwartz, A. M. Brown, A. Malliani, and A. Zanchetti, 123–138. New York, NY: Raven Press. Schraeder, P. L., and C. M. Lathers. 1983. Cardiac neural discharge and epileptogenic activity in the cat: An animal model for unexplained death. Life Sci 32: 1371–1382. Snider, R. S., and W. T. Neimer. 1970. A Stereotaxic Atlas of the Brain. Chicago, IL: University of Chicago Press. Spivey, W. H., H. D. Unger, C. M. Lathers, and R. M. McNamara. 1987. Intraosseous diazepam suppression of pentylenetetrazol-induced epileptogenic activity in pigs. Ann. Emergency Med. 16: 156–159. Suter, L. E., and C. M. Lathers. 1984. Modulation of presynaptic gamma aminobutyric acid release by prostaglandin E2: Explanation for epileptogenic activity and dysfunction in autonomic cardiac neural discharge leading to arrhythmias? Med Hypotheses 15: 15–30. Swinyard, E. A. 1972. Assay of antiepileptic drug activity in experimental animals: Standard tests. In Anticonvulsant Drugs, International Encyclopedia of Pharmacology and Therapeutics, Section 19.1, 47–65. Oxford: Pergamon Press. Tackett, R. L., J. G. Webb, and P. J. Privitera. 1981. Cerebroventricular propranolol elevates cerebrospinal fluid norepinephrine and lowers blood pressure. Science 213: 911–913. Tocco, D. J., B. V. Clineschmidt, A. E. W. Duncan, F. A. Deluna, and J. R. Baer. 1980. Uptake of the beta-adrenergic blocking agents propranolol and timolol by rodent brains: Relationship to central pharmacological action. J Cardiovasc Res 2: 133–143. Toman, J. E. P., and J. P. Davis. 1949. The effects of drugs upon the electrical activity of the brain. Pharmacol Rev 1: 425–492. Van Buren, J. M. 1958. Some autonomic concomitants of ictal autonomism. Brain 81: 505–528. Van Buren, J. M., and C. Ajmone-Marsan. 1960. Correlations of autonomic and EEG components in temporal lobe epilepsy. Arch Neurol 3: 683–703.

Arrhythmias Associated with Epileptogenic Activity Elicited by Penicillin

35

Claire M. Lathers Paul L. Schraeder

Contents 35.1 Introduction 35.2 Method 35.3 Results 35.4 Discussion 35.5 Summary Acknowledgments References

567 567 568 571 574 574 574

35.1â•…Introduction The association of autonomic dysfunction, clinical epilepsy, and sudden unexplained death has been the subject of many studies (Leestma et al. 1984; Terrence et al. 1975). Lathers and Schraeder (1982) and Schraeder and Lathers (1983) observed autonomic dysfunction in cats after epileptogenic activity induced by pentylenetetrazol. A marked increase in variability in mean autonomic cardiac sympathetic and parasympathetic neural discharge was associated with the epileptogenic activity. It was hypothesized that if altered cardiac neural discharge also occurs in the patient with epilepsy, cardiac arrhythmias and sudden unexplained death may occur. The ideal agent to prevent these events should possess anticonvulsant, antiarrhythmic, and cardiac neural depressant properties. This study developed a new small-animal model to study autonomic dysfunction in association with epileptogenic activity produced by injecting penicillin into the hippocampus of the cat. Epileptogenic activity was monitored as it spread to the left and right hippocampi and cerebral cortices. Data were analyzed to determine whether changes in the autonomic parameters of mean arterial blood pressure and heart rate were associated with both the interictal and the ictal epileptogenic activity. Phenobarbital was administered to determine whether it suppressed the epileptogenic and arrhythmic activities.

35.2â•…Method The stereotaxic hippocampal injection of aqueous penicillin solution in 11 cats anesthetized with general anesthesia elicited both interictal and ictal activities. Cats were anesthetized intravenously (i.v.) with alpha-chloralose (80 mg/kg) and surgically prepared for 567

568 Sudden Death in Epilepsy: Forensic and Clinical Issues

monitoring the mean arterial blood pressure, lead II ECG, and for drug administration as described by Lathers and Schraeder (1982). A burr hole was made in the region of the posterior sylvian and posterior ectosylvian gyri bilaterally after the animal was placed into a stereotaxic head holder (David Kopf Instruments). A microcannula and a concentric bipolar recording electrode were inserted into the hippocampus using coordinates obtained from a stereotaxic atlas of the cat brain (Snider and Niemer 1961). Electrocorticographic recording electrodes were placed on the left and right (motor) cortices and the hippocampi. Penicillin was injected into the right hippocampus (coordinates A +7, HD −6.0, and RL +11.8). Motor cortex activity was recorded because of evidence that the frontal cortex is involved in cardiovascular regulation (Yingling and Skinner 1976). Epileptogenic activity, interictal and ictal spikes, was elicited by the right hippocampal injection of penicillin as an aqueous solution of 400,000 U/mL colored with methylene blue to verify postmortem the injection recording site. A microsyringe in stereotaxic carrier was used to inject 0.0025 mL penicillin (1000 U). The epileptogenic activity, quantiἀed in spikes per minute, was correlated with changes in mean arterial blood pressure, heart rate, and ECG. Either 20 or 40 mg/kg sodium phenobarbital (Elkins Sinn, Inc.), dissolved in 5 mL physiologic (0.9%) saline, was infused into the femoral vein at a rate of 0.5 mL/min, followed by a 2-min wash at the same rate with saline. Phenobarbital was administered after the injection of penicillin into the hippocampus. One-factor repeated-measures analysis of variance were run where the independent variable was time (every 4 min) and the dependent measure was either heart rate or blood pressure. This was repeated for both penicillin and phenobarbital, creating four separate analyses. When a signiἀcant F ratio (using the Huynh–Feldt correction to degrees of freedom) was obtained, the Newman–Keuls post hoc procedure for determining which pairwise comparisons were signiἀcant was run at α = 0.05 (Winer 1962). Analyses of variance were done using biomedical programs, subprogram P2V. Post hoc tests were accomplished using the Statistical Package for the Social Sciences, subprogram one way.

35.3â•…Results Changes in the electrocardiogram that were observed after the administration of 1000 U penicillin in 11 cats included T-wave inversion in ἀve, changes in the ST and P–R intervals in four and three, respectively, alterations in the QRS complex in four, and ST depression in two. The administration of phenobarbital 20 mg/kg (i.v.) to four additional cats or 40 mg/kg (i.v.) to nine additional cats abolished the penicillin-induced changes in the ECG. The ECG changes included alterations in the P and QRS waves, the appearance of a U wave, and premature ventricular contractions. At some experimental times, the premature ventricular contractions occurred before the appearance of the epileptogenic activity; at other times in the same cat, the premature ventricular contractions appeared just after the initiation of the epileptogenic activity. The changes in the ECG were not caused by anesthesia or by surgical stress because they were not observed in the control period. In the rare event that anesthesia initiated arrhythmias, the cat was not included in the study. Data from one cat are depicted in Figure 35.1. Penicillin (1000 U/μL) induced interictal activity in the left motor cortex and in the left and right hippocampi 1 min after administration (not shown). Ictal activity developed in the right hippocampus 5 min after the injection of penicillin and was associated with a 5-mm Hg increase in the mean arterial

Electroencephalogram (µV)

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R. hippocampus

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30 min after penicillin injection

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6 242

5

R. hippocampus

R. motor cortex

3

L. hippocampus

L. motor cortex 2

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(d)

10 min after phenobarbital infusion

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50

(e)

Figure 35.1╇ Changes in the electroencephalogram and cardiovascular function observed in one cat after the administration of penicillin (100 U/ μL) into the right hippocampus. Phenobarbital (40 mg/kg, i.v.) was administered 2 h after the administration of penicillin. (a) Left motor cortex; (b) left hippocampus; (c) right motor cortex; (d) right hippocampus; (e) blood pressure; and row 6, electrocardiogram. The numbers above the mean arterial blood pressure and electrocardiogram tracings indicate the blood pressure and heart rate values in millimeters of mercury and beats per minute, respectively. Labels on the panels indicate data obtained in the control period and the times at which the data were obtained after the administration of penicillin and phenobarbital 40 mg/kg (i.v.).

Electrocardiogram (lead II)

(a)

Arrhythmias Associated with Epileptogenic Activity Elicited by Penicillin 569

570 Sudden Death in Epilepsy: Forensic and Clinical Issues

blood pressure (column B). Interictal activity was evident in all four electrocorticograms at minute 12 (not shown). Thirty minutes after the administration of penicillin (column C), the mean arterial blood pressure increased to 133 mm Hg and the heart rate to 246 bpm. Interictal spikes were observed in both motor cortices and ictal discharge in both hippocampi 1 h (column D) and 2 h (not shown) after penicillin administration. Mean arterial blood pressure and heart rate values were still increased from control. Penicillin-induced interictal and ictal activities were suppressed at minute 5 of the infusion of phenobarbital (not shown) and were abolished at minute 10 after 40 mg/kg (i.v.) phenobarbital (column E). Penicillin-induced increases in blood pressure and heart rate were also reversed to values lower than the control. Blood pressure and heart rate values were slightly higher than the control 30 min after phenobarbital; no epileptogenic activity was apparent (not shown). The hippocampal injection of penicillin (1000 U/μL) in six cats increased the mean arterial blood pressure from a control of 92 ± 12 to 106 ± 10 mm Hg at 30 min after penicillin. Heart rate was increased from the control of 179 ± 15 to 199 ± 13 bpm at this time. The change in heart rate was signiἀcant (p < 0.05), but the change in blood pressure was not. The administration of phenobarbital (20 mg/kg i.v.) decreased mean arterial blood pressure from the pre-phenobarbital control of 115 ± 14 to 79 ± 14 mm Hg (p < 0.05) 22 min after phenobarbital. Heart rate was decreased from 204 ± 19 to 162 ± 12 bpm (p < 0.05) at this time. To determine whether a higher dose of phenobarbital (40 mg/kg, i.v.) would completely abolish the penicillin-induced epileptogenic activity, ἀve additional cats

Mean arterial blood pressure (mean ± SE; mm Hg)

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N = 5 cats Cats

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40 0 250 200 150 100 0

0

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Penicillin (1000 U, hippocampal)

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60

70

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100 110 120 Time (min)

Figure 35.2╇ Effect of hippocampal injection of penicillin (1000 U/μL) on mean arterial blood pressure (mm Hg) and heart rate (bpm). Data are graphed as a function of time in minutes and are expressed as the mean ± SE for another group of five cats. Asterisks indicate values that are significantly different from control.

Arrhythmias Associated with Epileptogenic Activity Elicited by Penicillin

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received hippocampal injections of penicillin (1000 U/μL). The effect of penicillin on the mean arterial blood pressure and heart rate in these ἀve additional cats is depicted in Figure 35.2. Mean arterial blood pressure increased from the control of 105 ± 5 to 143 ± 13 mm Hg 52 min after the administration of penicillin; heart rate increased from 170 ± 22 to 218 ± 16 bpm (p < 0.05) 34 min after penicillin. When phenobarbital (40 mg/kg, i.v.) was administered to these ἀve cats, it decreased mean arterial blood pressure from the prephenobarbital control of 128 ± 14 to 56 ± 28 mm Hg and heart rate from 201 ± 15 to 117 ± 14 bpm (p < 0.05) at 12 and 22 min, respectively (Figure 35.3). Comparison of the effect of 20 and 40 mg/kg (i.v.) phenobarbital revealed that the magnitude of the decrease in blood pressure and heart rate after the larger dose was twice that of the lower dose.

35.4â•…Discussion This study showed that penicillin-induced hippocampal epileptogenic discharges were associated with increases in mean arterial blood pressure and heart rate and changes in the ECG. The dose of 20 mg/kg (i.v.) phenobarbital reversed the associated increases in blood 160 N = 5 cats

Mean arterial blood pressure (Mean ± SE; mm Hg)

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0 250 200 150 100 0

0

10

Phenobarbital (40 mg/kg; i.v.)

20 30 Time (min)

Figure 35.3╇ Effect of phenobarbital (40 mg/kg, i.v.) on penicillin-induced changes in blood

pressure (mm Hg) and heart rate (bpm). Data are graphed as a function of time in minutes and are expressed as the mean ± SE and were obtained in the same five cats depicted in Figure 35.2. Phenobarbital was given 2 h after the administration of penicillin. Asterisks indicate values that are significantly different from control.

572 Sudden Death in Epilepsy: Forensic and Clinical Issues

pressure and heart rate and attenuated the epileptogenic activity; 40 mg/kg (i.v.) phenobarbital completely abolished epileptogenic activity and reversed the associated changes in the cardiovascular parameters. This study demonstrated that the use of general anesthesia with hippocampal injections of aqueous penicillin elicited both interictal and ictal spike activities, in contrast to intracortical penicillin into the cerebral convexity, which does not usually progress to ictal activity in cats under general anesthesia (Prince 1972). Several of our preliminary experiments (unpublished observations), using alpha-chloralose anesthesia and cortical injection of penicillin, elicited only interictal spike activity in the primary focus and in the minor focus, that is, the homologous contralateral cortical area, within 3 to 10 min. Afterdischarges did not develop for as long as 7 h after the intracortical injection of penicillin. In contrast, when ether was used for induction of anesthesia, followed by local anesthesia, afterdischarges occurred within a mean time of 105 min after penicillin injection (Schraeder and Celesia 1977). Thus, the use of alpha-chloralose and cortical convexity injection of penicillin reliably elicits only interictal spikes and therefore is useful only in the examination of the effect of interictal discharge on autonomic cardiovascular function. In contrast, this study found that injection of penicillin into the hippocampus in animals anesthetized only with alpha-chloralose resulted in the progressive development of interictal to ictal discharges. Thus, the use of general anesthesia in the model using hippocampal injection of penicillin does not preclude investigation into the effects of ictal discharge. The signiἀcance of the data reported in this study is that interneuronal pathways connect the hippocampal area to the autonomic cardiovascular areas within the hypothalamus. The hippocampal formation, the amygdaloid complex, the septal region, the gyrus fornicatus, the piriform lobe, and the caudal orbital frontal cortex constitute the limbic forebrain structures (Nauta and Haymaker 1969). The fornix system forms the main efferent pathways from the hippocampus. Fiber systems originating in the limbic forebrain are among the most conspicuous afferents of the hypothalamus. Hippocampal afferents come from the medial septal nucleus and cingulate and the parahippocampal regions of the gyrus fornicatus. The amygdaloid complex is connected with the hypothalamus by the stria terminalis and the ventral amygdalofugal pathway. The septoamygdalar complex projects directly to the hippocampus (Swanson and Cowan 1979). The hypothalamus, at least in part, is then under cerebral cortical control in its influence on the maintenance of homeostasis by virtue of its neural relationships with both divisions of the autonomic nervous system and with both lobes of the pituitary gland. “When the connections of the septohippocampal complex are considered as a whole, the conclusion emerges that it essentially forms the gateway between the hypothalamus and the limbic cortical regions” (Swanson 1983). It is quite possible that with spread of interictal activity in the hippocampus to the hypothalamus, the subclinical epileptogenic activity alters the function of other areas of the brain, with resultant simultaneous changes in the autonomic control of mean arterial blood pressure, heart rate and rhythm, and cardiac neural discharge in the periphery. Furthermore, cardiovascular regulation is a function of neuronal activity in the cerebral cortex, the amygdala, and the medullary reticular formations. Cardioacceleratory and cardioinhibitory centers exist at these levels of the nervous system, with selective activation producing either increased or decreased heart rate. Vasopressor and vasodepressor centers also exist at these central sites and produce their effects through reticulospinal connections to the preganglionic sympathetic neurons of the intermediolateral cell column and through connections to preganglionic parasympathetic neurons. In addition to

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descending input from higher centers, the cardiovascular centers also receive input from peripheral receptors, the most important of which are the baroreceptors of the carotid sinus and the aortic arch. Although peripheral autonomic dysfunction in cardiac autonomic nerves can precede the changes in the ECG associated with subconvulsant interictal discharge, interictal activity alone can also be associated with premature ventricular contractions (Lathers and Schraeder 1982). Thus, minimal epileptogenic activity (single spikes) can be associated with altered cardiac neural discharge and arrhythmias. Schraeder and Celesia (1977) reported that even minimal epileptogenic activity has a wide-ranging effect on cerebral functions monitored at the auditory cortex of the cat. If, then, subclinical epileptogenic activity were to likewise have an effect on other functions of the brain, that is, autonomic regulation, producing autonomic imbalance in cardiac autonomic neural discharge with subsequent arrhythmias, this type of activity could be a contributing factor to the mechanism of unexpected death in epilepsy. That this sequence could occur in the person with epilepsy is supported by the anatomical relationships among the cerebral cortex, the hippocampi, and the hypothalamus. The anatomical and physiological relationship of the frontal cortex with the hypothalamus is complex; studies stimulating the dorsolateral surface of both hemispheres have reported both a rise and a drop in blood pressure and increases or decreases in heart rate (Hoff et al. 1963). Cortical stimulation evoked dilatation of pupils, retraction of the nictitating membrane, piloerection, salivation, sweating, and gastric motility and secretion. The autonomic localization in the motor and premotor cortex corresponds closely with the somatotopic representation (Brooks and Koizumi 1974). The focal model of epilepsy used in this study produced cardiovascular changes that were similar to those produced by pentylenetetrazol-induced epileptogenic activity (Lathers and Schraeder 1982; Schraeder and Lathers 1983). These data support the hypothesis that focal epileptogenic activity can produce alterations in cardiac electrical activity making the heart susceptible to arrhythmias that may cause sudden unexplained death in epileptic persons. The clinical signiἀcance of the data obtained in this type of epileptogenic model is emphasized by Blumhardt et al. (1986). They reported that in some patients with temporal lobe epilepsy, cardiac acceleration preceded the onset of recognizable rhythmic surface EEG seizure activity; this may reflect the onset of electrical discharge in deep limbic circuits and the connections of these structures with the autonomic nervous system. Arrhythmias were observed at times when there were no seizure discharges on the EEG in some patients. Blumhardt and others also noted that the autonomic effects of temporal lobe epilepsy on heart rate and rhythm may be more severe in untreated younger patients. Their suggestion agrees with the observation that young epileptic patients are at high risk of sudden unexplained death. The present study used an animal model that allowed testing of a pharmacologic agent that possesses antiepileptic, antiarrhythmic, and neural depressant activity. Future use of this model should help in the development of better therapeutic regimens designed to eliminate the autonomic dysfunction and arrhythmias associated with epileptogenic activity and ultimately contribute to our understanding of the risk factors for sudden unexplained death in epilepsy. If the data indicate that the autonomic changes are secondary to seizures, the primary clinical therapeutic goal would be to use a pharmacologic agent with maximum anticonvulsant potency. However, if interictal activity is associated with a risk of autonomic dysfunction, questions must be raised about the current therapeutic goal for

574 Sudden Death in Epilepsy: Forensic and Clinical Issues

epilepsy, which is to suppress seizures but not interictal discharges. In the latter case, a new type of drug may be required.

35.5â•…Summary Penicillin-induced epileptogenic activity (1000 U/mL) was recorded bilaterally from the hippocampi and the motor cortices of 11 anesthetized cats. The onset of epileptogenic activity ranged from 1 s to 16 min. Epileptiform activity, consisting of interictal discharges (n = 3) or ictal discharges (n = 3), ἀrst occurred at the injection site, the right hippocampus. Blood pressure increased from 92 ± 12 (control) to 106 ± 10 at 30 min and 115 ± 10 mm Hg at 60 min after penicillin (p > 0.05). Heart rate increased from 179 ± 15 (control) to 194 ± 13 at 30 min and 216 ± 13 bpm 60 min after penicillin (p > 0.05). Maximum increases in blood pressure and heart rate were 55 ± 15 mm Hg and 59 ± 15 bpm, respectively (p < 0.05). ECG alterations included P–R interval changes, increased P-wave amplitude, QRS complex changes, T-wave inversion, ST elevation, and the appearance of premature ventricular contractions. Phenobarbital (20, mg/kg i.v.) diminished the epileptogenic activity and depressed the blood pressure to 79 ± 14 mm Hg at 23 min from 115 ± 14 mm Hg (10 min before phenobarbital; p < 0.05). Heart rate was decreased to 162 ± 12 from the pre-phenobarbital control of 204 ± 19 bpm (p > 0.05). To determine whether a higher dose of phenobarbital (40 mg/kg, i.v.) would completely abolish the penicillin-induced epileptogenic activity, ἀve additional cats received 1000 U/μL penicillin G sodium into the right hippocampus. In these cats the penicillin also produced epileptogenic activity and increased the blood pressure from 105 ± 5 to 143 ± 13 and the heart rate from the control 170 ± 22 to 218 ± 16 (p < 0.05). Phenobarbital (40 mg/kg, i.v.) signiἀcantly reversed the effect of penicillin on the blood pressure and heart rate. Blood pressure dropped from the pre-phenobarbital control of 128 ± 14 to 56 ± 18 mm Hg and heart rate dropped from 201 ± 15 to 117 ± 14 bpm (p < 0.05). This dose of phenobarbital also prevented the penicillininduced epileptogenic activity. Thus, phenobarbital diminished the epileptogenic activity and autonomic dysfunction induced by penicillin. The autonomic dysfunction and epileptogenic activity induced by the peripheral intravenous administration of pentylenetetrazol (Lathers and Schraeder 1982) are similar to those induced by the hippocampal injection of penicillin.

Acknowledgments This study was funded by the Epilepsy Foundation of America. The authors are indebted to Dr. Nihal Tumer, Valerie Farris, and Larry Pratt for technical help, Dr. Edward Gracely for statistical analyses, and Michele Spino for typing the manuscript.

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Hoff, E. C., J. F. Kell Jr., and M. N. Carrol Jr. 1963. Effects of cortical stimulation and lesions on cardiovascular function. Physiol Rev 43: 68–114. Lathers, C. M., and P. L. Schraeder. 1982. Autonomic dysfunction in epilepsy: Characterization of autonomic cardiac neural discharge associated with pentylenetetrazol-induced epileptogenic activity. Epilepsia 23: 633–647. Leestma, J. E., M. B. Kalelkar, S. S. Teas, G. W. Jay, and J. R. Hughes. 1984. Sudden unexpected death associated with seizures: Analysis of 66 cases. Epilepsia 25: 84–88. Nauta, W. J. H., and W. Haymaker. 1969. Hypothalamic nuclei and ἀber connections. In The Hypothalamus, ed. W. Haymaker, E. Anderson, and W. J. H. Nauta, 136–209. Springἀeld, IL: Thomas. Prince, D. A. (1972). Topical convulsion drugs and metabolic antagonists. In Experimental Models of Epilepsy. A Manual for the Laboratory Worker, ed. D. P. Purpura, J. K. Peney, D. Tower, D. M. Woodbury, and R. Walter, 51–84. New York, NY: Raven Press. Schraeder, P. L., and G. G. Celesia. 1977. The effects of epileptogenic activity on auditory evoked potentials in cats. Arch Neurol 34: 677–682. Schraeder, P. L., and C. M. Lathers. 1983. Cardiac neural discharge and epileptogenic activity in the cat: An animal model for unexplained death. Life Sci 32: 1371–1382. Snider, R. S., and W. T. Niemer. 1961. A Stereotaxic Atlas of the Cat Brain. Chicago, IL: University of Chicago Press. Swanson, L. W. 1983. The hippocampus and the concept of the limbic system. In Neurobiology of the Hippocampus, ed. W. Seifert, 3–20. London: Academic Press. Swanson, L. W., and W. M. Cowan. 1979. The connections of the septal region in the rat. J Comp Neurol 186: 621–656. Terrence, C. F., H. M. Wisotzkey, and J. A. Perper. 1975. Neurogenic pulmonary edema in unexpected, unexplained death in epileptic patients. Neurology 25: 594–598. Winer, B. 1962. Statistical Principles in Experimental Design, 2nd ed. New York, NY: McGraw-Hill. Yingling, C. D., and J. E. Skinner. 1976. Selective regulation of thalamic sensory relay nuclei by nucleus reticularis thalami. Electroencephalogr Clin Neurophysiol 41: 476–482.

Role of Neuropeptides in the Production of Epileptogenic Activity and Arrhythmias

36

Claire M. Lathers

Contents 36.1 Introduction 36.1.1 PTZ-Induced Increased Concentrations of Central Enkephalins and Epileptogenic Activity 36.1.2 Central Neuropeptide-Induced Epileptogenic Activity 36.1.3 Enkephalin Modulation of GABA Release 36.1.4 Met-Enkephalin Modulation of Acetylcholine Release 36.2 Central Cardiovascular and Neurological Effects of Enkephalins 36.2.1 Action on Mean Arterial Blood Pressure, Heart Rate, and Brain Electrical Activity in Conscious Cats 36.2.2 Action on Mean Arterial Blood Pressure, Heart Rate, and Brain Electrical Activity in Anesthetized Animals 36.3 Discussion 36.4 Summary References

577 578 578 578 578 580 580 583 585 588 589

36.1â•…Introduction Pentylenetetrazol (PTZ)-induced interictal and ictal epileptogenic activity associated with autonomic dysfunction—that is, changes in autonomic cardiac neural discharge, mean arterial blood pressure, and heart rate and rhythm—has been reported in the cat (Schraeder and Lathers 1989; Lathers and Schraeder 1982). If the autonomic dysfunction, including the development of arrhythmias, also occurs in humans, it may be a contributory factor to sudden unexplained death in a person with epilepsy. Elevation of immunoreactive (IR) met-enkephalin content in the septum, hypothalamus, amygdala, and hippocampus of rats occurs after PTZ-induced convulsions (Vindrola et al. 1984). This elevation may ultimately change central sympathetic neural discharge to the heart, resulting in the development of arrhythmias. Indeed, numerous reports indicate that neuropeptides may produce epileptic seizures (Elazor et al. 1979; Frenk et al. 1978). Resolution of the question of whether enkephalins elicit epileptogenic activity and autonomic dysfunction via an action to inhibit the release of GABA (Brennan et al. 1980; Snead and Bearden 1980) is important because an understanding of this mechanism should eventually allow the design of pharmacologic agents to prevent the epileptogenic activity and autonomic dysfunction.

577

578 Sudden Death in Epilepsy: Forensic and Clinical Issues

36.1.1â•… P  TZ-Induced Increased Concentrations of Central Enkephalins and Epileptogenic Activity PTZ-induced kindling was associated with a long-lasting elevation in brain content of IR met-enkephalin in the septum, hypothalamus, amygdala, and hippocampus of rats (Vindrola et al. 1984). Kindling was produced by the administration of intraperitoneal injections of 40 mg/kg PTZ every 24 h for 10 days. The control group received an equivalent volume of saline on the same schedule. Every animal was observed for 1 h after each injection for the appearance of convulsions. IR met-enkephalin was quantiἀed in several brain areas 16 days after the last injection of PTZ in both the control and experimental groups. Additional rats received a PTZ dose on day 16 and were sacriἀced 1 and 24 h later. Brain tissue was prepared and enkephalin content was assayed by radioimmunoassay. A long-lasting elevation in amygdala, septum, hypothalamus, and hippocampus€ IR€ metÂ�enkephalin content occurred in animals subjected to kindling and sacriἀced 16 days after the last dose of PTZ. A decrease in IR met-enkephalin occurred 1 h after the PTZ-induced seizure but increased to newly elevated levels 24 h later. Thus, PTZ-induced kindling increased levels of enkephalins that were temporally related to the appearance of seizures. 36.1.2â•… Central Neuropeptide-Induced Epileptogenic Activity In addition to the ἀndings of increased brain concentrations of enkephalins after induction of seizures by PTZ, injection of these agents has been shown to elicit seizure activity. Speciἀcally, the intracerebroventricular injection (Urca and Frenk 1983) and hippocampal injection (Elazor et al. 1979) of leu-enkephalin induced seizures in rats and cats. Snead and Bearden (1980) also found that neuropeptides administered into the central nervous system induced epileptogenic activity in rats. Intraventricular leu-enkephalin produced a consistent dramatic paroxysmal electrical response within the ἀrst 60 s of administration (Figure 36.1), which persisted for up to 6 min. The enkephalin-induced paroxysms increased the 3- to 6-Hz band of the EEG spectrum. This indicated that enkephalin is directly involved in the production of epileptogenic activity (Snead and Bearden 1980). 36.1.3â•… Enkephalin Modulation of GABA Release Met-enkephalin inhibited K+ depolarization-induced release of 3H-GABA from rat synaptosomes in a dose-dependent fashion (Brennan et al. 1980). The concentration of metenkephalin that inhibited 50% of the K+-stimulated release was approximately 5 × 10−10 M (Figure 36.2). In every instance, the reduction of GABA release was prevented by naloxone, suggesting that met-enkephalin may interact with opiate receptors to modulate the release of GABA. 36.1.4â•… Met-Enkephalin Modulation of Acetylcholine Release Met-enkephalin reversibly and speciἀcally reduces the quantal content of acetylcholine release from peripheral nerve terminals in the frog cutaneous pectoris muscle by blocking voltage-dependent Ca+ channels (Bixby and Spitzer 1983). It is likely that met-enkephalin also blocks the release of Ca2+-dependent neurotransmitters, such as GABA, from central synapses. Bixby and Spitzer applied met-enkephalin (10–30 μM) by pressure ejection

Role of Neuropeptides in the Production of Epileptogenic Activity and Arrhythmias 579

RF-RP LF-LP

50 µV

1s

RF-RP LF-LP 50 µV

1s RF-RP LF-LP

50 µV

50 µV

1s

1s

Figure 36.1╇ ECoG changes produced by 100 μg leu-enkephalin injected intracerebroventricularly. The insets show a faster time trace. RF and RP, right frontal and parietal leads; LF and LP, left frontal and parietal leads. The rat was immobile during this paroxysmal electrical activity. The first change in the ECoG occurred within 1 min of administration and was a paroxysm of spikes at a frequency of 7–9 Hz lasting 30–40 s. This tapered off to 2–3 Hz slow-wave activity, which was followed by 20–25 s of low-voltage fast activity. A few seconds of 1-Hz high-voltage slow-wave activity then built up to 25–30 s of low-voltage activity. Finally, a prolonged period of high-voltage single spikes occurred at a rate of 1 paroxysm/5 s. (Reproduced from Snead, O.C., and Bearden, L.J., Science, 210, 1031–1033, 1980. With permission.)

% Inhibition K+-stimulated GABA release

through a “puffer” pipette to the presynaptic terminals of frog neuromuscular junctions before compound nerve stimulation with a suction electrode. Met-enkephalin was also applied in the presence of 15 μM naloxone. Application of saline to the presynaptic terminals before stimulation served as a control. Finally, puffer application of enkephalin was used on the postsynaptic membrane, followed by both iontophoretic application of acetylcholine and nerve stimulation. Application of met-enkephalin to the presynaptic membrane led to a consistent decrease in the size of the evoked response (Figure 36.3a).

100 80 60 40 20 10–13 10–12 10–11 10–10 10–9 10–8 10–7 10–6 10–5 10–4 [Met-enkephalin] M

Figure 36.2╇ A dose–response curve for the inhibition of K+ (55 mM)-induced GABA release

by met-enkephalin. Each point is the mean percentage of inhibition ± SD (n = 5). Basal release of GABA was 7651 ± 980 dpm (n = 46). (From Brennan, M., et al., Life Sci, 27, 1097–1101, 1980. With permission.)

580 Sudden Death in Epilepsy: Forensic and Clinical Issues (a)

Normal

Enkephalin

Normal

4 ms (b)

Normal

10 mV

Normal

Enkephalin

10 mV 200 ms

Figure 36.3╇ (a) Compound nerve stimulation with a suction electrode elicits an endplate

potential that is reduced by focal puffer application of 20 μM met-enkephalin. Saline contained 0.8 mM Ca2+ and 8.0 mM Mg 2+. (b) Responses to iontophoretically applied acetylcholine; the amplitude of the response is increased by focal application of 20 μM met-enkephalin. Note that the response with enkephalin is longer and larger. (Reproduced from Bixby, L., and Spitzer, C., Nature, 301, 431–432, 1983. With permission.)

The decrease, which averaged 40%, was not seen when met-enkephalin was applied in the presence of 15 μM naloxone or when normal saline substituted for enkephalin. In addition, met-enkephalin not only did not reduce but also slightly increased the size of response to iontophoretically applied acetylcholine on the postsynaptic membrane (Figure 36.3b). Thus, the opiates appear to be exerting its effect presynaptically, possibly by blocking the Ca2+ channels. When these channels are blocked, there is decreased release of acetylcholine from nerve terminals in the frog cutaneous pectoris muscle (Bixby and Spitzer 1983). GABA release in the central nervous system has been reported to be Ca2+-dependent (DeBelleroche and Bradford 1972). Therefore, met-enkephalin may be able to inhibit GABA release in the central nervous system by preventing Ca2+ influx into the presynaptic nerve terminal in a manner similar to that by which met-enkephalin reduces the presynaptic release of acetylcholine.

36.2â•… Central Cardiovascular and Neurological Effects of Enkephalins 36.2.1â•…Action on Mean Arterial Blood Pressure, Heart Rate, and Brain Electrical Activity in Conscious Cats The administration of neuropeptides elicits cardiovascular changes as well as epileptogenic activity in conscious male cats (Schaz et al. 1980). After intracerebroventricular application of [(d-Ala 2) methionine-enkephalinamide (DAME)] at a dose of 425 nmol in the cat, arterial systolic and diastolic blood pressures increased, suggesting that (d-Ala2)met-enk may produce a centrally mediated vasopressor response (Figure 36.4). A small increase in heart rate occurred. The maximal cardiovascular response was seen 16 min after the

Role of Neuropeptides in the Production of Epileptogenic Activity and Arrhythmias 581 (-Ala2)-Met-Enkephalin 425 nMol i.c.v. N = 4, n = 9 BP sys BP dio HR

16

32

64

178

40

40

30

30

20

20

10

10

∆ HR%

∆ Bp%

8

Time after injection (min)

Figure 36.4╇ Changes in blood pressure and heart rate (given as percent change of the corresponding control values) elicited by intracerebroventricular injection of DAME, 425 nmol, in freely moving cats. Data are expressed as means ± SEM and have been obtained at different time intervals after the injections of (d-Ala 2)met-enk. Nine experiments were performed in four cats. In control experiments, using intracerebroventricular injections of the same volumes of 0.9% NaCl, changes in arterial blood pressure did not exceed 5–10 mm Hg. Pretreatment values of blood pressure and heart rate were 92 ± 3 mm Hg and 145 ± 3 bpm, respectively. (Reproduced from Schaz, K., et al., Hypertension, 2 (4), 395–407, 1980. With permission.)

intracerebroventricular injection and was attenuated after 64 min. A 170-nmol dose of DAME had no effect on blood pressure and heart rate. A dose of 850 nmol increased arterial pressure and produced catatonia-like behavior during the ἀrst 30 min; this was followed by an excitatory behavior that lasted up to 2 h. Spike-wave complexes occurred within the amygdala and hippocampus after 850 nmol. The time course of electrical activity changes did not exactly follow the hemodynamic changes (Figure 36.5). Spike-wave complexes appeared 5 min after the changes in hemodynamic parameters and lasted only 40 min (Schaz et al. 1980). Yukimura et al. (1981) studied the intracerebroventricular injection of 5, 10, 25, 50, and 100 nmol DAME in cats. In additional experiments, 500 nmol naloxone was injected intracerebroventricularly 3 min before DAME to test the effects of the opioid antagonist on enkephalin action. DAME induced dose-dependent increases in systolic blood pressure and heart rate. Doses of 50 nmol or less produced a maximal increase in blood pressure within 15 min; heart rate did not reach maximum until 30 min. For more than 2 h after 50 and 100 nmol of DAME, sharp waves were seen in the hippocampus recording; theta activity was attenuated. Seizures were not observed. Naloxone given before the injection

582 Sudden Death in Epilepsy: Forensic and Clinical Issues

Am cent

100 µV

Hyphotal

100 µV

Hipp.

500 µV

Sups Gyr lat 200 µV HR beats/min BP mm Hg

240 180 150 50

Am cent

100 µV

Hyphotal

100 µV

Hipp.

500 µV

C

i.c.v. injection (-Ala2)-Met-Enkepahlin 850 nMol

Sups Gyr lat 200 µV

BP mm Hg

240 180 120 150 50

Am cent

100 µV

Hyphotal

100 µV

Hipp.

500 µV

HR beats/min

5’

10’

30’

60’

Sups Gyr lat 200 µV HR beats/min BP mm Hg

240 180 120 150 50

Figure 36.5╇ Recordings of the electrical activity of the central amygdala (Am. cent.), hypo-

thalamus (Hypothal.), hippocampus (Hipp.), and lateral suprasylvian gyrus (Subs. Gyr. lat.); of heart rate (HR), instantaneously recorded as intervals between two heartbeats; and of arterial blood pressure (BP) before, immediately after, and 5, 10, 30, and 60 min after intracerebroventricular injection of (d-Ala 2)met-enk 850 nmol in a freely moving cat. The paper speed can be seen by the continuous marks on the top of each panel: each point represents 1 s. Five minutes (5′) after application of the peptide, there is an increase in arterial pressure by approximately 20 mm Hg. At 10′, arterial pressure is markedly increased by 30 mm Hg, and in the subcortical recordings, there are hypersynchronous waves and spike-wave complexes. At 60 min after intracerebroventricular application of (d-Ala 2)met-enk, electrical recordings are not different from the control period; however, arterial blood pressure is still elevated by 35 mm Hg. (Reproduced from Schaz,€K., et al., Hypertension, 2 (4), 395–407, 1980. With permission.)

Role of Neuropeptides in the Production of Epileptogenic Activity and Arrhythmias 583 Table 36.1â•… Effects of DAME on Blood Pressure, Heart Rate, and Baroreceptor Reflex Sensitivity in Conscious Catsa Treatment

Control

15 min

30 min

60 min

25 nmol DAME Naloxone + 25 nmol DAME 50 nmol DAME Naloxone + 50 nmol DAME

133 ± 8 133 ± 11 143 ± 9 136 ± 9

Systolic Blood Pressure (mm Hg) 154 ± 14* 149 ± 13 144 ± 11 124 ± 17 133 ± 18 118 ± 14 168 ± 15* 163 ± 12 148 ± 11 150 ± 10 153 ± 9 148 ± 21

134 ± 13 125 ± 18 129 ± 7 146 ± 25

25 nmol DAME Naloxone + 25 nmol DAME 50 nmol DAME Naloxone + 50 nmol DAME

154 ± 12 149 ± 24 147 ± 6 144 ± 5

Heart rate (bpm) 188 ± 13* 182 ± 12* 164 ± 21 158 ± 20 166 ± 8* 193 ± 9* 180 ± 20* 193 ± 29*

146 ± 12 172 ± 23 142 ± 6 149 ± 10

164 ± 10 158 ± 27 160 ± 9 146 ± 9

120 min

Source: Yukimura, J., et al., Hypertension, 3 (5), 528–533, 1981. Data are expressed as means ± SEM. *p < 0.05. a

of 25 nmol of DAME blocked all cardiovascular responses (Table 36.1). A 50-nmol dose blocked only the blood pressure responses; the heart rate increases and baroreceptor reflex attenuations were unaltered. The baroreceptor reflex was attenuated for 15–60 min after DAME; higher doses were effective for a longer time (Table 36.1). Naloxone administered before enkephalin injection produced no changes in central electrical activity. It was concluded that enkephalins may play a role in central mechanisms of cardiovascular control by interacting with opiate receptors in the brain (Yukimura et al. 1981). 36.2.2â•…Action on Mean Arterial Blood Pressure, Heart Rate, and Brain Electrical Activity in Anesthetized Animals The injection of DAME into the cisterna magna of anesthetized dogs induced a short period of moderate hypertension followed by a marked and prolonged decrease in blood pressure, heart rate, and splanchnic nerve discharge (Laubie et al. 1977). Intravenous (i.v.) naloxone produced a transient increase in all three parameters and antagonism of DAME, which was extended by a subsequent injection of naloxone (Figure 36.6). It was concluded that the opioid peptides may be involved in central cardiovascular control. The intracerebroventricular injection of DAME (500 μg/kg) has been shown to produce hypotension, bradycardia, and seizure activity when administered to anesthetized cats (Kraras et al. 1987; Lathers et al. 1988). In general, intravenous naloxone (100 μg/kg) reversed the effects of DAME on blood pressure and heart rate while eliminating seizure activity. Figure 36.7 illustrates the effect of DAME in one cat. Although the mean arterial blood pressure dropped from the control value of 108 to 93 mm Hg, the heart rate increased to 132 bpm 18 min after the administration of DAME compared to the control interval rate of 108 bpm (Figure 36.7b). The subsequent administration of 100 μg/kg (i.v.) naloxone to this cat then decreased the heart rate elevated by the administration of DAME; a further decrease in blood pressure occurred after naloxone. The epileptogenic activity induced by DAME was decreased but not abolished by naloxone (Figure 36.7c). DAME also produced brief ictal activity beginning several minutes postadministration in most cats. Brief ictal activity consists of repetitive bilateral bursts of polyspike activity,

584 Sudden Death in Epilepsy: Forensic and Clinical Issues

200 BP mm Hg

mean

0 200 0

20 s 220

72

180

HR beats/min splanchnic discharges 50 µV

500 ms

[-Ala2] met-enkephalin

control

500 µg/kg ic

20 min

naloxone 100 µg/kg, i.v.

Figure 36.6╇ The inhibitory effect of (d-Ala 2)met-enk (500 μg/kg) injected into the cisterna

108

200

93

86

150 100

Electrocorticogram (µV)

Mean arterial blood pressure (mm Hg)

magna on blood pressure, heart rate, and splanchnic neural discharges on a dog anesthetized with alpha-chloralose and the reversal produced by naloxone (100 μg/kg, i.v.). (Reproduced from Laubie, M., et al., Eur J Pharmacol, 46, 67–71, 1977. With permission.)

50 0

132

Heart rate (beats/min)

106

114

2 sec

0 Control

(a) T = 0 min DAME (500 µg/kg) i.c.v.

T = 18 min (b)

T = 4 min (c) post naxalone

T = 0 min naxalone (100 µg/kg) i.v.

Figure 36.7╇ Brief ictal activity produced by DAME and eliminated by naloxone in cats anesthetized with alpha-chloralose. Heart rate and blood pressure changes are also shown. (From Kraras, C. M., et al., Med Hypothesis, 23, 19–31, 1987. With permission.)

Role of Neuropeptides in the Production of Epileptogenic Activity and Arrhythmias 585

each lasting less than 10 s, interspersed with brief periods of depression of cerebral activity. Administration of naloxone (100 μg/kg, i.v.) eliminated brief ictal activity in some cats within 4 min of its administration, whereas in other cats the seizure activity was somewhat depressed although still present. DAME-induced depression of heart rate and blood pressure was generally reversed by naloxone.

36.3â•…Discussion In the studies of Lathers and Schraeder (1982) and Schraeder and Lathers (1983), in the control period, the mean heart rate increased with a decrease in the mean arterial blood pressure in anesthetized cats. This relationship did not always occur with the development of epileptogenic activity induced by the intravenous administration of PTZ. The autonomic cardiac nerves did not always respond in a predictable manner to changes in blood pressure after the development of epileptogenic activity. In contrast, during the control period, all postganglionic cardiac sympathetic nerves exhibited an increased discharge as blood pressure dropped after the administration of a vasodilating test dose of histamine. Discharge in the parasympathetic cardiac nerves followed the changes in the mean arterial blood pressure. These relationships of cardiac neural discharges (sympathetic and parasympathetic) to blood pressure changes represent the normal physiological function (Bronk et al. 1936). With the development of interictal activity, the variability of mean neural discharge for the parasympathetic nerves began to increase, as demonstrated by an increase in the standard deviation. With greater degrees of epileptogenic activity, the standard deviation continued to increase; that is, the variability in the discharge among the parasympathetic nerves monitored became larger. A neural variability, again evidenced by a large standard deviation, also occurred in the mean postganglionic cardiac sympathetic discharge. The variability observed for the mean sympathetic discharge developed subsequent to that occurring in the parasympathetic discharge. Thus, autonomic cardiac neural dysfunction was observed within both divisions of the autonomic cardiac nervous systems and between the two divisions. The altered cardiac neural discharge was associated with minimal epileptogenic activity (i.e., interictal discharges) and the development of cardiac arrhythmias. The proposed mechanisms involved in the development of these arrhythmias and the possible role of enkephalins in the induction of sudden unexplained death in some epileptic patients are summarized in Figure 36.8 and are discussed below. The injection of enkephalins into the central nervous system elicits seizure activity (Frenk et al. 1978; Snead 1983). Intraperitoneal administration of PTZ produced increases in enkephalin content of the amygdala, striatum, and septum (Vindrola et al. 1983). An increase in the level of enkephalin in the amygdala may have initiated seizure activity because the amygdala is extensively interconnected with the hypothalamus; indeed, it is considered to have a higher-order modulating influence on the hypothalamus. Furthermore, almost any visceral or somatic activity, including cardiovascular and respiratory changes, elicited by stimulating the amygdala can also be elicited by stimulating various areas within the hypothalamus (Nolte 1981). Seizure activity originating in the amygdala may have induced changes in the discharge to the hypothalamus; disturbances in hypothalamic function may result in autonomic dysfunction. PTZ (intraperitoneal) has also been shown to induce an increase in enkephalin levels within the hypothalamus (Vindrola et al. 1984). Because the hypothalamus contains autonomic centers, it may be that the PTZ-induced increases

586 Sudden Death in Epilepsy: Forensic and Clinical Issues PTZ

Concentration of central enkephalin acting on oplate receptors K+-evoked release of GABA and/or, Ca+2 entry into presynaptic GABA nerve terminals and/or, K+ conductance in the GABA nerve terminal indirect Ca+2 entry in the same nerve terminal Anesthetized Animals

Conscious Animals

Sympathetic and parasympathetic central neuron outflow and enhancement of central reflex-induced vagal bradycardia and blood pressure

Inhibition of central GABA release epileptogenic activity

Blood pressure and heart rate due to attenuation of the vagal component of the baroreceptor reflex

Imbalance in peripheral sympathetic and parasympathetic neural discharge Arrhythmia

Sudden unexplained death in the epileptic person

Figure 36.8╇ Postulated mechanism by which central enkephalins could antagonize GABA, resulting in autonomic dysfunction, epileptogenic activity, and sudden death. (From Kraras, C.€M., et al., Med Hypothesis, 23, 19–31, 1987. With permission.)

in central enkephalin levels led to the production of epileptogenic activity and autonomic dysfunction in the experiments of Lathers and Schraeder (1982). A central mechanism by which increased concentrations of enkephalins inhibit K+-dependent GABA release may exist because met-enkephalin has been shown to inhibit the release of GABA from rat brain synaptosomes (Brennan et al. 1980). There is also evidence suggesting that increased concentrations of enkephalins directly decrease the entry of Ca2+ into the presynaptic GABA nerve terminals (Bixby and Spitzer 1983). Metenkephalin reduced the amount of acetylcholine released at the frog neuromuscular junction, most likely by blocking voltage-dependent Ca2+ channels in the presynaptic terminal. However, it is also possible that enkephalin reduced Ca2+ entry indirectly, by increasing K+ conductance in the terminal. Nevertheless, it may be that met-enkephalin acts within the central nervous system by interfering with the K+- and/or Ca2+-dependent mechanism of GABA release (Figure 36.8). Decreased GABA levels are thought to initiate epileptogenic activity (Krnjevic 1980; Ribak et al. 1979). Enkephalins may inhibit the release of GABA by acting on central opiate receptors. Inhibition of GABA release by met-enkephalin was prevented by administration of naloxone (Brennan et al. 1980). Pretreatment with intracerebroventricular naloxone also prevented DAME from inducing changes in blood pressure and heart rate as well as producing seizure activity in conscious cats (Yukimura et al. 1981). Administration of intravenous naloxone after DAME reversed the effects of DAME on heart rate and blood pressure (Laubie et al. 1977). Naloxone (i.v.) had the same action on heart rate and blood pressure and either eliminated or depressed DAME-induced seizure activity in anesthetized cats in the experiments of Kraras et al. (1987) and Lathers et al. (1988). Thus, it may be that

Role of Neuropeptides in the Production of Epileptogenic Activity and Arrhythmias 587

enkephalins act on central opiate receptors to inhibit GABA release because the actions of these agents are blocked by opioid antagonists such as naloxone. Inhibition of GABA release in anesthetized cats produces increased sympathetic and parasympathetic neural outflow and the enhancement of central reflex–induced vagal bradycardia (DiMicco et al. 1979; Gillis et al. 1980). The resultant increased parasympathetic central outflow and enhancement of central reflex–induced vagal bradycardia via the enkephalin-induced inhibition of GABA release, as depicted in Figure 36.8, may explain the decrease in heart rate observed after the intracerebroventricular injection of DAME in the experiments of Kraras et al. (1987) and Lathers et al. (1988). The data of Gillis et al. (1980) suggested that an increase in blood pressure should occur in anesthetized cats after removal of the tonically active GABAergic system present in the brain. However, the intracerebroventricular injection of DAME in our experiments and the injection of DAME into the cisterna magna in anesthetized dogs (Laubie et al. 1977) to inhibit the release of GABA produced hypotension. We hypothesize that the unanticipated drop in blood pressure is due to the ability of the epileptogenic activity to produce autonomic dysfunction, as suggested by the studies of Lathers and Schraeder (1982) and Schraeder and Lathers (1983, 1989) and as indicated by the broken arrow in Figure 36.8. Altered central parasympathetic and sympathetic neural outflow may induce an imbalance within each division as well as an imbalance between both peripheral autonomic divisions that innervate the heart. This imbalance may result in the production of arrhythmia (Lathers et al. 1977, 1978) and/or sudden unexplained death (Carnel et al. 1985; Lathers and Schraeder 1982, 1987; Lathers et al. 1984, 1988; Suter and Lathers 1984). The cardiovascular effects of enkephalins in the central nervous system vary in a dose-dependent manner and according to the state of the animal, that is, conscious versus anesthetized. Met-enkephalin had no effect after intracerebroventricular injection in dogs anesthetized with alpha-chloralose; met-enkephalin has a half-life of several seconds and the lack of a visible effect may be due to its rapid inactivation. However, DAME, a synthetic analogue of met-enkephalin that is metabolically more stable than the natural peptide, produced prolonged hypotension and bradycardia in alpha-chloralose-Â�anesthetized dogs€when injected into the cisterna magna (Laubie et al. 1977). In alpha-Â�chloralose-Â�â•›anesthetized cats, the intracerebroventricular administration of DAME also produced a€ marked€ decrease in€blood pressure with a decrease in heart rate occurring in most animals (Kraras et al. 1987; Lathers et al. 1988). In contrast, a dose-dependent increase in blood pressure and heart rate was induced by administration of (d-Ala 2)met-enk in conscious cats (Schaz et al. 1980). Similar changes were reported by Yukimura et al. (1981) when they injected DAME intracerebroventricularly into conscious cats. Maximal increases in blood pressure occurred approximately 15 min before the greatest increase in heart rate. Blood pressure increased 20 min before the increase in heart rate occurred (Kraras et al. 1987; Lathers et al. 1988). The observation of differences in the physiological effects of DAME, depending on whether a conscious or anesthetized preparation is used, raises the question of whether the presence of the anesthetic agent alpha-chloralose explains the differences found in the two experimental models. Alpha-chloralose has been shown to be a good anesthetic agent for neurological studies because many reflexes, including the baroreceptors, are present and, in fact, enhanced (Clifford and Soma 1969). This anesthetic also causes minimal change in the amount of epinephrine present in the adrenal glands of cats and does not depress cardiac renal discharge (Clifford and Soma 1969; Cox et al. 1936). These data indicate

588 Sudden Death in Epilepsy: Forensic and Clinical Issues

that the baroreceptor mechanism was intact in the anesthetized animals receiving alphaÂ�chloralose and centrally administered DAME in the studies of Kraras et al. (1987), Lathers et al. (1988), and Laubie et al. (1977). The occurrence of epileptogenic activity in conscious cats began 5 min after the administration of (d-Ala 2)met-enk and ended before the changes in cardiovascular parameters (Schaz et al. 1980). Epileptogenic activity was also observed in anesthetized cats to which DAME was administered (Kraras et al. 1987; Lathers et al. 1988), although it began during the ἀrst several minutes after the administration of DAME and continued throughout the duration of the experiments. Because the epileptogenic activity began after the cardiovascular changes in the experiments of Schaz et al. (1980), they concluded that the epileptogenic activity was independent of the autonomic changes. However, there are studies that support the concept that autonomic cardiovascular changes may occur initially and be followed by the development of seizure activity. Indeed, seizure activity in patients was abolished when cardiac arrhythmias were eliminated with the insertion of pacemakers or with the initiation of antiarrhythmic agents (Schott et al. 1977). The possibility that cardiac arrhythmias may result in the development of seizure activity via impaired peripheral cardiac neural discharge going back to the central nervous system is depicted in Figure 36.8 by the heavy arrows beginning with arrhythmia. In addition, the studies of Lathers and Schraeder (1982) and Schraeder and Lathers (1983) found that epileptogenic activity may lead to cardiovascular dysfunction in animals and substantiate earlier observations made in humans. As early as 1941, Penἀeld and Erickson reported a patient with temporal lobe seizures and episodes of tachycardia. Additional studies by Mulder et al. (1954), Phizackerly et al. (1954), White et al. (1961), and Walsh et al. (1968) reported changes in the electrocardiogram in humans that were associated with epileptogenic activity. Thus, Figure 36.8 illustrates how epileptogenic activity may initiate an enhanced autonomic central neural outflow that impairs peripheral cardiac neural discharge and results in the production of arrhythmia. Further experiments are needed to determine whether enkephalins elicit epileptogenic activity and autonomic dysfunction in both conscious and anesthetized animal preparations. It will be important to determine whether enkephalins impair autonomic dysfunction via an inhibition of the release of GABA from the nerve terminal because delineation of this mechanism will allow the design of experiments to evaluate the ability of pharmacologic agents to prevent the enkephalin-induced epileptogenic activity and autonomic dysfunction. Suppression of progression to cardiac arrhythmias induced by the autonomic dysfunction should ultimately decrease the incidence of sudden unexplained death in the epileptic patient.

36.4â•… Summary Autonomic dysfunction, including arrhythmias, is often associated with epileptogenic activity. This study examines the potential role for enkephalins in this process. Brennan et al. (1980) reported a greater percentage of inhibition of K+-stimulated GABA release with increasing concentrations of met-enkephalin. Snead and Bearden (1980) found that leuenkephalin in the central nervous system may induce epileptogenic activity. In addition, DAME has been shown to produce a centrally mediated vasopressor response as well as attenuation of the baroreceptor reflex in conscious cats (Schaz et al. 1980) possibly leading

Role of Neuropeptides in the Production of Epileptogenic Activity and Arrhythmias 589

to autonomic imbalance. The latter may precipitate arrhythmias and be a contributor to sudden unexplained death in the epilepsy. Resolution of the question of whether enkephalins elicit epileptogenic activity and autonomic dysfunction via inhibition of GABA release is important because an understanding of this mechanism should eventually allow the design of pharmacologic agents to prevent the epileptogenic activity, autonomic dysfunction, and associated sudden death.

References Bixby, L., and C. Spitzer. 1983. Enkephalin reduces quantal content at the frog neuromuscular junction. Nature 301: 431–432. Brennan, M., R. C. Cantrill, and B. A. Wylie. 1980. Modulation of synaptosomal GABA release by enkephalin. Life Sci 27: 1097–1101. Bronk, D. W., R. Ferguson, and R. Margaria. 1936. The activity of the cardiac sympathetic center. Am J Physiol 117: 237–249. Carnel, S. B., P. L. Schraeder, and C. M. Lathers. 1985. The effect of phenobarbital pretreatment on cardiac neural discharge and pentylenetetrazol-induced epileptogenic activity. Pharmacology 30: 225–240. Clifford, D. H., and L. R. Soma. 1969. Feline anesthesia. Fed Proc 28: 1479–1499. Cox, W. V., M. E. Lewiston, and H. F. Robertson. 1936. The effect of stellate ganglionectomy on the cardiac function of intact dogs (and its effect on the extent of myocardial infarction and on cardiac function following coronary artery occlusion). Am Heart J 12: 285–300. DeBelleroche, J., and J. Bradford. 1972. Metabolism of beds of mammalian cortical synaptosomes: Response to depolarizing influences. J Neurochem 19: 585–602. DiMicco, J., K. Gale, B. L. Hamilton, and R. A. Gillis. 1979. GABA receptor control of parasympathetic outflow to heart: Characterization and brainstem localization. Science 204: 1106–1109. Elazor, F., E. Motles, Y. Elv, and R. Simantov. 1979. Acute tolerance to the excitatory effect of enkephalin microinjections into hippocampus. Life Sci 24: 541–548. Frenk, H., G. Urca, and J. C. Leibeskind. 1978. Epileptic properties of leucine- and methionineÂ�enkephalin: Comparison with morphine and reversibility by naloxone. Brain Res 147: 327–337. Gillis, R. A., J. DiMicco, D. Williford, B. L. Hamilton, and K. Gale. 1980. Importance of the CNS GABAergic mechanisms in the regulation of cardiovascular function. Brain Res Bull 5 (Suppl. 2): 303–315. Kraras, C. M., N. Tumer, and C. M. Lathers. 1987. The role of neuropeptides in the production of epileptogenic activity and autonomic dysfunction: Origin of arrhythmias and sudden death in the epileptic patient? Med Hypothesis 23: 19–31. Krnjevic, K. 1980. Principles of synaptic transmission. In Advances in Neurology, vol. 27, Antiepileptic Drugs: Mechanisms of Action, ed. G. Glaser, J. Penry, and D. Woodbury, 127. New York, NY: Raven Press. Lathers, C. M., and P. L. Schraeder. 1982. Autonomic dysfunction in epilepsy: Characterization of autonomic cardiac neural discharge associated with pentylenetetrazol-induced epileptogenic activity. Epilepsia 27: 633–647. Lathers, C. M., and P. L. Schraeder. 1987. Review of autonomic dysfunction, cardiac arrhythmias, and epileptogenic activity. J Clin Pharmacol 27: 346–356. Lathers, C. M., J. Roberts, and G. J. Kelliher. 1977. Correlation of ouabain-induced arrhythmia and nonuniformity in the histamine-evoked discharge of cardiac sympathetic nerves. J Pharmacol Exp Ther 203: 461–479. Lathers, C. M., G. J. Kelliher, J. Roberts, and A. B. Beasley. 1978. Nonuniform cardiac sympathetic nerve discharge: Mechanism for coronary occlusion and digitalis-induced arrhythmias. CirÂ� culation 57: 1058–1065.

590 Sudden Death in Epilepsy: Forensic and Clinical Issues Lathers, C. M., P. L. Schraeder, and S. B. Carnel. 1984. Neural mechanisms in cardiac arrhythmias associated with epileptogenic activity: The effect of phenobarbital. Life Sci 34: 1919–1936. Lathers, C. M., N. Tumer, and C. M. Kraras. 1988. The effect of intracerebroventricular d-Ala2 methiÂ� onine enkephalinamide and naloxone on cardiovascular parameters in the cat. Life Sci 43: 2287–2298. Laubie, M., H. Schmitt, M. Vincent, and G. Remond. 1977. Central cardiovascular effects of morphinomimetic peptides in dogs. Eur J Pharmacol 46: 67–71. Mulder, D. W., D. Daly, and A. A. Bailey. 1954. Visceral epilepsy. Arch Intern Med 93: 481–493. Nolte, J. 1981. Olfactory and limbic systems. In The Human Brain: An Introduction to Its Functional Anatomy, ed. J. Lotz, 304. St. Louis, MO: C. V. Mosby. Penἀeld, W., and I. C. Erickson. 1941. Epilepsy and Cerebral Localization, 320–362. Springἀeld, IL: Thomas. Phizackerly, P. J. R., E. W. Poole, and C. W. M. Whitty. 1954. Sinoauricular heart block as an epileptic manifestation: A case report. Epilepsia 3: 89–91. Ribak, C. E., A. B. Harris, J. E. Vaughn, and E. Roberts. 1979. Inhibitory GABAergic nerve terminals decrease at sites of focal epilepsy. Science 205: 211–214. Schaz, K., G. Stock, W. Simon, K. Schlor, T. Unger, R. Rockhold, and D. Ganten. 1980. Enkephalin effects on blood pressure, heart rate and baroreceptor reflex. Hypertension 2 (4): 395–407. Schott, G. D., A. A. McLeod, and D. E. Jewitt. 1977. Cardiac arrhythmias that masquerade as epilepsy. Br Med J 1: 1454–1457. Schraeder, P. L., and C. M. Lathers. 1983. Cardiac neural discharge and epileptogenic activity in the cat: An animal model for unexplained death. Life Sci 32: 1371–1382. Schraeder, P. L., and C. M. Lathers. 1989. Paroxysmal cardiovascular dysfunction and epileptogenic activity. Epilepsy Res 3: 55–62. Snead, O. C. 1983. Seizures induced by carbachol, morphine, leucine-enkephalin: A comparison. Ann Neurol 13: 445–451. Snead, O. C., and L. J. Bearden. 1980. Anticonvulsants speciἀc for petit mal antagonist epileptogenic effect of leucine enkephalin. Science 210: 1031–1033. Suter, L. E., and C. M. Lathers. 1984. Modulation of presynaptic gamma aminobutyric acid release by prostaglandin E2: Explanation for epileptogenic activity and dysfunction in autonomic cardiac neural discharge leading to arrhythmias? Med Hypothesis 15: 15–30. Urca, G., and H. Frenk. 1983. Intracerebral opiates block the epileptic effect of intracerebroventricular (I.C.V.) leucine-enkephalin. Brain Res 259: 103–110. Vindrola, O., M. Asai, M. Zubieta, and G. Linares. 1983. Brain content of immunoreactive (leu5) enkephalin and (met5)enkephalin after pentylenetetrazol-induced convulsions. Eur J Pharmacol 90: 85–89. Vindrola, O., M. Asai, M. Zubieta, E. Talavera, R. Rodriquez, and G. Linares. 1984. Pentylenetetrazol kindling produces a long lasting elevation of IR-met-enkephalin but not IR-leu-enkephalin in rat brain. Brain Res 297: 121–125. Walsh, G., W. Masland, and E. Goldensohn. 1968. Paroxysmal cerebral discharge associated with paroxysmal atrial tachycardia. Electroencephalogr Clin Neurophysiol 24: 187. White, P. T., P. Grant, J. Mosier, and A. Craig. 1961. Changes in cerebral dynamics associated with seizures. Neurology 11: 354–361. Yukimura, J., G. Stock, H. Stumpf, T. Unger, and D. Ganten. 1981. Effects of (d-Ala2)-methionineenkephalin in blood pressure, heart rate, and baro-receptor reflex sensitivity in conscious cats. Hypertension 3 (5): 528–533.

Sudden Epileptic Death in Experimental Animal Models Ombretta Mameli Marcello Alessandro Caria

37

Epilepsy is one of the most serious and most common neurological diseases. Although epidemiological studies provide evidence that 70–80% of patients who develop epilepsy go into remission after treatment, the remaining are often resistant to the common therapeutic treatments and continue to have seizures (Kwan and Sander 2004). In these patients, sudden unexplained epileptic death (SUDEP) is the most common cause of mortality related to seizures (Hauser et al. 1980; Neuspiel and Kuller 1985; Tennis et al. 1995; Nashef 1999; Nashef and Brown 1996; Leestma et al. 1997; Ficker et al. 1998; Annegers and Coan 1999; Sperling et al. 1999). The risk of SUDEP has been reported to be up to 24-fold greater than in the general population (Leestma et al. 1989; Nashef and Shorvon 1997; Schraeder et al. 2006), the overall incidence being 1:680, that is, 1:100 per year. Recent studies aimed at identifying the risk factors for SUDEP (Nilsson et al. 2001; Walczak et al. 2001; Opeskin and Berkovic 2003; Monte et al. 2007; Nashef et al. 2007) concluded that the most important risk factors are related to being a young adult male, having generalized tonic–clonic seizures, and lying in bed. Of great interest would be analysis of the results of autopsies that should be performed in all patients with a history of epilepsy according to a common standardized protocol for detailed macro- and microscopic analysis of the brain, the autonomic nervous system, the lungs, and the heart. Comparison of the incidence estimates for SUDEP is difficult. In fact, evidence for epileptic seizures immediately before death is reported in 24–80% of patients (Leestma et al. 1997; Langan et al. 2000). Furthermore, not all patients have postmortem examinations. Case ascertainment methods and source populations have varied, and different deἀnitions of SUDEP have been used (Tomson et al. 2005). To clarify this matter and drawing on the opinions of several specialists, SUDEP has been deἀned as a “sudden, unexpected, witnessed or unwitnessed, nontraumatic, and non drowning death in patients with epilepsy, with or without evidence of a seizure, and excluding documented status epilepticus, in which postmortem examination does not reveal a toxicological or anatomical cause of death” (Nashef 1997). Different physiopathological events may contribute to SUDEP, and its genesis is probably multifactorial and includes cardiac arrhythmias induced by epileptic seizures (Nei et al. 2000), neurogenic pulmonary edema (Smith and Matthay 1997), respiratory failure (O’Regan and Brown 2005), and asphyxia (Johnston et al. 1995). In a systematic report of patients undergoing simultaneous EEG and ECG monitoring for temporal lobe epilepsy, the most common ἀnding was sinus tachycardia, occurring in 92% of recordings (Blumhardt et al. 1986). Bradycardia was seen in only 4% of patients. Whether these arrhythmias are primary or secondary to other phenomena, including respiratory changes, is unknown. A recent review by Lathers et al. (2008) extensively analyzed the overlapping mechanisms that may enhance the risk of SUDEP in epilepsy and in cardiac disease. 591

592 Sudden Death in Epilepsy: Forensic and Clinical Issues

Cardiac arrhythmias during both seizures and interictal activity may result in heart failure caused by complete atria-ventricular conduction block (Wilder-Smith 1992). In a reported case of a patient with epilepsy who died unexpectedly while undergoing cardiac monitoring, a nonreversible malignant ventricular arrhythmia occurred, indicating that it was the likely arrhythmogenic cause of SUDEP (Dasheiff and Dickinson 1986). Respiratory complications such as obstruction of air pathways, central apnea, neurogenic pulmonary edema, and metabolic impairments are probably concurrent ἀnal events (Tomson 2000). However, the precise role of these factors in the pathogenesis of SUDEP has yet to be clariἀed despite a number of possibilities examined by epidemiological studies. A signiἀcant contribution to better understanding of the physiopathological mechanisms involved in SUDEP and experimental conἀrmation of clinical observations in human beings has been inferred from basic research studies in animals. Among the hypotheses explored is the involvement of the autonomic nervous system, as seizures may be preceded by autonomic symptoms that are also evident during seizure evolution (Venit et al. 2004; Johnson and Davidoff 1964; Lathers 1990; Lathers and Schraeder 1987; Lathers et al. 1987; Schraeder and Lathers 1983, 1989; Kalviainen et al. 1990; Toichi et al. 1998; Freeman 2006; Sathyaprabha et al. 2006). This fact may be dependent on the propagation of electric activity from the epileptic focus to the autonomic centres (Van Buren 1958). From the analysis of heart rate variability in humans, about 30 s before seizures begin, a signiἀcant reduction of parasympathetic tone along with a signiἀcant increase of sympathetic activity occurs (Novak et al. 1999). On the other hand, during epileptic convulsions in both animals (Doba et al. 1975; Benowitz et al. 1986) and humans (Smith and Matthay 1997), elevations of epinephrine and norepinephrine to potentially arrhythmogenic levels have been documented. However, although few cases of potentially fatal arrhythmias have been recorded in humans with epilepsy (Phizackerley et al. 1954; Liedholm and Gudjonsson 1992), the bulk of electrocardiographic recordings during seizures shows nothing more malignant than sinus tachycardia. In fact, some clinical studies conclude that ventricular arrhythmias are no more common in epileptic than in nonepileptic patients (Keilson et al. 1987). Early studies in a variety of species demonstrated that cardiac arrhythmias could be induced by stimulation of a number of areas in the diencephalon, mesencephalon, and medulla (Allen 1931; Dikshit 1934; Van Bogaert 1936; Boeles et al. 1957; Purpura et al. 1958; Fuster and Weinberg 1960; Weinberg and Fuster 1960; Manning and Peiss 1960; Parker et al. 1962; Ueda 1962; Attar et al. 1963; Melville et al. 1963; Hockman et al. 1966; Gunn et al. 1968; Hall et al. 1974; Lisander et al. 1975; Evans and Gillis 1974, 1978; De Riu 1983; McCown et al. 1984) and may be prevented by cooling the vagus nerve and even by ablation of the stellate ganglia (Manning and Peiss 1960). These experiments helped to clarify the autonomic and reflex mechanisms mediating the post-stimulation-induced arrhythmias elicited by brain stimulation and may explain the autonomic disturbances described in epileptic patients. Pathological studies have raised questions about arrhythmia as the cause for epileptic sudden death. Lathers and Schraeder (1982) and Schraeder and Lathers (1983) developed an experimental model of generalized epilepsy in the cat that used pentylenetetrazol to explore the hypothesis that an altered autonomic function may be one cause for unexplained sudden epileptic death. Their studies showed for the ἀrst time that altered sympathetic and parasympathetic cardiac neural discharges preceded the cardiac arrhythmias that occurred with the development of interictal activity and worsened with increasing degrees of ictal activity. An imbalance within and between sympathetic and parasympathetic cardiac

Sudden Epileptic Death in Experimental Animal Models

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neural discharges was found to be associated with a signiἀcant disruption of the physiological relationships between heart rate and blood pressure. All animals died after 2000 mg/kg pentylenetetrazol of cardiovascular failure, asystole, or ventricular ἀbrillation. The authors concluded that these cardiac arrhythmias could be a major contributing factor in SUDEP even in those patients who showed only interictal spikes at the time of death and thus did not have overt seizure activity. Their hypothesis was consistent with that of Han and Moe (1964) who demonstrated that cardiac sympathetic disturbances secondary to direct sympathetic nerve stimulation increased temporal dispersion of recovery of ventricular excitability and led to an underlying electrical instability that predisposes the ventricular myocardium to arrhythmia. However, other studies showed that pretreatment with phenobarbital induced a delay of onset of paroxysmal activity, without, however, showing protective effects on the associated autonomic neural changes once the epileptiform discharges were established (Lathers et al. 1984; Carnel et al. 1985). Similar results have been also obtained in rats with epilepsy induced by pilocarpine (Colugnati et al. 2005). The cardiac sympathetic nerves are more often activated by epileptogenic events than are the cardiac parasympathetic nerves, with tachyarrhythmias being far more common clinically than epileptogenic bradycardia (Schernthaner et al. 1999; Leutmezer et al. 2003). Despite these observations, some evidence suggests that epileptogenic activation of the cardiac parasympathetic nerves, which is revealed by ictal bradyarrhythmias or cardiac asystole, might be involved in causing sudden death of epileptic patients (Nashef et al. 1996; Fuhr and Leppert 2000; Weinstein and Albertario 2000; Kelly et al. 2001; Seeck et al. 2001; Tinuper et al. 2001; Mondon et al. 2002). Preganglionic cardiac parasympathetic neurons are primarily located in the nucleus ambiguous and in the dorsal motor nucleus of the vagus; these neurons participate in the control of heart rate and other cardiac functions (Izzo et al. 1993; Standish et al. 1994; Standish et al. 1995; Taylor et al. 1999). Little is known about the ἀring pattern of preganglionic cardiac parasympathetic neurons during an epileptic attack. In a recent study (Wang et al. 2006), a fluorescent tracer was injected into the cardiac sac of newborn rats for retrograde labeling of the parasympathetic neurons in the nucleus ambiguous. Fluorescence-labeled NA neurons were further examined using a whole-cell patch-clamp method in medulla slices with a respiratory-like rhythm, and neurons with an inspiratory-related increase of the mixed inhibitory synaptic activity were identiἀed as preganglionic cardiac parasympathetic neurons. The authors demonstrated that blockade of the GABAergic and the glycinergic receptors in medulla slices evoked intermittent seizure-like ἀring (synchronized intensive firing of a mass of neurons) in the preganglionic cardiac parasympathetic neurons under a current-clamp conἀguration and evoked intermittent excitatory inward currents under a voltage-clamp conἀguration. Results of this study, therefore, provided new evidence that preganglionic parasympathetic neurons might ἀre in a seizure-like pattern of activity (Wang et al. 2006). Therefore, during an epileptic attack, these neurons may be responsible for neurogenic ictal bradyarrhythmias, cardiac asystole, or even sudden death in epileptic patients. Convulsive seizures triggered by maximal electroshock also induced a severe disruption of cardiac rhythm in rats. In particular, in the immediate postictal state, marked cardiac arrhythmia often appears, the duration of which relates to the seizure activity (Darbin et al. 2003). These data seem to support the hypothesis that cardiac arrhythmias may be an important risk factor for SUDEP in epileptic patients (Oppenheimer et al. 1990), although in the opinion of several clinicians, the role in human SUDEP remains uncertain (Keilson et al. 1987).

594 Sudden Death in Epilepsy: Forensic and Clinical Issues

Animal models of generalized epilepsy do not help, however, to localize the cortical structures that spread paroxysmal stimulation to forebrain areas involved with cardiovascular regulation that are able to desynchronize sympathovagal cardiac neural ἀring and possibly induce SUDEP. Furthermore, a few studies during human brain surgery have investigated the cardiovascular effect of cortical stimulation. In this regard, stimulation of the cingulate gyrus, tips of the temporal lobes, and orbitofrontal cortex induced both pressor and depressor responses (Chapman et al. 1949; Pool and Ransohoff 1949; Chapman et al. 1950; Delgado 1960), and more recently, superἀcial insular stimulation in patients undergoing surgery for intractable epilepsy-induced cardiovascular changes (Oppenheimer et al. 1991). Emotional stress has been shown to increase the frequency and the severity of ventricular ectopic beats in patients with or without ischemic cardiac disease, suggesting a role for cortical regions connected with the limbic structures (Lown et al. 1976; Lown and DeSilva 1978; Taggart et al. 1973; Lathers and Schraeder 2006). Experimental results in animals showed an area of cardiac representation within the posterior conἀnes of the rat€insular cortex (Oppenheimer and Cechetto 1990), in an area known to have profuse reciprocal connections with the limbic system (Zhang and Oppenheimer 2000). Using a novel technique of phasic microstimulation linked to the R wave of the ECG, Oppenheimer and Cechetto (1990) ἀrst€demonstrated a cardiac chronotropic map of the insula. They identiἀed sites generating pure tachycardia independent from other autonomic or respiratory effects within the rostral posterior insula. More caudal sites within this region generated bradycardia after phasic microstimulation. Moreover, prolonged phasic microstimulation within the rat insular cortex resulted in bradyarrhythmia, complete heart block, QT interval prolongation, ventricular ectopy, and asystolic death (Oppenheimer et al. 1991). These parasympathetic arrhythmias were accompanied by elevated plasma norepinephrine levels, increased sympathetic tone and myocytolisis, a form of cardiac damage of sympathetic neural origin, and subendocardial hemorrhages. On the other hand, left anterior insular damage by stroke is associated, in some patients, with signiἀcant tachyarrhythmias, and in the rat with a reduction in baroreflex sensitivity and resulting parasympathetic tone (Oppenheimer et al. 1996; Zhang et al. 1998). The rat insula receives taste information and gastrointestinal stimuli, respiratory afferents, and chemoreceptor and cardiovascular inputs organized in a viscerotopic fashion. This area has reciprocal connections with the parabrachial nucleus, the contralateral insula, adjacent cortical regions, the infralimbic cortex, the thalamus, the lateral hypothalamic area, and the amygdala. Evidence exists for lateralized effects, although nonmyelinated transcallosal pathways (both inhibitory and excitatory) linking the cardiovascular regions of the two insulae have been recently described (Zhang and Oppenheimer 2000). The left insular cortex is involved in the regulation of the vagal cardiac parasympathetic neuronal pool, and the right insular cortex regulates sympathetic neurones involved in the regulation of cardiac function and in the control of vascular resistance and blood pressure. This structure may therefore play a crucial role in brain–heart interaction and perhaps even additionally by its direct and reciprocal ipsilateral connections with the amygdala. The amygdala represents an important central cardiovascular control structure within the limbic system because it seems to provide the neural basis for cardiovascular responses to stressful stimuli (Cheung et al. 1997). In agreement with this latter consideration, preemptive low-frequency sine wave stimulation of amygdala-kindled animals induced a dramatic decrease in the incidence of stage 5 seizures in fully kindled

Sudden Epileptic Death in Experimental Animal Models

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animals, demonstrating the possibility that low-frequency sine wave stimulation may be an effective therapy for prevention of seizures in patients with epilepsy (Goodman et al. 2005). The amygdala is a nucleus of the temporal lobe, showing complex interconnections with multiple cortical and brainstem regions involved in the production of autonomic temporal lobe epilepsy. An altered postganglionic cardiac sympathetic innervation that may increase the risk of cardiac abnormalities and/or SUDEP has been described in patients with chronic temporal epilepsy (Druschky et al. 2001). In fact, after temporal lobe epilepsy surgery, a reduction of sympathetic cardiovascular modulation has been demonstrated (Hilz et al. 2002). In a rat kindled seizure model, in which paroxysmal activity is similar to that described during secondary spontaneous seizures, amygdala involvement has been demonstrated in seizure-related autonomic disturbances that involved both branches of the autonomic nervous system (Goodman et al. 1990, 1999). Changes in heart rate and blood pressure were observed during amygdala-kindled seizures, but they were apparently independent of the kindling stimulus because they did not appear at the beginning of the kindling process. On the other hand, microdialysis experiments in conscious kindled rats showed decreases in extracellular concentrations of noradrenaline and dopamine levels in the dorsomedial nucleus of the hypothalamus (Goren et al. 2003), suggesting that autonomic changes in kindling require further studies to explain their relationship to SUDEP. Instead, after insular involvement by ischemic stroke or excitatory injury, increased immunostaining for neuropeptide Y, leucine-enkephalin, dynorphin, and neurotensin was seen in the amygdala of the damaged side (Allen et al. 1995; Cheung and Cechetto 1995; Cheung et al. 1995). Because these neurochemical changes in the amygdala were greatest 3 days after ischemic stroke and subsided by 10 days (Cheung et al. 1995), it can be hypothesized that they participate in mediating the cerebrogenic cardiovascular disturbances originating from the insula. The role of neuropeptides in the origin of arrhythmias and SUDEP in epileptic patients has been analyzed in some studies, and the results suggested that prostaglandin E2 and enkephalins may play a signiἀcant role in the genesis of autonomic dysfunction associated with seizure activity and cardiac arrhythmias (Suter and Lathers 1984; Kraras et al. 1987; Lathers et al. 1985, 1988; Lathers 1990; Schwartz and Lathers 1990). In rats, pentylenetetrazol kindling produces a long-lasting elevation of IR-Met-enkephalin in the septum, hypothalamus, amygdala, and the hippocampus after convulsions (Walczak et al. 2001) and is associated with a signiἀcant inhibition of potassium-stimulated GABA release (Brennan et al. 1980). The enkephalins may elicit epileptogenic activity and autonomic dysfunction by inhibiting GABA release. This possibility has been recently conἀrmed by a study in mice showing that a selective cyclooxygenase-2 inhibitor potentiates the anticonvulsant activity of tiagabine against pentylenetetrazol-induced convulsions (Dhir and Kulkarni 2006). Pathological studies in cases of SUDEP have raised questions about pulmonary complications, as autopsies in patients who died from epileptic sudden death revealed pulmonary edema (Terrence et al. 1981; Leestma et al. 1989; Earnest et al. 1992). In anesthetized and ventilated animals, Johnston et al. (1996) showed elevated left atrial and pulmonary vascular pressures that represent a possible mechanism for the pulmonary edema found in patients who have died from SUDEP. However, the pulmonary edema alone does not appear to be fatal because lung congestion requires some time to develop. In an interesting model of SUDEP in which pulmonary edema and sudden death were generated (Johnston et al. 1995), the authors suggested that arrhythmia was not an important

596 Sudden Death in Epilepsy: Forensic and Clinical Issues

factor in SUDEP as they demonstrated a primary role for hypoventilation in the etiology of epileptic sudden death. Their model of SUDEP used chronically monitored unanesthetized sheep with generalized tonic–clonic status epilepticus induced by bicuculline. Some animals died within 5 min after the induction of seizures, although no signiἀcant differences were found in the epileptic activity, in arrhythmias, and in plasma epinephrine and norepinephrine concentrations compared to the group living the longest. Furthermore, in no instance could the death of an animal be ascribed to a malignant rhythm. On the contrary, marked differences in ventilation were found between those convulsing animals that died suddenly and those that survived. A sudden drop in pO2, a marked elevation in pCO2, and a decline in arterial blood pH were observed in animals that died, whereas animals that survived maintained ventilation and oxygenation at levels close to baseline. Hypoventilation in these experiments, probably centrally induced and indistinguishable from apnea, was independent of preterminal arrhythmias or hypotension and was proposed as the cause of death. In agreement with this experimental ἀnding, hypoventilation and central apnea have been documented in several patients with seizures (Nashef and Shorvon 1997) or after stimulation involving various elements of the limbic system (Nelson and Ray 1968). However, in these experimental animals, respiratory function was not directly measured so that central and obstructive hypoventilation could not be distinguished. Extending their studies, Johnston et al. (1997) monitored awake epileptic sheep with tracheostomies that allowed measurements of airway flow and prevented upper airway obstruction. These experiments proved that central apnea and hypoventilation were causes of death in the sheep. Endogenous opioids that may be released during seizures have been implicated in the pathogenesis of this central hypoventilation (Ramabadran and Bansinath 1990) and could well account for the suppression of respiratory drive, although why this should happen is unclear (Darnell and Jay 1982). Changes in respiratory-modulated neural activities, consistent with obstructive and central apnea, have been conἀrmed during seizures in an in situ anesthetized rat preparation (St. John et al. 2006). This preparation has an advantage over in vivo preparations in that delivery of oxygen to the brain is not dependent on the lungs or the cardiovascular system. The EEG activity was recorded, as was activity of the hypoglossal, vagus, and phrenic nerves. The hypoglossal and vagus nerves innervate muscles of the upper airway and larynx, and the phrenic nerve innervates the diaphragm. Seizures were elicited by injections of penicillin into the parietal cortex or the carotid artery. Results showed that after elicitation of the seizures, activity of the hypoglossal and vagal nerves declined greatly, whereas phrenic activity was slightly affected. The authors concluded that such a differential depression of activity of nerves of the upper airway and larynx compared to that of the diaphragm would predispose to obstructive apnea in intact preparations. Moreover, given more time, even the activity of the phrenic nerve declined or ceased, resulting in changes that are known to characterize central apnea. The major conclusion of this study is that seizures may result in recurrent periods of obstructive and central apnea that may account for SUDEP. Recently, severe postictal laryngospasm, as observed in a patient with refractory epilepsy during monitoring, has been described as a potential mechanism for SUDEP (Tavee and Morris 2008). Partial seizures may be associated with prominent oxygen desaturation and ictal ventilatory dysfunction, which could play a role in certain cases of SUDEP in adult patients (Blum et al. 2000). Experimental studies conducted in DBA/2 mice that exhibit sudden death due to respiratory arrest (Collins 1972; Willott and Henry 1976) in the period

Sudden Epileptic Death in Experimental Animal Models

597

immediately after audiogenic seizure have shown that oxygenation prevents sudden death (Venit et al. 2004). The function of respiratory neurons is largely controlled by speciἀc neurotransmitters, among which serotonin has been implicated as modulating respiratory responses to hypoxia (Feldman et al. 2003; Mitchell et al. 2001). However, serotonin receptors have also been implicated in the modulation of seizures (Browning et al. 1997; Pericic et al. 2005) and serotonin agents (fluoxetine) reduced respiratory arrest in DBA/2 mice at doses that did not reduce seizure severity (Tupal and Faingold 2006). The physiopathological mechanisms of SUDEP have also been analyzed in a series of studies on focal epilepsy induced in hemispherectomized rats. In this experimental animal model, independent of cerebral cortex influence, cardioarrhythmogenic triggers may be activated by paroxysmal activity focally induced at hypothalamic, midbrain, and hindbrain levels by topical application of penicillin G (Mameli et al. 1988, 1990). The cardioarrhythmogenic potential of these epileptic foci decreased in the rostrocaudal direction; being more relevant the cardiovascular impairments observed as a consequence of the hypothalamic epileptic focus ἀring, particularly during simultaneous coactivation of the mesencephalic focus (Mameli et al. 1993). Cardiovascular impairments were characterized by sinus bradyarrhythmias, alterations of the repolarization and atriaventricular blocks of different degrees, and signiἀcant decreases in systolic blood pressure (Mameli et al. 1988, 1989, 1990, 1993) temporally correlated to a signiἀcant increase in spontaneous vagal nerve activity. The cardiac arrhythmias became life-threatening when blood gases and electrolytic parameters were simultaneously impaired (Mameli et al. 2001). However, when paroxysmal activity ended, the cardiovascular alterations always disappeared, and vagal nerve ἀring returned to basal values. This demonstrated that in supported ventilation, and in the absence of metabolic derangements, the cardioarrhythmogenic trigger activation was not sufficient to explain SUDEP. These experiments suggested to the authors that fatal evolution consequent to heart impairment was probably related not only to cardiac dysfunction of autonomic origin but also to concomitant metabolic derangement that most likely shared the same genesis. Further experiments, performed using the same experimental animal model, tested the existence of pulmonary complications during the activation of the central cardioarrhythmogenic triggers (Mameli et al. 2006). In the hemispherectomized and artiἀcially ventilated animals, the following parameters were simultaneously analyzed before, during, and after epileptic foci induced both at hypothalamic and mesencephalic levels: spontaneous electrical activity of the hypothalamic neurons, electrothalamogram, spontaneous multiunit vagal nerve ἀber activity, systemic artery blood pressure, pulmonary artery blood pressure, dynamic ECG, and blood gas analysis (pO2, pCO2, bicarbonate, sodium, potassium, Hgb concentrations, pH value, O2% saturation, and bases excess). Metabolic derangements developing throughout the experiment were not purposely adjusted, and only body temperature was kept constant. This study showed that after hypothalamic epileptic focus and mesencephalic epileptic foci, the paroxysmal activity induced, within a short latency, a signiἀcant increase of spontaneous vagal nerve ἀring that was strictly correlated to ECG impairments such as wandering pacemaker, biphasic or negative P waves, extrasystolia, A-V blocks, derangement of A-V conduction and recovery phase, bundle branch blocks, bradyarrhythmias, flattened T waves, and hypotension. Together with a parasympathetic hypertonicity, a concomitant functional imbalance of the orthosympathetic division also developed. When paroxysmal activity began, despite that vagal activity signiἀcantly increased and corresponding bradycardia was expected, heart rate remained around its basal value, sometimes even

598 Sudden Death in Epilepsy: Forensic and Clinical Issues

showing a tendency to increase (Figure 37.1c). Under the same circumstances, supraventricular and ventricular extrasystoles and ventricular complexes of high voltage appeared concomitantly, which also strongly suggested a possible increase in cardiac inotropism that was dependent on orthosympathetic involvement (Figure 37.2d). In the surviving animals (approximately 75%), when paroxysmal activity ended, vagal nerve activity and cardiovascular parameters returned to basal conditions. Macro- and microscopic examination of their lungs never showed any alterations of pulmonary parenchyma, pulmonary vessels, or the bronchial tree. In the deceased animals (approximately 25%) that had manifested interictal and ictal activity, spontaneous vagal nerve ἀring showed similar electrophysiological features, as well as a time course that overlapped the one observed in animals that survived. However, as previously observed (Mameli et al. 2001), the occurrence of cardiac arrhythmias was always accompanied by hyperkalemia and other metabolic derangements, followed by death, which occurred after 3 to 4 h of paroxysmal activity (Figures 37.1 and 37.2). Systemic hypotension was accompanied by signiἀcant pulmonary hypertension, similar to what was described by Johnston and coworkers (1996) in sheep, that further worsened during ictal activity (50% increase). Postmortem macroscopic examination of the lungs demonstrated no relevant alterations in any case. However, histological preparations demonstrated a slight alveolar and perivascular edema in the subinterstitial spaces of the arterial vessels and a concomitant edematous inἀltration in the alveolar and bronchial spaces. Finally, the bronchial tree was ἀlled with considerable intraluminal mucous secretions. Comparison between surviving and deceased animals during ictal activity showed signiἀcant differences in the deceased animals in heart rate, systolic and diastolic pressures, pulmonary artery pressure, potassium and bicarbonate concentrations, pH value, pO2, and pCO2. Regarding the pattern of ECG impairment, during interictal activity, no signiἀcant differences were observed, whereas during ictal activity, signiἀcant differences were observed in the incidence of sinoatrial blocks, bundle branch blocks, and T-wave impairment. In addition, signiἀcant differences were found in the histological patterns of the lungs, which were most likely caused by a state of pulmonary hypertension concomitant with paroxysmal activity and parasympathetic overflow (Figure 37.3). In the opinion of Mameli et al. (2001), a possible explanation of this observation was that at the level of the respiratory apparatus, the paroxysmal activity triggered an increase of the parasympathetic tone, inducing bronchoconstriction and increased mucous secretion. Bronchoconstriction determined, in turn, a reduction of alveolar ventilation with a consequent fall in pO2 as conἀrmed by blood gas data. Furthermore, the decrease in pO2 could have triggered a reflex constriction of pulmonary vessels. Although the mechanism of this phenomenon is still unknown, it is possible that it is induced by a local reflex whose functional signiἀcance is to shunt blood flow from hypoventilated to normally ventilated zones. In the deceased animals, the parasympathetic hypertonicity prejudiced the normal ventilation of the pulmonary parenchyma, although the animals were artiἀcially ventilated. The parasympathetic hypertone caused, therefore, a hypoxic condition that probably extended to the entire lung and in turn caused a reflex vessel constriction and pulmonary artery blood pressure increase. Pulmonary hypertension then resulted in perivascular edema and the edematous inἀltration in the alveolar and bronchial spaces observed in histological preparations (Mameli et al. 2006). Disruption of pulmonary function has been repeatedly reported both in animal and in human epilepsy (Nelson and Ray 1968; Terrence et al. 1975; Bayne and Simon 1981; Harper et

Sudden Epileptic Death in Experimental Animal Models

599

B

A 1

28583 counts

300

2

19724 counts

300

(Scale = 46.22 s/div)

(Scale = 46.22 s/div)

3

C

D

1

56372 counts

38374 counts 300

300

2

3

(Scale = 46.22 s/div)

(Scale = 46.22 s/div) a b c d

Figure 37.1╇ Simultaneous recordings of spontaneous vagal nerve activity and ECG in a deceased animal. Trace 1: spontaneous electrical activity of multiunit vagal nerve fibers recorded using tungsten in glass electrodes. Trace 2: frequency distribution histograms of the same activity constructed during 231.1 s analysis. Trace 3: electrocardiogram. All the events were simultaneously recorded in basal conditions (a) and after the activation of hypothalamic epileptic focus and mesencephalic epileptic foci at 60 (b), 120 (c), and 130 min (d), respectively. Traces a–d: impairment of the ECG, 130 min after hypothalamic epileptic focus and mesencephalic focus induction. The concomitant imbalance of the orthosympathetic function can be indirectly inferred by analyzing the parasympathetic activity. In fact, despite a reduction in vagal nerve firing (b) compared to basal values (a), heart rate did not increase and ventricular extrasystoles appeared. On the other hand, when the vagal nerve firing markedly increased (c) and a corresponding bradycardia was expected, the heart rate also remained unaffected. Bradyarrhythmias appeared only after 130 min of epileptic foci activity. (From Mameli, O., et al., Seizure, 10 (4), 269–278, 2001. With permission.)

600 Sudden Death in Epilepsy: Forensic and Clinical Issues A

1

B

2

3 2547 counts

100

5816 counts

100 50 50

50 4

(Scale = 45.15 s/div)

(Scale = 45.15 s/div)

5

C

D

1 2

3 100

9225 counts

11322 counts

50

50 4

100

(Scale = 45.15 s/div)

(Scale = 45.15 s/div)

5 (Scale = 500.9 ms/div)

Figure 37.2╇ Simultaneous recordings of electrothalamogram, vagal nerve firing, and ECG in

a deceased animal. Trace 1: electrothalamographic signals were recorded using a pair of silver ball electrodes positioned on the thalamic surface. Recordings were performed with a Grass 7P5 and 7DA polygraph. Trace 2: the same event simultaneously analyzed by a computer (Tecfen Computer Scope Analysis ISC-16 software). Trace 3: spontaneous electrical activity of multiunit vagal nerve fibers. Trace 4: frequency distribution histograms of the same activity during 231.1 s analysis. Trace 5: Electrocardiogram. All the events were simultaneously recorded in basal conditions (a) and after the activation of both hypothalamic epileptic focus and mesencephalic epileptic foci at 40 (b), 60 (c), and 120 min (d), respectively. The concomitant imbalance of the orthosympathetic division is shown by the appearance of ventricular complexes of high voltage (c–d). (From Mameli, O., et al., Seizure, 10 (4), 269–278, 2001. With permission.)

Sudden Epileptic Death in Experimental Animal Models

601

al. 1984; James et al. 1991; Graham 1992; Hanning and Alexander-Williams 1995) to worsen the neurogenic arrhythmias, together with metabolic impairment. In agreement with the observations in sheep (Johnston et al. 1996, 1995, 1997), the ἀndings obtained in hemispherectomized rats (Mameli et al. 1988, 1989, 1990, 1993, 2001, 2006) showed that when considered alone, neurogenic arrhythmias are insufficient to cause the animals’ death. However, it is not clear why, given that the same experimental protocol was applied to all animals, only some of these developed clinical symptoms so severe that survival was unfailingly compromised. Because paroxysmal activity involved the same cerebral structures, it seems difficult to hypothesize that activation of a fatal trigger responsible for animal death acts only in some animals. A more convincing hypothesis to explain these ἀndings could be the existence of animals characterized by a low threshold of excitability, whose central structures are unable during epileptic seizure to maintain a balanced ratio between sympathetic and parasympathetic activities. In particular, orthosympathetic activation could paradoxically synergize the vagal influence on heart activity and transform a serious, but reversible, cardiac bradyarrhythmia into a fatal event. This hypothesis coÂ�Â� incides with the ἀnding of increased concentrations of circulating catecholamines during epileptic seizures to potentially arrhythmogenic levels in both animals (Johnston et al. 1995; Doba et al. 1975; Benowitz et al. 1986) and human beings (Simon et al. 1984). At a peripheral level, in the animals with a low threshold of excitability, these high epinephrine levels could activate the alpha-membrane receptors that are responsible for cellular potassium depletion (Williams et al. 1984) at muscular cell levels (Mauger et al. 1982), with a consequent increase in their plasma concentration. Stimulation of alpha-receptors impairs extrarenal potassium disposition, a speciἀc effect that can be reversed by alpha-blockade (Williams et al. 1984). Although alpha-receptor stimulation is known to account for a transient release of hepatic potassium reserves in response to an epinephrine infusion, an effect that occurs within minutes and lasts briefly (Craig and Mendell 1959; Ellis 1956; Vick et al. 1972; Sterns et al. 1981; Giugliano et al. 1979; Guerra and Kitabchi 1976; DeFronzo et al. 1980; Minaker and Rowe 1982), a sustained effect may be observed in a continuous stimulation, as occurs during seizures. Therefore, these effects on potassium availability probably result from a decreased net cellular uptake of potassium, which depends on an enhanced alpha-adrenergic activity in those animals with a low threshold of excitability. This condition would have worsened the vagal-mediated cardiac arrhythmias to a point capable of inducing their fatal evolution into SUDEP. The short latency of hyperkalemia observed in the deceased animals (Mameli et al. 2001, 2006) seems to support this hypothesis and provides evidence for a likely neurogenic extrarenal origin of the phenomenon. Further evidence is suggested in these experiments by the appearance of sharpened T waves that were always related to the increased potassium plasma concentration. These results agree with the severe changes in potassium plasma concentrations detected during generalized seizures in adolescent baboons (Mello et al. 1993). Finally, extending the above considerations to human epilepsy, it can be postulated that patients with a low threshold of excitability may also exist. In these subjects, the cardioarrhythmogenic triggers, activated by hypothalamic and mesencephalic epileptic foci (hypothalamic epileptic focus and mesencephalic focus), may represent the ἀnal common pathway of a storm of signals originating at the level of cortical epileptic foci. In fact, the extensive neural connections, originating in the cerebral cortex and particularly in the frontal and temporal lobes, converge on hypothalamic and brain stem structures (Papez

602 Sudden Death in Epilepsy: Forensic and Clinical Issues 350 300

(a)

250

Basal conditions

200

p = ns

150 100

Surviving Deceased

Deceased

ASP

ADP

PAP

MUAV

HEF -MEF

121±9.8

80±4.5

13.3±1.4

22.88±4.9

0.0

335.1±10.9

121.34±8.4

82±10

14.58±1.8

19.4±6.5

0.0

Na

+

HCO -

pH

pO2

pCO2

Hb

136.4±4.5

3.45±0.44

27.36±3.3

7.38 ±0.16

93.1±10.3

40.6±3.1

14.9±3.4

136 ±6

3.6±0.4

29.2±2.8

7.39±0.6

95 ±4

40.5 ±2

14.6 ±3.7

K

3

Hb

pCO2

pO2

pH

3

K+ HCO-

Na+

MUAV

HEF-MEF

HR

336.2±17.5

+

Surviving

ADP

t test

PAP

HR

0

ASP

50

350 300

(b) Interictal activity

p < 0.005

250

*

200 150

*p = ns

*

100

*

Surviving Deceased

Surviving Deceased

HR 325±4.3 238.3±43.7

ASP 114.5±5.8 109.3±6.9

ADP 76.6±4.6 64.4±5.3

MUAV 156.7±7 159.9±50.4

PAP 11.2±4.4 20.7±3.6

Hb

pCO2

pH

pO2

K+ HCO-3

Na+

MUAV

*

HEF-MEF

ADP

PAP

HR

0

ASP

50

HEF -MEF 0.097±0.02 0.102± 0.17

Na+

K+

pH 7.40±0.09

pCO2

3.59±0.24

HCO3-26.09±3.4

pO2

137.3±2.4

92.1±7.7

41.7±1.5

Hb 15.1±1.3

135 ±0.6

7.2±1.8

25.8 ±1.9

7.20±0.17

66.7±9.1

44.8 ±3.6

15.5 ±0.9

450 * 400 Figure 37.3╇ Main metabolic, cardiovascular, and respiratory parameters determined in (a) 350 = ns basal conditions and during (b) interictal and (c) ictal activities in surviving and*pdeceased ani300 + (c) p < 0.005 mals. All values are expressed as means ± standard deviation. Sodium (Na ), potassium (K+), 250 − bicarboÂ�nateIctal (HCO as milliequivalent per liter. Hemoglobin (Hb) activity 3 ), and pH values are expressed 200 values are expressed as grams per milliliter. arterial systolic (ASP), 150 pO2 and pCO2 pressures, * arterial dystolic pressures (PAP) are expressed as millimeters of * t test (ADP), and pulmonary artery 100 mercury. Heart rate (HR) values are expressed 50 as beats per minute. Multiunit electrical activity 0 of vagal nerve fibers (MUAV) as well as the electrical activity of hypothalamic epileptic focus

Deceased

325±4.3 238.3±43.7 +

114.5±5.8 109.3±6.9 +

156.7±7 159.9±50.4

0.097±0.02 0.102±0.17

Surviving

Na

K

pCO2

3.76±0.45

24.9±2.8

pH 7.36±0.2

pO2

136.4±6.2

88 ±9.3

42.4±2.7

Hb 15.8±0.7

Deceased

136.5±2

8.6 ±4

13.6 ±4

7.18 ±0.1

47.8 ±17

49.9 ±5.3

16.07 ±2.4

Hb

pCO2

pH

pO2

3

K+ HCO-

Na+

HEF-MEF

PAP

MUAV

11.2±4.4 20.7±3.6

76.6±4.6 64.4±5.3

HCO3-

ADP

HR

Surviving

ASP

* and mesencephalic focus cardioarrhythmogenic trigger values are expressed as the number of spikes per second. Statistical significance of differences between surviving and deceased animals was analyzed by paired t tests. (From Mameli, O., et al., Seizure, 15 (5), 275–287, 2006. With permission.) HR ASP ADP PAP MUAV HEF -MEF

ADP 76.6±4.6 64.4±5.3

MUAV 156.7±7 159.9±50.4

PAP 11.2±4.4 20.7±3.6

HCO -pO pH Sudden Epileptic Na Death in KExperimental Animal Models

Surviving Deceased

HR 325±4.3 238.3±43.7 +

ASP 114.5±5.8 109.3±6.9 +

44.8 ±3.6

15.5 ±0.9

*

* *

MUAV 156.7±7 159.9±50.4

PAP 11.2±4.4

20.7±3.6

HEF -MEF 0.097±0.02 0.102±0.17

Surviving

Na

K

pCO2

3.76±0.45

24.9±2.8

pH 7.36±0.2

pO2

136.4±6.2

88 ±9.3

42.4±2.7

Hb 15.8±0.7

Deceased

136.5±2

8.6 ±4

13.6 ±4

7.18 ±0.1

47.8 ±17

49.9 ±5.3

16.07 ±2.4

3

Hb

*

ADP 76.6±4.6 64.4±5.3

HCO -

*p = ns p < 0.005

pO2

t test

66.7±9.1

pCO2

(c) Ictal activity

7.20±0.17

603

3

450 400 350 300 250 200 150 100 50 0

HEF-MEF

25.8 ±1.9

Hb 15.1±1.3

PAP

7.2±1.8

41.7±1.5

MUAV

135 ±0.6

pCO2

92.1±7.7

ADP

26.09±3.4

7.40±0.09

2

3

3.59±0.24

HR

Deceased

+

137.3±2.4

ASP

+

Surviving

HEF -MEF 0.097±0.02 0.102± 0.17

pH

ASP 114.5±5.8 109.3±6.9

K+ HCO-

Deceased

HR 325±4.3 238.3±43.7

Na+

Surviving

Figure 37.3╇ (Continued)

1937; Wall and Davis 1951; Langan et al. 2000; Landau 1953; Walker 1966; Gray 1973; Saper et al. 1976; Korner 1979; Willis and Grossman 1981; Breusch 1984; Natelson 1985). Therefore, the possibility cannot be excluded that under certain circumstances the cortical signals activate the arrhythmogenic triggers simultaneously, thus inducing cardiopulmonary and metabolic impairments that in these patients with a low threshold of excitability may result in sudden death. As for the existence of individuals with a low threshold of excitability, it may be of some interest to consider studies that investigated genetic conditions related to SUDEP. In double-mutant mice that express GM3 as their major ganglioside, a “sudden death phenotype” has been described that was extremely susceptible to induction of lethal seizures by a sound stimulus (Kawai et al. 2001). The gangliosides are a family of glycosphingolipids that contain sialic acid and, although they are abundant on neuronal cell membranes, their speciἀc functions in the CNS remain largely undeἀned. Results of this study showed that these compounds play essential roles in the proper functioning of the CNS and that their absence may contribute to SUDEP susceptibility. In other transgenic mice, the Sema TG, characterized by cardiac-speciἀc overexpression of Sema3a, reduced sympathetic innervation and attenuation of epicardial-to-endocardial innervation gradient have been described. These mice show susceptibility to ventricular tachycardia due to catecholamine supersensitivity and prolongation of the action potential duration, which can terminate in SUDEP. Results of this study showed that appropriate cardiac Sema3a expression is needed for proper sympathetic heart rate control (Ieda et al. 2007). Another interesting hypothesis for the risk of SUDEP considers the neurogenesis process in the CNS. It has long been believed that in mammals, the origin of new neurons in most CNS regions was a process limited to embryogenesis (Hilz et al. 2002) because once development is complete, the progenitor cells that mature into neurons go through a differentiation process and become incapable of division. In contrast, a neurogenesis process in the CNS of adults has been described in several species such as crustaceans (Hilz et al. 2002), reptiles (Lopez-Garcia et al. 1988), amphibians (Polenov and Chetverukhin 1993),

604 Sudden Death in Epilepsy: Forensic and Clinical Issues

birds (Nottebohm 1989), rodents (Altman and Das 1965), primates (Eckenhoff and Rakic 1988), and human beings (Eriksson et al. 1998). In all the mammalian species already studied, including humans, the mitotically active progenitor cells, capable of generating new neurons in the adult phase, are located in speciἀc regions (Eriksson et al. 1998; Gould et al. 1998) such as the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampal formation. In adult mice, these cells migrate to the olfactory bulb, where they differentiate into a large variety of cell types, such as periglomerular neurons and interneurons, as well as astrocytes and oligodendrocytes (Lois and Alvarez-Buylla 1994). In the rat, these new cells proliferate and migrate continuously into the granular cell layer (Kuhn et al. 1996) where they develop a morphology typical of granule cells (Cameron et al. 1993), express neuronal differentiation markers (Kuhn et al. 1996), and extend their axons to the pathway of mossy ἀbers that project into the CA3 region of the hippocampus (Stanἀeld and Trice 1988). Several brain insults, including epileptogenic activity associated with epilepsy, are able to stimulate progenitor cell proliferation in the dentate gyrus (Parent 2007; Zhao et al. 2008). Using the pilocarpine model of temporal lobe epilepsy, for the ἀrst time in rats, this status epilepticus has been shown to cause a dramatic and prolonged increase in cell proliferation in the dentate subgranular proliferative zone (Parent et al. 1997). This observation has been conἀrmed in humans and adult rodent models of temporal lobe epilepsy (Parent et al. 2006; Mello et al. 1993), showing the possibility that these cells aberrantly migrated after the status epilepticus and were abnormally integrated. Resultant hyperexcitability may contribute to seizure generation and/or propagation (Parent et al. 1997, 2006; Dashtipour et al. 2001; Scharfman et al. 2000). In a recent study, aberrant neurogenesis was hypothesized to negatively influence the cardiovascular system of patients with epilepsy, leading to cardiac abnormalities and hence SUDEP (Scorza et al. 2008). The analysis of the literature reviewed in the present report shows some inconsistencies concerning risk factors for SUDEP. In our opinion, differences in data collected using experimental animal models could derive from the variability in study design. Moreover, the different behaviors displayed by the same brain structures could be related not only to differences between focal and generalized models but also to the intrinsic characteristics of the same structures when considered in different species, as well as to speciἀc epileptogenic characteristic of the chemicals used to induce the epileptic foci (Prince 1969, 1972; Mameli et al. 1999, 1991). With regard to penicillin-G epileptogenic activity, for instance, the sensitivity of nervous structures has been shown to signiἀcantly decrease in the rostrocaudal direction (Mameli et al. 2006). Moreover, at the bulbar level, where cardiorespiratory neurons are localized, penicillin G–induced discharges are not as severe as those induced at the mesencephalic level and disappear after midcollicular transection (Mameli et al. 1991), showing their dependence on rostral nervous structures (De Riu et al. 1994). Instead, in drug-induced generalized epilepsy, the simultaneous general involvement of all cortical and subcortical neuronal networks must be considered. These can be impaired directly and/or indirectly by the epileptogenic drugs as well as by endogenous opioids and neurotransmitters released during generalized seizures. In conclusion, the different models of experimental epilepsy used in animals to analyze the physiopathological mechanisms of SUDEP conἀrm the clinical events detected in patients as well as the overlapping mechanisms proposed to explain human SUDEP. They€show that in fatal conditions, the cortical signals simultaneously activate the central autonomic regulatory triggers, inducing cardiopulmonary and metabolic impairments€that in some subjects with a low threshold of excitability might result in a sudden death. This

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is particularly true when the parasympathetic division is involved. In fact, its activation might be responsible for neurogenic ictal bradyarrhythmias, respiratory and metabolic impairments, cardiac asystole, or even SUD in epileptic patients.

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Sympathetic Nervous System Dysregulation of Cardiac Function and Myocyte Potassium Channel Remodeling in Rodent Seizure Models Candidate Mechanisms for SUDEP

38

Steven L. Bealer Cameron S. Metcalf Jason G. Little Matteo Vatta Amy Brewster Anne E. Anderson

Contents 38.1 Introduction 38.2 Effects of Seizure Activity on Cardiac Sympathovagal Balance 38.3 Effects of Seizures on Cardiac Responses to Environmental Stress 38.4 Effects of Seizure Activity on Cardiac Ion Channels 38.5 Discussion References

615 617 620 621 622 623

38.1â•…Introduction Although the precise causes of SUDEP have not been completely deἀned, a number of studies indicate that cardiac ventricular abnormalities, and the resulting arrhythmias and sudden cardiac death may contribute (Dasheiff 1991; Lathers and Schraeder 2002; Leung et al. 2006; Nei et al. 2004; P-Codrea Tigaran et al. 2005). Indeed, it has been proposed that cumulative ischemic damage resulting from sympathetic nervous system activation during the repeated seizures characteristic of intractable epilepsy may progressively increase susceptibility to ventricular arrhythmias and SUDEP (McGugan 1999; Shimizu et al. 2008; Tigaran et al. 1997). The proposal that multiple seizures enhance the risk of cardiac-related death is supported by numerous reports that patients with uncontrolled, intractable seizures are at the greatest risk of SUDEP (Nilsson et al. 1999; Opeskin et al. 1999; Opeskin and Berkovic 2003; Tennis et al. 1995).

615

616 Sudden Death in Epilepsy: Forensic and Clinical Issues

Lethal ventricular arrhythmias can be induced by repeated, acute, transient elevations in sympathetic nervous system activity, as well as by chronic increases in sympathetic dominance of cardiac function, particularly acting on a background of cardiac structural changes (Anderson 2003; Campbell 1991). For example, a number of recent studies demonstrate that both the magnitude and duration of sympathetic nervous system responses to experimental stressors are enhanced in pathological conditions characterized by increased vulnerability to lethal arrhythmias, including postmyocardial infarction (CudnochJedrzejewska et al. 2007; Dobruch, Cudnoch-Jedrzejewska, and Szczepanska-Sadowska 2005), experimental obesity (D’Angelo et al. 2006), depression (Grippo et al. 2003, 2006), and hypertension (Giulumian et al. 1999; McDougall et al. 2005). Consequently, it is evident that both enhanced basal cardiac sympathetic nervous system tone, as well as large, transient increases in activation can increase risk of sudden cardiac death. Seizures in epilepsy are accompanied by intense stimulation of the sympathetic nervous system (Simon et al. 1984), with a resulting increase in both heart rate and blood pressure (Di Gennaro et al. 2004; Mayer et al. 2004; Rugg-Gunn et al. 2004). In addition to sympathetic nervous system activity during seizures, it is possible that responses to other environmental stressors are enhanced in patients with epilepsy. Although one recent epidemiological study reported mental stress as a risk factor for SUDEP (Lear-Kaul et al. 2005), the relationship between sympathetic nervous system activation in response to environmental stress and seizure activity has not been determined. Recently, Lathers and Schraeder (2006) elucidated the lack of knowledge in this area and the potential importance of evaluating the relationship between stress and SUDEP. The repeated activation of the sympathetic nervous system during seizures, particularly in conjunction with exaggerated autonomic responses to environmental stressors, may induce progressive cardiac deterioration and contribute to cardiac arrhythmic activity observed during the ictal and immediate postictal period (Rugg-Gunn et al. 2004), which could progress to SUDEP. However, the relationship between seizure activity, sympathetic nervous system tone, and reactivity, in control of the heart in patients with seizure disorders, has not been completely elucidated. The balance between the influence of the sympathetic (sympathetic nervous system) and parasympathetic components of the autonomic nervous system, known as sympathovagal balance or the vagal-sympathetic effect (sympathovagal balance) (Goldberger 1999), is a major regulator of cardiac function. Normally, parasympathetic nervous system (or vagal) tone predominates and reduces the proarrhythmic effects of the sympathetic nervous system activity (Anderson 2003), and activation of the sympathetic nervous system, which occurs during stress or exercise, is normally short-lived and highly regulated. However, pathological conditions such as myocardial infarction, congestive heart failure, and coronary artery disease are associated with chronic alterations in normal sympathovagal balance, characterized by dominance of sympathetic nervous system activity, and an associated increased risk of cardiac arrhythmias (La Rovere et al. 2001; La Rovere and Schwartz 1997; Stein and Kleiger 1999; Stein et al. 1994; Vanoli et al. 2008; Liao et al. 1996; Verrier and Antzelevitch 2004). Therefore, a shift in sympathovagal balance toward sympathetic nervous system dominance, either by increased sympathetic nervous system or decreased parasympathetic nervous system activity, can contribute to increased cardiac risk. Sympathovagal balance can be determined by comparing the normal, control heart rate to the intrinsic heart rate. Intrinsic heart rate is deἀned as the heart rate in the absence of autonomic influence and represents the intrinsic rate of the cardiac pacemaker. If the intrinsic heart rate is greater than the control heart rate, the heart is being predominantly

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influenced by the parasympathetic nervous system. However, if the intrinsic heart rate is less than the control heart rate, the sympathetic nervous system is providing the dominant influence on cardiac rate. There are some indirect indications that sympathovagal balance may be altered in the direction of sympathetic nervous system dominance as a result of seizure activity. For example, heart rate variability, the spontaneous fluctuations in the intervals between heart beats, is decreased in patients with established epilepsy (Ansakorpi et al. 2002; Ronkainen et al. 2006; Tomson et al. 1998). Heart rate variability represents the interaction between the sympathetic nervous system and parasympathetic nervous system on the cardiac pacemaker (Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology 1996; Stein and Kleiger 1999). Decreased heart rate variability is indicative of increased sympathetic dominance of cardiac control (Stein and Kleiger 1999; van Ravenswaaij-Arts et al. 1993), and is associated with cardiomyopathies that increase risk of sudden cardiac death including coronary artery disease (Krittayaphong et al. 1997), congestive heart failure (van Ravenswaaij-Arts et al. 1993), depression (Grippo et al. 2002), and following recovery myocardial infarction (Kleiger et al. 1987). Although heart rate variability is indicative of increased sympathetic dominance of cardiac function, the effects of seizures on sympathovagal balance have not been previously deἀned. As noted earlier, enhanced basal sympathetic nervous system tone and transient increases in catecholamine stimulation can be a facilitatory factor initiating ventricular arrhythmias, particularly when acting on abnormal cardiac tissue (Anderson 2003; Chen et al. 2007; Dorian 2005). However, the cardiac effects of seizures that provide the arrhythmogenic substrate for adrenergic facilitation of potentially lethal arrhythmias has not been identiἀed. One mechanism that increases susceptibility to sudden cardiac death is ion channel remodeling in cardiac myocytes. Ion channel remodeling, secondary to enhanced sympathetic nervous system activation, mimics what occurs in ion channel dysfunction caused by primary mutations in the genes encoding for the ion channel subunits or for channel interacting proteins (Schimpf et al. 2009; Ueda et al. 2008; Vatta et al. 2006; Wu et al. 2008). In diseases such as long QT syndrome, loss of function of potassium channels occurs due to genetic mutations or acquired inactivation subsequent to blood alkalosis, antibiotics, or other drug-induced inactivation. These ion channel defects caused by primary gene defects in ion channels or channel-interacting proteins deἀne the underlying diseases as a channelopathy (Schimpf et al. 2009). We propose that a similar remodeling may occur after acquired prolonged or recurrent seizures, which would predispose to sudden cardiac death. In summary, it is possible that repeated seizure activity may increase basal sympathetic nervous system dominance of cardiac function and enhance sympathetic nervous system responsiveness, inducing ion channel remodeling in cardiac myocytes. These effects would result in increased susceptibility to ventricular arrhythmias, which would contribute to SUDEP.

38.2â•… Effects of Seizure Activity on Cardiac Sympathovagal Balance To determine the effects of seizures on the relative sympathetic nervous system and parasympathetic nervous system control of cardiac function, we evaluated sympathovagal balance after recovery from a single, long-lasting seizure in male, Sprague–Dawley rats.

618 Sudden Death in Epilepsy: Forensic and Clinical Issues

Seizures were induced with lithium–pilocarpine injections and were terminated after 90 min (Metcalf et al. 2009). Either 1 or 2 weeks after seizures, cardiac sympathovagal balance (sympathovagal balance) was determined by comparing intrinsic heart rate to control heart rate in animals that had experienced seizures (Pilo) or control procedures (saline injection, Cont). Furthermore, in addition to evaluating cardiac function in the absence of all autonomic influences, the individual contributions of the sympathetic nervous system and parasympathetic nervous system were individually determined by measuring changes in heart rate after blockade of the sympathetic nervous system with atenolol and blockade of the parasympathetic nervous system with atropine (Goldberger 1999). All cardiovascular measures were obtained from conscious, unrestrained animals. The relationships between intrinsic heart rate and control heart rate, that is, the sympathovagal balance, which represents a measure of sympathovagal balance (Goldberger 1999), observed in pilocarpine-treated and control-treated rats 1 week (panel a) and 2 weeks (panel b) after treatment are shown in Figure 38.1. As mentioned earlier, a lower sympathovagal balance is indicative of increased sympathetic nervous system dominance of cardiac function. At both periods, the sympathovagal balance was signiἀcantly lower in animals that underwent seizures (Figure 38.1). This observation suggests seizure activity resulted in a long-lasting shift in sympathovagal control of cardiac function toward sympathetic nervous system dominance. However, increased sympathetic nervous system influence on cardiac function may result from enhanced sympathetic nervous system tone, decreased parasympathetic nervous system tone, or both. To elucidate the origin of the shift in cardiac sympathovagal balance toward sympathetic nervous system dominance, we evaluated sympathetic nervous system tone (i.e., the fall in heart rate in response to sympathetic nervous system blockade in the presence of parasympathetic nervous system blockade) and parasympathetic nervous system tone (i.e., the rise in heart rate in response to parasympathetic nervous system blockade in the presence of sympathetic nervous system blockade) (Goldberger 1999). The increase in heart rate in response to atropine (parasympathetic nervous system antagonist) in the presence of sympathetic nervous system blockade was signiἀcantly smaller in animals experiencing seizures (pilocarpine) (Figure 38.2) both 1 week (panel a) and 2 weeks (panel c) after treatment compared to control-treated rats. These data indicate that parasympathetic nervous system tone was signiἀcantly lower in animals undergoing seizures, compared to control rats, for at least 2 weeks after treatment. However, the decrease in

1.10 1.05 1.00 0.95 0.90 0.85 0.80

1.10 1.05 1.00 0.95 0.90 0.85 0.80

VSE (iHR/HR)

(b)

VSE (iHR/HR)

(a)

Cont

Pilo

Cont

Pilo

Figure 38.1╇ Vagal-sympathetic effect (sympathovagal balance) in animals undergoing con-

trol procedures (Cont) or seizure (SE) animals 1 week (a) and 2 weeks (b) after treatment. *p < 0.05, compared to Cont. (From Metcalf, C. S., et al., Epilepsia, 50 (4), 747–754, 2009. With permission.)

45 40 35 30 25 20 15 10 5 0

(a) 0 –25 –50 –75

–100

(c)

(d)

50

HR change (beats/min)

HR change (beats/min)

60

40 30 20 10 0

619

(b) HR change (beats/min)

HR change (beats/min)

Sympathetic Nervous System Dysregulation of Cardiac Function

Cont

Pilo

–10 –35 –60 –85 –110

Cont

Pilo

Figure 38.2╇ Changes in heart rate (heart rate) resulting from atropine after atenolol (parasympathetic nervous system tone) 1 week (a) and 2 weeks (c) after treatment. Changes in heart rate resulting from atenolol after atropine (sympathetic nervous system tone) 1 (b) and 2 (d) weeks after treatment. *p < 0.05 compared to Cont. (From Metcalf, C. S., et al., Epilepsia, 50 (4), 747–754, 2009. With permission.)

heart rate in response to atenolol (sympathetic nervous system antagonist) during parasympathetic nervous system blockade was equivalent between pilocarpine and control rats both 1 and 2 weeks after treatment (Figure 38.2, panels b and d, respectively). This ἀnding suggests that seizures did not alter basal cardiac sympathetic nervous system. Taken together, these data demonstrate that seizure activity resulted in a prolonged increase in sympathetic nervous system dominance of cardiac function, resulting primarily from decreased parasympathetic nervous system tone, with little or no alteration in sympathetic nervous system activity. This chronic increase in sympathetic nervous system influence on the heart after seizures provides support for the proposal that decreased heart rate variability observed in patients with established epilepsy (Ansakorpi et al. 2002; Ronkainen et al. 2006; Tomson et al. 1998) results from increased cardiac sympathetic nervous system tone (Stein and Kleiger 1999; van Ravenswaaij-Arts et al. 1993). In addition, consistent with the ἀndings in this animal model, recent clinical studies have reported patients with intractable epilepsies exhibited higher sympathetic nervous system tone, lower parasympathetic nervous system tone, and signiἀcant autonomic dysregulation (Mukherjee et al. 2009; Sathyaprabha et al. 2006). Because susceptibility to lethal ventricular arrhythmias is enhanced by chronic, sustained increases in sympathetic nervous system control of cardiac function (Airaksinen 1999; Anderson 2003; Chen et al. 2007), these data support the proposal that seizure-induced changes in basal sympathovagal balance predispose patients to SUDEP.

620 Sudden Death in Epilepsy: Forensic and Clinical Issues

38.3â•…Effects of Seizures on Cardiac Responses to€Environmental Stress In addition to the arrhythmogenic effects of chronic, basal sympathetic nervous system dominance on cardiac function, lethal ventricular arrhythmias can also be precipitated by more acute and transient elevations in sympathetic nervous system activity (Anderson 2003; Campbell 1991). Enhanced sympathetic nervous system responses to environmental stressors, and the resulting increase in catecholamine stimulation of the heart, is characteristic of cardiac pathologies that often result in sudden cardiac death (CudnochJedrzejewska et al. 2007; D’Angelo et al. 2006; Dobruch et al. 2005; Grippo et al. 2003, 2006; Giulumian et al. 1999; McDougall et al. 2005). Indeed, it has been proposed that enhanced responses to mental stress may be a risk factor for SUDEP (Lear-Kaul et al. 2005). This would suggest that in addition to the documented activation of the sympathetic nervous system (Simon et al. 1984) and associated increase in heart rate and blood pressure (Di Gennaro et al. 2004; Mayer et al. 2004; Rugg-Gunn et al. 2004) that occurs during seizures, patients with epilepsy may experience more intense sympathetic nervous system activation to non-seizure-related environmental stressors, further increasing the risk of lethal arrhythmias (Anderson 2003; Campbell 1991; Cudnoch-Jedrzejewska et al. 2007). We suggest that environmental stress produces enhanced sympathetic nervous system–mediated cardiac responses in patients with epilepsy that, in conjunction with basal sympathetic nervous system dominance and acute sympathetic nervous system activation during seizures, contributes to progressive deterioration in cardiac function and potentially results in SUDEP. To determine if seizures affect autonomic responses to stress, we measured changes in heart rate and blood pressure before and during administration of a moderate, environmental stressor in animals 10 days to 2 weeks after seizures induced by lithium– pilocarpine treatment. Blood pressure and heart rate were measured in rats subjected to the moderate stress of an air jet aimed at the animal’s head for 3 min. Figure 38.3 shows control heart rate recorded before administration of the stress (Pre), and the maximum heart rate measured during the 3 min of air jet administration (Stress) in animals undergoing seizures (Pilo) and in control-treated rats. As can be seen, there were no differences in basal heart rate between control and pilocarpine rats before administration of the air jet. Furthermore, although mean heart rate tended to increase in control rats in response to the stress, this tachycardia was not statistically signiἀcant. However, in rats that had experienced seizures, air jet stress increased heart rate signiἀcantly above both prestress levels and the values observed in control animals during stress. In contrast, blood pressure was not elevated by air jet stress in either group of animals (data not shown). These ἀndings suggest that seizure activity produces a chronic increase in cardiac sympathetic nervous system responses to environmental stressors, which is reflected in a signiἀcant tachycardia. This increased cardiac reactivity during stress may contribute to SUDEP in patients with recurrent seizures because a similar relationship between enhanced responses to stress and increased risk of lethal arrhythmias has been reported in other pathological conditions characterized by sudden cardiac death, such as post-myocardial infarction (Cudnoch-Jedrzejewska et al. 2007; Dobruch, Cudnoch-Jedrzejewska, and Szczepanska-Sadowska 2005), experimental obesity (D’Angelo et al. 2006), depression (Grippo et al. 2003, 2006), and hypertension (Giulumian et al. 1999; McDougall et al. 2005).

Sympathetic Nervous System Dysregulation of Cardiac Function 500

621

*#

Cont Heart rate (beats/min)

Pilo 450

400

350

0

Stress

Pre

Pre

Stress

Figure 38.3╇ Basal heart rate measured before stress (Pre), and the maximum heart rate

observed during 3 min of air jet stress (Stress) in control (Cont) rats and animals undergoing seizures induced with lithium–pilocarpine (Pilo). *p < 0.05 compared to Pilo-Pre; #p < 0.05 compared to Control-Stress.

38.4â•… Effects of Seizure Activity on Cardiac Ion Channels We have observed sudden death after kainate convulsant stimulation in Kv4.2 knockout mice (Barnwell et al. 2009). These mice do not have a cardiac phenotype at rest. However, after prolonged seizure stimulation with presumed ongoing sympathetic nervous system dominance based on the above ἀndings, these animals suffered sudden death. Given that Kv4.2 subunits contribute to channels that underlie the transient outward current (Ito,f ) encoded in rodent myocytes, one possible mechanism underlying sudden death in these animals after seizure stimulation is a lethal cardiac arrhythmia. Subsequently, we have 125 Optical density (% Control)

100 75 50 25 0

Control

KA

Kv4.2 Actin

Figure 38.4╇ Reduction in cardiac Kv4.2 channel protein levels after kainate-induced seizures.

Immunoblotting of normalized cardiac membranes prepared from animals with sham treatment (Control) vs. kainate-induced seizures (KA) was performed using Kv4.2 and actin (lane loading control) antibodies. *p < 0.05, kainate-treated animals (KA) compared to Control.

622 Sudden Death in Epilepsy: Forensic and Clinical Issues

begun to evaluate whether remodeling of Kv4 channels occurs in models of acquired seizures or epilepsy. As a ἀrst step in these studies, we evaluated Kv4.2 protein levels in rats after kainate- or pilocarpine-induced seizures. We found signiἀcant decreases in Kv4.2 channel levels in both of these models (Figure 38.4 for kainate model data; pilo model data not shown). Thus, we conclude that ion channel remodeling occurs after seizures and may contribute to sudden death in epilepsy. Although the link remains to be shown, one candidate mechanism underlying ion channel remodeling in acquired epilepsy is through altered sympathetic tone.

38.5â•…Discussion These studies have demonstrated that convulsant-induced seizures in rodents result in long-lasting alterations in autonomic control of cardiac function, sympathetic nervous system responses to stress, and cardiomyocyte potassium channels. Speciἀcally, seizures produce an increase in sympathetic nervous system dominance in cardiac control, resulting from diminished parasympathetic nervous system tone, enhanced sympathetic nervous system–induced tachycardia during environmental stress, and reduced expression of Kv4.2 channels in cardiomyocytes. These effects of seizures would be expected to increase susceptibility to ventricular arrhythmias and sudden cardiac death contributing to SUDEP. Lethal ventricular arrhythmias can be produced when a physiological facilitator interacts with abnormal anatomical and electrical substrates in cardiac tissue (Anderson 2003; Campbell 1991). A number of previous studies demonstrated that sympathetic nervous system dominance of cardiac function and enhanced sympathetic nervous system responses to environmental stimuli are associated with increased risk of sudden death in several cardiac pathologies including post-myocardial infarction (Cudnoch-Jedrzejewska et al. 2007; Dobruch, Cudnoch-Jedrzejewska, and Szczepanska-Sadowska 2005), experimental obesity (D’Angelo et al. 2006), depression (Grippo et al. 2003, 2006), and hypertension (Giulumian et al. 1999; McDougall et al. 2005). These data suggest that excessive catecholaminergic stimulation of cardiac tissue is an important facilitator of arrhythmogenesis in these conditions. Our studies extend these ἀndings by demonstrating that seizures that can result in sudden cardiac death are similarly associated with increases in sympathetic nervous system dominance of cardiac death and exaggerated responses to environmental stressors lasting well beyond the period of seizure activity. In addition, these studies suggest that seizure-induced decreases in Kv4.2 channels may provide the electrical substrate for arrhythmogenic activity and contribute to sudden cardiac death in epilepsy. It has previously been shown that severe reduction in channel function caused by the dominant negative W362F mutation leads to prolonged QT interval, enhanced dispersion of repolarization, and refractoriness (London et al. 2007). In addition, a reduction in Kv4.2 levels may also affect the transmural gradient between epicardium and endocardium, leading to an imbalance in homogeneity of cardiac depolarization and thereby providing a setup for risk of cardiac dysrhythmia. Cardiac ion channel remodeling has been previously associated with autonomic imbalance or primary genetic mutations, which are both important causes of cardiac arrhythmias; however, ion channel remodeling acquired in association with various cardiac pathologies is an additional important cause of cardiac arrhythmias (for review, see Shah et al. 2005). Experimentally induced tachycardia through rapid cardiac pacing has been

Sympathetic Nervous System Dysregulation of Cardiac Function

623

associated with K+ channel remodeling. Speciἀcally, levels of Kv4.2 and Kv4.3 decreased in myocardium after prolonged cardiac pacing in rats (Yamashita et al. 2000). Thus, a disruption of the ἀnely tuned balance of ion channels normally expressed in the heart, which may occur through a variety of candidate mechanisms, is a risk for cardiac arrhythmia. Future studies will no doubt begin to shed light on the role of cardiac ion channel remodeling and the link to altered sympathetic tone in epilepsy and SUDEP. In summary, these animal studies suggest that lethal ventricular arrhythmias that contribute to SUDEP may occur in response to chronic sympathetic nervous system dominance of cardiac function, combined with periodic, transient, and exaggerated catecholaminergic stimulation, acting on cardiac myocytes that are predisposed to arrhythmogenesis due to altered potassium channel function. These data support the proposal that single intense seizures and/or repeated seizure activity may increase the risk of SUDEP in patients with intractable epilepsy by (1) increasing exposure of cardiac tissue to an arrhythmogenic facilitator, catecholamines, and (2) providing the electrical substrate, decreased Kv4.2 channels, on which the substrate acts to induce arrhythmic activity. These data further indicate that patients with epilepsy who are at increased risk of SUDEP could beneἀt from cardioprotective agents shown to diminish the incidence of lethal arrhythmias in other pathological conditions. For example, beta-adrenergic antagonists prevent lethal arrhythmias and detrimental cardiac adaptations associated with several cardiomyopathies, including coronary artery disease, heart failure, and myocardial infarction (Adamson and Gilbert 2006; Dorian 2005; Hohnloser 2005).

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McDougall, S. J., R. E. Widdop, and A. J. Lawrence. 2005. Differential gene expression in WKY and SHR brain following acute and chronic air-puff stress. Brain Res Mol Brain Res 133 (2): 329–336. McGugan, E. A. 1999. Sudden unexpected deaths in epileptics—A literature review. Scott Med J 44 (5): 137–139. Metcalf, C. S., P. B. Radwanski, and S. L. Bealer. 2009. Status epilepticus produces chronic alterations in cardiac sympathovagal balance. Epilepsia 50 (4): 747–754. Mukherjee, S., M. Tripathi, P. S. Chandra, R. Yadav, N. Choudhary, R. Sagar, R. Bhore, R. M. Pandey, and K. K. Deepak. 2009. Cardiovascular autonomic functions in well-controlled and intractable partial epilepsies. Epilepsy Res 85 (2–3): 261–269. Nei, M., R. T. Ho, B. W. Abou-Khalil, F. W. Drislane, J. Liporace, A. Romeo, and M. R. Sperling. 2004. EEG and ECG in sudden unexplained death in epilepsy. Epilepsia 45 (4): 338–345. Nilsson, L., B. Y. Farahmand, P. G. Persson, I. Thiblin, and T. Tomson. 1999. Risk factors for sudden unexpected death in epilepsy: A case-control study. Lancet 353 (9156): 888–893. Opeskin, K., M. P. Burke, S. M. Cordner, and S. F. Berkovic. 1999. Comparison of antiepileptic drug levels in sudden unexpected deaths in epilepsy with deaths from other causes. Epilepsia 40 (12): 1795–1798. Opeskin, K., and S. F. Berkovic. 2003. Risk factors for sudden unexpected death in epilepsy: A controlled prospective study based on coroners cases. Seizure 12 (7): 456–464. P-Codrea Tigaran, S., S. Dalager-Pedersen, U. Baandrup, M. Dam, and A. Vesterby-Charles. 2005. Sudden unexpected death in epilepsy: Is death by seizures a cardiac disease? Am J Forensic Med Pathol 26 (2): 99–105. Ronkainen, E., J. T. Korpelainen, E. Heikkinen, V. V. Myllyla, H. V. Huikuri, and J. I. Isojarvi. 2006. Cardiac autonomic control in patients with refractory epilepsy before and during vagus nerve stimulation treatment: A one-year follow-up study. Epilepsia 47 (3): 556–562. Rugg-Gunn, F. J., R. J. Simister, M. Squirrell, D. R. Holdright, and J. S. Duncan. 2004. Cardiac arrhythmias in focal epilepsy: A prospective long-term study. Lancet 364 (9452): 2212–2219. Sathyaprabha, T. N., P. Satishchandra, K. Netravathi, S. Sinha, K. Thennarasu, and T. R. Raju. 2006. Cardiac autonomic dysfunctions in chronic refractory epilepsy. Epilepsy Res 72 (1): 49–56. Schimpf, R., C. Veltmann, C. Wolpert, and M. Borggrefe. 2009. Channelopathies: Brugada syndrome, long QT syndrome, short QT syndrome, and CPVT. Herz 34 (4): 281–288. Shah, M., F. G. Akar, and G. F. Tomaselli. 2005. Molecular basis of arrhythmias. Circulation 112 (16): 2517–2529. Shimizu, M., A. Kagawa, T. Takano, H. Masai, and Y. Miwa. 2008. Neurogenic stunned myocardium associated with status epileptics and postictal catecholamine surge. Intern Med 47 (4): 269–273. Simon, R. P., M. J. Aminoff, and N. L. Benowitz. 1984. Changes in plasma catecholamines after tonic–clonic seizures. Neurology 34 (2): 255–257. Stein, P. K., M. S. Bosner, R. E. Kleiger, and B. M. Conger. 1994. Heart rate variability: A measure of cardiac autonomic tone. Am Heart J 127 (5): 1376–1381. Stein, P. K., and R. E. Kleiger. 1999. Insights from the study of heart rate variability. Annu Rev Med 50: 249–261. Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology. 1996. Heart rate variability: Standards of measurement, physiological interpretation and clinical use. Circulation 93 (5): 1043–1065. Tennis, P., T. B. Cole, J. F. Annegers, J. E. Leestma, M. McNutt, and A. Rajput. 1995. Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada. Epilepsia 36 (1): 29–36. Tigaran, S., V. Rasmussen, M. Dam, S. Pedersen, H. Hogenhaven, and B. Friberg. 1997. ECG changes in epilepsy patients. Acta Neurol Scand 96 (2): 72–75. Tomson, T., M. Ericson, C. Ihrman, and L. E. Lindblad. 1998. Heart rate variability in patients with epilepsy. Epilepsy Res 30 (1): 77–83.

626 Sudden Death in Epilepsy: Forensic and Clinical Issues Ueda, K., C. Valdivia, A. Medeiros-Domingo, D. J. Tester, M. Vatta, G. Farrugia, M. J. Ackerman, and J. C. Makielski. 2008. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci U S A 105 (27): 9355–9360. van Ravenswaaij-Arts, C. M., L. A. Kollee, J. C. Hopman, G. B. Stoelinga, and H. P. van Geijn. 1993. Heart rate variability. Ann Intern Med 118 (6): 436–447. Vanoli, E., P. B. Adamson, R. D. Foreman, and P. J. Schwartz. 2008. Prediction of unexpected sudden death among healthy dogs by a novel marker of autonomic neural activity. Heart Rhythm 5 (2): 300–305. Vatta, M., M. J. Ackerman, B. Ye, J. C. Makielski, E. E. Ughanze, E. W. Taylor, D. J. Tester, R. C. Balijepalli, J. D. Foell, Z. Li, T. J. Kamp, and J. A. Towbin. 2006. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114 (20): 2104–2112. Verrier, R. L., and C. Antzelevitch. 2004. Autonomic aspects of arrhythmogenesis: The enduring and the new. Curr Opin Cardiol 19 (1): 2–11. Wu, G., T. Ai, J. J. Kim, B. Mohapatra, Y. Xi, Z. Li, S. Abbasi, E. Purevjav, K. Samani, M. J. Ackerman, M. Qi, A. J. Moss, W. Shimizu, J. A. Towbin, J. Cheng, and M. Vatta. 2008. alpha-1-syntrophin mutation and the long-QT syndrome: A disease of sodium channel disruption. Circ Arrhythm Electrophysiol 1 (3): 193–201. Yamashita, T., Y. Murakawa, N. Hayami, E. Fukui, Y. Kasaoka, M. Inoue, and M. Omata. 2000. Shortterm effects of rapid pacing on mRNA level of voltage-dependent K(+) channels in rat atrium: Electrical remodeling in paroxysmal atrial tachycardia. Circulation 101 (16): 2007–2014.

The Urethane/Kainate Seizure Model as a Tool to Explore Physiology and Death Associated with Seizures

39

Mark Stewart

Contents 39.1 Introduction 39.2 Autonomic Consequences of Seizures 39.3 The Urethane/Kainate Model 39.4 Results Relevant to Sudden Death in Epilepsy 39.5 Quantitative Activity Differences 39.6 Pathways 39.7 Insights into the Mechanism for Sudden Death in Epilepsy 39.8 Closing Comments on This and Other Animal Models References

627 628 629 630 636 637 638 639 639

39.1â•…Introduction The anesthetized whole animal or acute preparation has been supplanted in recent decades by a choice of preparations that offer different advantages. Brain slices and cell cultures offer much better access to the neurons for physiological and pharmacological studies; and provided the questions addressed relate to relatively simple neuronal circuits, the preparations are superior to an intact animal preparation—the specimen visualization and recording advantages (intracellular, whole cell patch, calcium and voltage sensitive dyes, neuronal imaging) are signiἀcant. In preparations where the behavior is important (e.g., to observe convulsions or maze learning), the freely moving, freely behaving animal preparation is the only choice. The acute animal preparation in fact has signiἀcant advantages for neurophysiology and physiology studies. Among these is access to measurements and recordings that can be impossible in freely moving animals. In the whole animal preparation, one has access to the entire central nervous system circuitry, something that cannot be preserved in a brain slice or cell culture. The acute animal preparation has been reexamined by us for studies of the autonomic consequences of seizures because we need access to the entire physiology of the animal. One has options for a host of invasive measures or procedures and considerable control of an animal’s condition (e.g., ventilation, temperature, blood pressure, and even blood volume). It is the preparation to explore the limits of the physiology associated with functional or anatomical neuropathology. One can directly address questions such as, Can a seizure 627

628 Sudden Death in Epilepsy: Forensic and Clinical Issues

cause death? If so, how? If not, why not? Can autonomic nervous system activity itself cause death? These questions and many others can be explored in detail to address fundamental questions of physiology. In addition to its flexibility, the acute animal preparation offers efficiency that comes from the control of conditions such as seizure activity to eliminate issues of “capturing” the right conditions. The trade-off, of course, is that although the animal is intact, the conditions of the animal are always a subset of the conditions that would be observed during “captured” events in behaving animals. In short, the acute whole animal preparation is ideally suited for efficiently deἀning boundary conditions and making certain kinds of manipulations or measurements that would later guide studies of activity such as seizures in behaving animals.

39.2â•… Autonomic Consequences of Seizures In the context of sudden death in epilepsy, most would agree that the autonomic nervous system provides the link between seizures and death. Autonomic dysfunction during seizures can have serious clinical consequences (Devinsky 2004; Goodman et al. 2008). Changes in heart rate and rhythm and blood pressure can occur during complex partial seizures (Baumgartner et al. 2001; Lathers et al. 1998; Locatelli et al. 1999; Nei et al. 2000; Wilder-Smith 1992). Generalized tonic–clonic seizures are sometimes associated with severe increases in blood pressure and arrhythmias (Schraeder and Lathers 1989), and some individuals experience more ominous autonomic derangements such as marked bradycardia or asystole (Smith-Demps and Jagoda 1998; Cheung and Hachinski 2000; Mameli et al. 2001). The causes of sudden unexpected death in epilepsy (SUDEP) are suspected to involve cardiovascular or respiratory dysfunction provoked by seizures (Cheung and Hachinski 2000; Langan 2000; Liedholm and Gudjonsson 1992; Mameli et al. 2001; SmithDemps and Jagoda 1998; Tinuper et al. 2001). Animal experimentation has replicated features of human epilepsy and autonomic dysfunction associated with seizures (reviewed by Lathers and Schraeder 2006). Amygdalakindled seizures in rats coactivate sympathetic and parasympathetic systems and were shown to produce ictal hypertension and bradycardia (Goodman et al. 1990, 1999). Left insular cortex stimulation in rats caused degrees of heart block (Oppenheimer et al. 1991), resembling ἀndings from a study of epilepsy surgery patients (Oppenheimer et al. 1992; Hilz et al. 2001). In our own model (described in more detail below), left-sided limbic seizure activity was associated with a more pronounced vagus nerve activity increase and associated blood pressure decrease (Saito et al. 2006) than right-sided limbic seizure activity. Focal and generalized seizures in anesthetized cats (Schraeder and Lathers 1983; Lathers et al. 1998, 1993) were associated with cardiac sympathetic and parasympathetic activity that was intermittently synchronized with interictal spike activity (“lockstep phenomena”) (Lathers et al. 1987; Stauffer et al. 1989). Application of penicillin G to the hypothalamus and mesencephalic centers of hemispherectomized rats produced increases in vagus nerve activity and various cardiovascular disturbances (Mameli et al. 2001, 1993) including death (Mameli et al. 2001, 2006). Mice that exhibit audiogenic seizures frequently display respiratory arrest that can be fatal and prevented by increasing oxygen in the environment (Venit et al. 2004; Willott and Henry 1976). Hypoventilation was reported as an important correlate of death during seizures in a sheep model (Johnston et€al. 1997, 1995).

The Urethane/Kainate Seizure Model A

Urethane

B

Ketamine+xylazine

Hippo EEG Face EMG Leg EMG

Hippo EEG Face EMG Leg EMG

629

5s

1s

Figure 39.1╇ Urethane permits limbic cortical seizure activity with minimal motor convul-

sions. (A) Urethane-anesthetized rat (1.5 g/kg i.p. with intra-arterial (i.a.) supplements). Three 50-s sweeps of simultaneously recorded (a) EEG (dorsal hippocampus area CA1), (b) EMG from face (in the area of vibrissae), and (c) EMG from the lower leg (gastrocnemius and soleus muscles). Seizure activity after systemic kainic acid (10 mg/kg) is present throughout all three sweeps, with some changes in frequency components. Very low EMG activity levels from leg recordings (third trace in each set) did not change during seizures. Minimal EMG activity is apparent in the face EMG recordings, but rarely (indicated by asterisks in sweeps 2 and 3). (B) Ketamine and xylazine–anesthetized rat (60 mg/kg ketamine + 10 mg/kg xylazine i.p. with i.a. supplements). Similar set of three 50-s sweeps with simultaneously recorded dorsal hippocampal EEG, and EMG from face and hind leg. Seizure activity is more pronounced in some, but not all, of the time shown. Most significantly, there was substantial EMG activity in all recording locations. Thick black bar indicates time period for faster sweep shown below. Synchronous phasic activity in both the face and leg EMG electrodes is clearly apparent. Motor convulsions were stopped by Nembutal (10 mg i.a.). EEG spikes are clipped in the display. Calibrations: time, 5 s for both A and B; voltage, 400 µV for EEG A and B, 600 µV for EMG A face and B leg, 400 µV for EMG A leg, and 300 µV for EMG B face. (From Figure 2 in Saito, T., et al., J Neurosci Methods, 155, 241–50, 2006.)

39.3â•… The Urethane/Kainate Model We have developed an acute rat preparation based on urethane anesthesia and systemic or focal kainic acid to deἀne the autonomic consequences of seizure activity. Initially, we€compared anesthetics such as urethane and ketamine/xylazine combinations for acute seizure studies because these anesthetics permit several kinds of polysynaptic activity (Flecknell

630 Sudden Death in Epilepsy: Forensic and Clinical Issues

1996). Hippocampal theta rhythm is one example of a complex polysynaptic brain oscillation that is readily and well studied in urethane-anesthetized animals (Brankack et€al. 1993; Stewart and Fox 1990). In urethane-anesthetized rats, systemic kainic acid can cause repeated long episodes of seizure activity ranging in duration from 10 s to more than 1€min€(Saito et al. 2006; Sakamoto et al. 2008; Hotta et al. 2009a). Seizures are typically characterized by an initial period of high-frequency activity that progresses to slower, larger amplitude waves until the seizure episode terminates leaving low-voltage activity in the EEG until the next seizure episode. Remarkably, the EMG during seizures in urethaneanesthetized rats is essentially flat from all locations except the face, even during limbic status epilepticus (Saito et al. 2006). Animals breathe spontaneously, but motor convulsions during seizure activity are absent. By contrast, motor convulsions accompany electroencephalographic seizures in animals anesthetized with ketamine/xylazine (Saito et al. 2006). Signiἀcant EMG activity can be recorded from multiple locations, and rhythmic muscle contractions corresponded to periodic activity in the EEG. These differences are highlighted in Figure 39.1. The fact that seizure activity in the urethane/kainate model was conἀned to limbic cortical areas without spread to neocortical areas meant that we had access to the autonomic consequences of seizure activity in an animal preparation that was breathing spontaneously and could be mechanically stable enough for many kinds of recordings. There was no need to paralyze the animal. Titration of the urethane level and the amount of kainic acid ensured mechanical stability and offered some flexibility in the durations of seizure activity, ranging from very brief to frank limbic status epilepticus. The reason for the limbic cortical–neocortical disconnect is unclear. Although urethane has been used for studies of activity in limbic cortical structures (e.g., hippocampal theta rhythm), including cingulate cortex (Feenstra and Holsheimer 1979), urethane has been described as anticonvulsant in somatosensory cortex (Heltovics et al. 1995). There is evidence that urethane can suppress glutamate release at some cortical synapses (Moroni et al. 1981).

39.4â•…Results Relevant to Sudden Death in Epilepsy Using the urethane/kainate model, we have deἀned massive increases in parasympathetic and sympathetic outflow that occur during limbic cortical seizures and the cardiovascular consequences of these changes (Saito et al. 2006; Hotta et al. 2009a; Sakamoto et al. 2008; Stewart 2008, Hotta et al. 2009b). Increases were 8–10 times baseline rates for parasympathetic (vagus nerve) activity and somewhat less in sympathetic pre-€and postganglionic nerve recordings (Sakamoto et