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WYLLIESTREATMENT OFEPILEPSYPRINCIPLES AND PRACTICE

F I F T H E D I T I O N

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Editor-in-Chief

Elaine Wyllie, MDProfessor of Pediatric MedicineCleveland Clinic Lerner College of MedicineDirector of the Center for Pediatric NeurologyNeurological InstituteCleveland ClinicCleveland, Ohio

Associate Editors

Gregory D. Cascino, MD, FAANProfessor of NeurologyMayo Clinic College of MedicineChair, Division of EpilepsyMayo ClinicRochester, Minnesota

WYLLIESTREATMENT OFEPILEPSYPRINCIPLES AND PRACTICE

F I F T H E D I T I O N

Barry E. Gidal, PharmDProfessor, School of Pharmacy andDepartment of NeurologyChair, Pharmacy Practice DivisionUniversity of WisconsinMadison, Wisconsin

Howard P. Goodkin, MD, PhDThe Shure Associate Professor of Pediatric NeurologyDepartments of Neurology and PediatricsUniversity of VirginiaCharlottesville, Virginia

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Acquisitions Editor: Fran Destefano Product Manager: Tom GibbonsVendor Manager: Alicia JacksonSenior Manufacturing Manager: Ben RiveraMarketing Manager: Brian FreilandDesign Coordinator: Steve DrudingProduction Service: MPS Limited, a Macmillan Company

5th Edition 2011 by Lippincott Williams & Wilkins, a Wolters Kluwer businessTwo Commerce Square2001 Market StreetPhiladelphia, PA 19103 USALWW.com

All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any formby any means, including photocopying, or utilized by any information storage and retrieval system withoutwritten permission from the copyright owner, except for brief quotations embodied in critical articles andreviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S.government employees are not covered by the above-mentioned copyright.

Printed in China.

Library of Congress Cataloging-in-Publication Data

Wyllies treatment of epilepsy : principles and practice. 5th ed. / editor-in-chief, Elaine Wyllie ; associate editors, Gregory D. Cascino, Barry E. Gidal, Howard P. Goodkin.

p. ; cm.Other title: Treatment of epilepsyRev. ed. of: The treatment of epilepsy. 4th ed. / editor-in-chief, Elaine Wyllie. c2006.Includes bibliographical references and index.Summary: In one convenient source, this book provides a broad, detailed, and cohesive overview of

seizure disorders and contemporary treatment options. For this Fifth Edition, the editors have replacedor significantly revised approximately 30 to 50 percent of the chapters, and have updated all of them.Dr. Wyllie has invited three new editors: Gregory Cascino, MD, at Mayo Clinic, adult epileptologist withspecial expertise in neuroimaging; Barry Gidal, PharmD, RPh, at University of Wisconsin, a pharmacologistwith phenomenal expertise in antiepileptic medications; and Howard Goodkin, MD, PhD, a pediatricneurologist at the University of Virginia. A fully searchable companion website will include the full textonline and supplementary material such as seizure videos, additional EEG tracings, and more colorillustrationsProvided by publisher.ISBN-13: 978-1-58255-937-7 (hardback)ISBN-10: 1-58255-937-6 (hardback)1. Epilepsy. I. Wyllie, Elaine. II. Treatment of epilepsy. III. Title: Treatment of epilepsy.[DNLM: 1. Epilepsytherapy. 2. Epilepsydiagnosis. WL 385 W983 2011]RC372.T68 2011616.853dc22

2010024726

Care has been taken to confirm the accuracy of the information presented and to describe generally acceptedpractices. However, the authors, editors, and publisher are not responsible for errors or omissions or for anyconsequences from application of the information in this book and make no warranty, expressed or implied,with respect to the currency, completeness, or accuracy of the contents of the publication. Application of theinformation in a particular situation remains the professional responsibility of the practitioner.

The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosageset forth in this text are in accordance with current recommendations and practice at the time of publica-tion. However, in view of ongoing research, changes in government regulations, and the constant flow ofinformation relating to drug therapy and drug reactions, the reader is urged to check the package insertfor each drug for any change in indications and dosage and for added warnings and precautions. This isparticularly important when the recommended agent is a new or infrequently employed drug.

Some drugs and medical devices presented in the publication have Food and Drug Administration(FDA) clearance for limited use in restricted research settings. It is the responsibility of the health careprovider to ascertain the FDA status of each drug or device planned for use in their clinical practice.

To purchase additional copies of this book, call our customer service department at (800) 638-3030 or faxorders to (301) 223-2320. International customers should call (301) 223-2300.

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10 9 8 7 6 5 4 3 2 1

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D E D I C AT I O N

To the Cleveland Clinic, which brought me on board as a young doctor and provided me career opportunities beyond my wildest imagination

To our Chief Executive Officer, Dr. Delos Cosgrove, whose visionary leadership has brought the Cleveland Clinic to where we are today, at the forefront of medical care

throughout the world

And to my husband, Dr. Robert Wyllie, Physician-in-Chief of the Cleveland Clinic Childrens Hospital, who provides the environment for all of us who care for children to

do our best work

Dr. Elaine Wyllie, on campus at the Cleveland Clinic

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vi

Harry S. Abram, M.D.Assistant Professor of Pediatrics and NeurologyMayo Clinic FloridaNemours Childrens ClinicDirector, Neurophysiology Laboratory, Departmentof PediatricsWolfson Childrens HospitalJacksonville, Florida

Andreas V. Alexopoulos, M.D., M.P.H.Cleveland Clinic Lerner Research InstituteCleveland Clinic Epilepsy CenterCleveland ClinicCleveland, Ohio

Ulrich Altrup, M.D. (Deceased)Department of NeurologyInstitute for Experimental Epilepsy ResearchMuenster, Germany

Frederick Andermann, O.C., M.D., F.R.C.P. (C.)Professor of Neurology and PediatricsMcGill UniversityDirector, Epilepsy ServiceMontreal Neurological Hospital and InstituteMontreal, Quebec, Canada

Anne Anderson, M.D.Associate Professor of Pediatrics, Neurology,and NeuroscienceBaylor College of MedicineMedical Director, Epilepsy Monitoring UnitInvestigator, Cain Foundation LaboratoriesTexas Childrens HospitalHouston, Texas

Gail D. Anderson, Ph.D.Professor of PharmacyUniversity of WashingtonSeattle, Washington

Alexis Arzimanoglou, M.D.Associate ProfessorUniversity Hospitals of Lyon and INSERM U821Head, Institute for Children and Adolescents with EpilepsyIDEE and Pediatric NeurophysiologyHopital Femme Mere Enfant (HCL)Lyon, France

Thomas Bast, M.D.Head PhysicianEpilepsy Clinic for Children and AdolescentsEpilepsy Centre KorkKehl, Germany

Jocelyn F. Bautista, M.D.Assistant Professor of MedicineCleveland Clinic Lerner College of MedicineCleveland ClinicCleveland, Ohio

Selim R. Benbadis, M.D.Professor of NeurologyUniversity of South FloridaDirector of Epilepsy and EEGTampa General HospitalTampa, Florida

T.A. Benke, M.D., Ph.D.Associate Professor of Pediatrics, Neurology, andPharmacologyUniversity of Colorado Denver, School of MedicineChildrens HospitalAurora, Colorado

Anne T. Berg, Ph.D.Research Professor of BiologyNorthern Illinois UniversityDeKalb, IllinoisProfessor, Epilepsy CenterNorthwestern Childrens Memorial HospitalChicago, Illinois

William E. Bingaman, M.D.Head, Epilepsy SurgeryVice Chairman, Neurological InstituteThe Richard and Karen Shusterman Family Endowed Chairin Epilepsy SurgeryProfessor in SurgeryCleveland Clinic Lerner College of Medicine of Case WesternReserve UniversityCleveland ClinicCleveland, Ohio

Angela K. Birnbaum, Ph.D.Associate Professor of Experimental and ClinicalPharmacologyUniversity of MinnesotaMinneapolis, Minnesota

Jane G. Boggs, M.D.Associate Professor of NeurologyWake Forest UniversityWinston Salem, North Carolina

C O N T R I B U T I N G A U T H O R S

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Blaise F. D. Bourgeois, M.D.Professor of NeurologyHarvard Medical SchoolDirector, Division of Epilepsy and Clinical NeurophysiologyChildrens HospitalBoston, Massachusetts

Jeffrey W. Britton, M.D.Assistant Professor of NeurologyDivisions of Clinical NeurophysiologyEEG and EpilepsyMayo ClinicRochester, Minnesota

Paula M. Brna, M.D., F.R.C.P. (C.)Assistant Professor of PediatricsDalhousie UniversityPediatric NeurologistIWK Health CentreHalifax, Nova Scotia, Canada

Martin J. Brodie, M.D.Professor of Medicine and Clinical PharmacologyDivision of Cardiovascular and Medical SciencesUniversity of GlasgowClinical and Research Director, Epilepsy UnitWestern InfirmaryGlasgow, Scotland

Amy R. Brooks-Kayal, M.D.Professor of Pediatrics and NeurologyUniversity of Colorado School of MedicineChief and Ponzio Family Chair in Pediatric NeurologyChildrens HospitalAurora, Colorado

Richard C. Burgess, M.D., Ph.D.Adjunct Professor of Biomedical EngineeringCase Western Reserve UniversityDirector, MEG LaboratoryCleveland ClinicCleveland, Ohio

Richard W. Byrne, M.D.Professor and Chairman, Department of NeurosurgeryRush University Medical SchoolChicago, Illinois

Carol S. Camfield, M.D.Professor Emeritus of Child NeurologyDalhousie UniversityHalifax, Nova Scotia, Canada

Peter R. Camfield, M.D.Professor Emeritus of Child NeurologyDalhousie UniversityHalifax, Nova Scotia, Canada

Gregory D. Cascino, M.D., F.A.A.N.Professor of NeurologyMayo Clinic College of MedicineChair, Division of EpilepsyMayo ClinicRochester, Minnesota

Kevin E. Chapman, M.D.Department of Pediatric NeurologyBarrow Neurological InstituteSt. Josephs Hospital and Medical CenterPhoenix, Arizona

Jean E. Cibula, M.D.Assistant Professor of NeurologyUniversity of FloridaMedical Director, EEG LabUniversity of Florida Comprehensive Epilepsy ProgramShands Hospital at the University of FloridaGainesville, Florida

Robert R. Clancy, M.D.Professor of Neurology and PediatricsUniversity of Pennsylvania School of MedicineChildrens Hospital of PhiladelphiaPhiladelphia, Pennsylvania

J. Helen Cross, M.B., Ch.B., Ph.D., F.R.C.P.C.H., F.R.C.P.Prince of Waless Chair of Childhood EpilepsyUCL Institute of Child HealthHonorary Consultant in Paediatric NeurologyGreat Ormond Street HospitalLondon, England

Luigi DArgenzio, M.D.Epilepsy Fellow, Neuroscience UnitUCLInstitute of Child HealthLondon, United KingdomClinical Fellow in Paediatric NeurologyNational Centre for Young People with EpilepsyLingfield, Surrey, United Kingdom

Stefanie Darnley, B.A.Research Assistant in NeurologyJohns Hopkins University School of MedicineBaltimore, Maryland

Rohit R. Das, M.D., M.P.H.Assistant Professor of NeurologyUniversity of LouisvilleAttending Neurologist and EpileptologistKosair Childrens and University of Louisville HospitalsLouisville, Kentucky

Anita Datta, M.D., F.R.C.P.C.Clinical Assistant Professor of Pediatric NeurologyPediatric Neurologist/EpileptologistUniversity of SaskatchewanRoyal University HospitalSaskatoon, Saskatchewan, Canada

Norman Delanty, M.D., F.R.C.P.I.Honorary Senior Lecturer in Molecular and Cellular TherapeuticsRoyal College of Surgeons in IrelandConsultant Neurologist, Epilepsy ProgrammeBeaumont HospitalDublin, Ireland

Robert J. DeLorenzo, M.D., Ph.D., M.P.H.George Bliley Professor of NeurologyProfessor of Pharmacology and ToxicologyProfessor of Molecular Biophysics and BiochemistryVirginia Commonwealth UniversityVirginia Commonwealth University HospitalRichmond, Virginia

Darryl C. De Vivo, M.D.Sidney Carter Professor of Neurology and Professorof PediatricsColumbia University College of Physicians and SurgeonsNew York Presbyterian HospitalUniversity Hospital of Columbia and CornellNew York, New York

Contributing Authors vii

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Beate Diehl, M.D.Department of Clinical and Experimental EpilepsyInstitute of Neurology, University College LondonConsultant Clinical NeurophysiologistNational Hospital for Neurology and NeurosurgeryLondon, United Kingdom

Ding Ding, M.D., M.P.H.Associate Professor of Biostatistics and EpidemiologyFudan UniversityHua Shan HospitalShanghai, Peoples Republic of China

Joseph Drazkowski, M.D.Associate Professor of NeurologyMayo Clinic ArizonaPhoenix, Arizona

Franois Dubeau, M.D.Assistant Professor of Neurology and NeurosurgeryMcGill UniversityMontreal Neurological Hospital and InstituteMontreal, Quebec, Canada

Michael Duchowny, M.D.Professor of Neurology and PediatricsUniversity of Miami Miller School of MedicineDirector, Comprehensive Epilepsy Center, Brain InstituteMiami Childrens HospitalMiami, Florida

Stephan Eisenschenk, M.D.Associate Professor of NeurologyUniversity of FloridaDirector, UF/Shands Comprehensive Epilepsy ProgramShands HospitalGainesville, Florida

Dana Ekstein, M.D.Hebrew University School of MedicineHadassah University Medical CenterJerusalem, Israel

Christian E. Elger, M.D., F.R.C.P.Professor of EpileptologyUniversity of BonnHead, Department of EpileptologyUniversity of Bonn Medical CentreBonn, Germany

Edward Faught, M.D.Professor of NeurologyEmory UniversityChief, Neurology ServiceEmory University Hospital MidtownAtlanta, Georgia

Jacqueline A. French, M.D.Professor of NeurologyNew York University School of MedicineAcademic Director, Comprehensive Epilepsy CenterNew York University-Langone Medical CenterNew York, New York

Neil Friedman, M.D., Ch.B.Center for Pediatric NeurologyNeurological Institute, Cleveland ClinicCleveland, Ohio

William Davis Gaillard, M.D.Professor of Neurology and PediatricsGeorge Washington University and Georgetown UniversityChief, Division of Epilepsy, Neurophysiology and CriticalCare NeurologyChildrens National Medical CenterWashington, D.C.

Deana M. Gazzola, M.D.Instructor in NeurologyNew York University School of MedicineNew York University-Langone Medical CenterNew York, New York

Barry E. Gidal, Pharm.D.Professor, School of Pharmacy and Department of NeurologyChair, Pharmacy Practice DivisionUniversity of WisconsinMadison, Wisconsin

Frank G. Gilliam, M.D., M.P.H.Director of NeurologyGeisinger Health SystemWilkes-Barre and Danville, Pennsylvania

Robin L. Gilmore, M.D.Staff NeurologistMaury Regional Medical CenterColumbia, Tennessee

Tracy A. Glauser, M.D.Professor of PediatricsUniversity of Cincinnati College of MedicineDirector, Comprehensive Epilepsy CenterCincinnati Childrens Hospital Medical CenterCincinnati, Ohio

Cristina Y. Go, M.D.Neurologist and Clinical NeurophysiologistPaediatric Epilepsy Fellowship Training Co-directorThe Hospital for Sick ChildrenToronto, Ontario, Canada

Jorge A. Gonzlez-Martnez, M.D., Ph.D.Staff, Epilepsy SurgeryEpilepsy CenterCleveland Clinic Neurological InstituteCleveland, Ohio

Howard P. Goodkin, M.D., Ph.D.The Shure Associate Professor of Pediatric NeurologyDepartments of Neurology and PediatricsUniversity of VirginiaCharlottesville, Virginia

L. John Greenfield, Jr., M.D., Ph.D.Professor and ChairmanDepartment of NeurologyUniversity of Arkansas for Medical SciencesLittle Rock, Arkansas

Varda Gross-Tsur, M.D.Associate Professor Hebrew UniversityHadassah HospitalDirector, Child Development UnitShaare Zedek Medical CenterJerusalem, Israel

Carlos A. M. Guerreiro, M.D., Ph.D.Professor of NeurologyUniversity of Campinas (Unicamp)Campinas, Sao Paolo, Brazil

viii Contributing Authors

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Marilisa M. Guerreiro, M.D., Ph.D.Professor of Pediatric NeurologyHead, Child Neurology SectionUniversity of Campinas (Unicamp)Campinas, Sao Paolo, Brazil

Renzo Guerrini, M.D.Professor of Child Neurology and PsychiatryUniversity of FlorenceDirector, Pediatric NeurologyChildrens Hospital A. MeyerFlorence, Italy

Ajay Gupta, M.D.Assistant Professor of Pediatric EpilepsyCleveland Clinic Lerner College of MedicineCleveland ClinicCleveland, Ohio

Andreas Hahn, M.D.Associate Professor of NeuropediatricsJustus-Liebig-University GiessenAssistant Medical Director, NeuropediatricsUniversity Hospital GiessenGiessen, Germany

Stephen Hantus, M.D.Associate StaffCleveland Clinic Epilepsy CenterCleveland, Ohio

Cynthia L. Harden, M.D.Professor of Neurology, Clinical Educator TrackDirector, Division of EpilepsyUniversity of Miami Miller School of MedicineAttending NeurologistJackson Memorial HospitalUniversity of Miami HospitalMiami, Florida

W. Allen Hauser, M.D.Professor of Neurology and EpidemiologyColumbia UniversityNew York, New York

Lara Jehi, M.D.Assistant Professor of NeurologyCleveland Clinic Lerner College of MedicineEpilepsy Center, Cleveland ClinicCleveland, Ohio

Stephen E. Jones, M.D., Ph.D.Imaging InstituteCleveland ClinicCleveland, Ohio

Stephen P. Kalhorn, M.D.Department of NeurosurgeryNew York University Langone Medical CenterNew York, New York

Andres M. Kanner, M.D.Professor of Neurological Sciences and PsychiatryRush Medical College at Rush UniversityDirector, Laboratories of Electroencephalography and Video-EEG TelemetryAssociate Director, Section of Epilepsy and RushEpilepsy CenterRush University Medical CenterChicago, Illinois

Christoph Kellinghaus, M.D.Head of Section, Epilepsy/EEGKlinikum OsnabrckOsnabrck, Germany

John F. Kerrigan, M.D.Assistant Professor of Clinical Pediatrics and NeurologyUniversity of Arizona College of MedicinePhoenixDirector, Pediatric Epilepsy ProgramCo-director, Hypothalamic Hamartoma ProgramBarrow Neurological InstituteSt. Josephs Hospital and Medical CenterPhoenix, Arizona

Prakash Kotagal, M.D.Head, Section of Pediatric EpilepsyEpilepsy CenterCleveland ClinicCleveland, Ohio

Gregory Krauss, M.D.Professor of NeurologyJohns Hopkins HospitalBaltimore, Maryland

Ruben Kuzniecky, M.D.Professor of NeurologyNew York UniversityCo-director, NYU Epilepsy CenterNew York University HospitalNew York, New York

Patrick Kwan, M.D.Division of NeurologyDepartment of Medicine and TherapeuticsThe Chinese University of Hong KongPrince of Wales HospitalHong Kong

Kay Kyllonen, Pharm.D., F.P.P.A.G.Clinical Specialist in PediatricsPharmacy DepartmentCleveland ClinicCleveland, Ohio

Beth A. Leeman, M.D.Assistant Professor of NeurologyEmory UniversityPhysician, Neurology ServiceAtlanta VA Medical CenterAtlanta, GeorgiaAssistant in Neuroscience, Department of NeurologyMassachusetts General HospitalBoston, Massachusetts

Louis Lemieux, B.Sc., M.Sc., Ph.D.Professor of Physics Applied to Medical ImagingDepartment of Clinical and Experimental EpilepsyUCL Institute of NeurologyLondon, United Kingdom

Ilo E. Leppik, M.D.Professor of Pharmacy and Adjunct Professor of NeurologyDirector of Epilepsy Research and Education ProgramCollege of PharmacyUniversity of MinnesotaDirector of ResearchMINCEP Epilepsy CareMinneapolis, Minnesota

Contributing Authors ix

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Christine Linehan, Ph.D.Senior Researcher, Centre for Disability StudiesUniversity College DublinDublin, Ireland

Tobias Loddenkemper, M.D.Assistant Professor of NeurologyHarvard Medical SchoolChildrens HospitalBoston, Massachusetts

Hans O. Lders, M.D., Ph.D.Professor of NeurologyCase Medical SchoolEpilepsy Center DirectorUniversity HospitalsCleveland, Ohio

Susan E. Marino, Ph.D.Assistant Professor and Director of Experimental and Clinical PharmacologyCenter for Clinical and Cognitive NeuropharmacologyUniversity of MinnesotaMinneapolis, Minnesota

Robert C. Martinez, M.D.Instructor in Neurology, Epilepsy DivisionUniversity of Miami Miller School of MedicineJackson Memorial Hospital, University of Miami HospitalMiami, Florida

Gary W. Mathern, M.D.Professor of Neurosurgery and Psychiatry & BehavioralSciencesIntellectual and Developmental Disabilities Research CenterBrain Research InstituteDavid Geffen School of Medicine University of California, Los AngelesNeurosurgical Director, Pediatric Epilepsy Surgery Programand Neurobiology of Epilepsy Research LaboratoryRonald Reagan Medical CenterLos Angeles, California

Michael J. McLean, M.D., Ph.D.Associate Professor of NeurologyVanderbilt University Medical CenterNashville, Tennessee

Kimford J. Meador, M.D.Professor of NeurologyEmory UniversityDirector of EpilepsyEmory University HospitalAtlanta, Georgia

Mohamad Mikati, M.D.Wilburt C. Davison Distinguished Professor of PediatricsProfessor of NeurobiologyDuke UniversityChief, Division of Pediatric NeurologyDuke University Medical CenterDurham, North Carolina

Ghayda Mirzaa, M.D.Fellow, Clinical GeneticsDepartment of Human GeneticsUniversity of ChicagoChicago, Illinois

Eli M. Mizrahi, M.D.Chair of NeurologyProfessor of Neurology and PediatricsDirector, Clinical Neurophysiology Residency ProgramBaylor College of MedicineChief, Neurophysiology ServiceSt. Lukes Episcopal HospitalHouston, Texas

Ahsan N.V. Moosa, M.D.Epilepsy Center, Neurological InstituteCleveland ClinicCleveland, Ohio

Diego A. Morita, M.D.Assistant Professor of Pediatrics and NeurologyUniversity of Cincinnati College of MedicineDirector, New Onset Seizure ProgramCincinnati Childrens Hospital Medical CenterCincinnati, Ohio

Bernd A. Neubauer, M.D.Head, Department of NeuropediatricsUniversity of GiessenGiessen, Germany

Katherine C. Nickels, M.D.Assistant Professor of NeurologySenior Associate ConsultantMayo ClinicRochester, Minnesota

Soheyl Noachtar, M.D.Professor of NeurologyHead, Epilepsy CenterUniversity of MunichMunich, Germany

Douglas R. Nordli, Jr., M.D.Professor of PediatricsNorthwestern University Feinberg School of MedicineLorna S. and James P. Langdon Chair of Pediatric EpilepsyChildrens Memorial HospitalChicago, Illinois

Christine ODell, R.N., M.S.N.Clinical Nurse Specialist, NeurologyMontefiore Medical CenterNew York, New York

Karine Ostrowsky-Coste, M.D.University Hospitals of FranceInstitute for Children and Adolescents with EpilepsyIDEEand Pediatric NeurophysiologyHopital Femme Mere Infant (HCL)Lyon, France

Alison M. Pack, M.D.Associate Professor of Clinical NeurologyColumbia UniversityNew York Presbyterian HospitalNew York, New York

Sumit Parikh, M.D.Center for Pediatric NeurologyNeurological InstituteCleveland ClinicCleveland, Ohio

x Contributing Authors

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John M. Pellock, M.D.Professor and Chair of Child NeurologyVirginia Commonwealth UniversityRichmond, Virginia

Page B. Pennell, M.D.Associate Professor of NeurologyHarvard Medical SchoolDirector of Research for Division of Epilepsy and SleepBrigham and Womens HospitalBoston, Massachusetts

Andrew Pickens IV, M.D., J.D., M.B.A.Medical Director, Duke Raleigh Emergency Department,Quality ImprovementRaleigh, North Carolina

Bernd Pohlmann-Eden, M.D., Ph.D.Professor of Neurology and PharmacologyDalhousie UniversityCo-director, Epilepsy ProgramQueen Elizabeth II Health Science CentreHalifax, Canada

Richard A. Prayson, M.D.Professor of PathologyCleveland Clinic Lerner College of MedicineSection Head, NeuropathologyCleveland ClinicCleveland, Ohio

Janet Reid, M.D., F.R.C.P.C.Section Head of Pediatric RadiologyChildrens Hospital Cleveland ClinicCleveland, Ohio

James J. Riviello, Jr., M.D.George Peterkin Endowed Chair in PediatricsProfessor of Pediatrics and NeurologyBaylor College of MedicineChief of NeurophysiologyTexas Childrens HospitalHouston, Texas

Howard C. Rosenberg, M.D., Ph.D.Professor of Physiology and PharmacologyUniversity of Toledo College of MedicineToledo, Ohio

William E. Rosenfeld, M.D.DirectorComprehensive Epilepsy Care Center for Children and AdultsChesterfield, Missouri

Jonathan Roth, M.D.Pediatric Neurosurgery FellowNew York University Langone Medical CenterNew York, New York

Paul M. Ruggieri, M.D.Head, Section of Neuroradiology and MRICleveland ClinicCleveland, Ohio

Steven C. Schachter, M.D.Professor of NeurologyHarvard Medical SchoolChief Academic OfficerCenter for Integration of Medicine and Innovative TechnologyBoston, Massachusetts

Stephan Schuele, M.D., M.P.H.Assistant Professor of Neurology Northwestern UniversityFeinberg School of MedicineDirector, Northwestern University ComprehensiveEpilepsy CenterChicago, Illinois

Raj D. Sheth, M.D.Professor of NeurologyMayo Clinic College of MedicineNemours Childrens ClinicJacksonville, Florida

Shlomo Shinnar, M.D., Ph.D.Professor of Neurology, Pediatrics and Epidemiology andPopulation HealthHyman Climenko Professor of Neuroscience ResearchAlbert Einstein College of MedicineDirector, Comprehensive Epilepsy Management CenterMontefiore Medical CenterNew York, New York

Joseph I. Sirven, M.D.Professor and Chairman, NeurologyMayo ClinicPhoenix, Arizona

Michael C. Smith, M.D.Professor of Neurological SciencesRush University Director and Senior Attending Neurologist, Rush Epilepsy CenterRush University Medical CenterChicago, Illinois

O. Carter Snead III, M.D.Professor of Medicine, Paediatrics and PharmacologyUniversity of TorontoHead, Division of Neurology (Pediatrics)Hospital for Sick ChildrenToronto, Ontario, Canada

Elson L. So, M.D.Professor of NeurologyMayo ClinicRochester, Minnesota

Norman K. So, M.B., B.Chir.Epilepsy CenterNeurological InstituteCleveland ClinicCleveland, Ohio

Erwin-Josef Speckmann, M.D.Professor EmeritusInstitute of Physiology (Neurophysiology)University of MnsterMnster, Germany

Martin Staudt, M.D.Professor of Developmental NeuroplasticityEberhard-Karls UniversityTbingen, GermanyVice Director, Clinic for Neuropediatrics andNeurorehabilitation, Epilepsy Center for Childrenand AdolescentsSchn-Klinik VogtareuthVogtareuth, Germany

Contributing Authors xi

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S. Matthew Stead, M.D., Ph.D.Assistant Professor of NeurologyMayo ClinicRochester, Minnesota

William O. Tatum IV, D.O.Professor of NeurologyMayo Clinic College of MedicineDirector, Epilepsy Monitoring UnitMayo HospitalJacksonville, Florida

Elizabeth A. Thiele, M.D., Ph.D.Associate Professor of NeurologyHarvard Medical SchoolDirector, Pediatric Epilepsy ProgramMassachusetts General HospitalBoston, Massachusetts

Elizabeth I. Tietz, M.D.Professor and Vice-Chair of Physiology and PharmacologyUniversity of Toledo College of MedicineToledo, Ohio

Ingrid Tuxhorn, M.D.Professor of MedicineCase Western Reserve UniversityCleveland Clinic Lerner Research CenterNeurologic Institute at the Cleveland Clinic Epilepsy CenterCleveland, Ohio

Basim M. Uthman, M.D., F.A.C.I.P., F.A.A.N.Professor of NeurologyDirector, Neurology ClerkshipWeill Cornell Medical College in QatarQatar Foundation Education CityDoha, Qatar

Fernando L. Vale, M.D.Professor and Vice-Chair, Department of NeurosurgeryUniversity of South FloridaTampa General HospitalTampa, Florida

Tonicarlo R. Velasco, M.D.NeurophysiologistDepartment of Neurology, Psychiatry andBehavioral SciencesUniversity of Sao PauloExecutive Director, Adult Epilepsy Surgery ProgramHospital das Clinicas de Ribeirao Preto-CIREPRibeirao Preto, Sao Paulo, Brazil

Elizabeth Waterhouse, M.D.Professor of NeurologyVirginia Commonwealth University School of MedicineRichmond, Virginia

Tim Wehner, M.D.Department of NeurologyPhillips-UniversityUniversity Hospital MarburgMarburg, Germany

Howard L. Weiner, M.D.Professor of Neurosurgery and PediatricsNew York University School of MedicineNew York University Langone Medical CenterNew York, New York

Timothy E. Welty, Pharm.D., F.C.C.P.Professor and ChairDepartment of Pharmacy PracticeUniversity of KansasLawrence, KansasUniversity of Kansas Medical CenterKansas City, Kansas

James W. Wheless, M.D.Professor and Chief of Pediatric OncologyLe Bonheur Chair in Pediatric NeurologyUniversity of Tennessee Health Science CenterDirector, Neuroscience InstituteLe Bonheur Comprehensive Epilepsy ProgramLe Bonheur Childrens Medical CenterClinical Chief and Director of Pediatric NeurologySt. Jude Childrens Research HospitalMemphis, Tennessee

H. Steve White, Ph.D.Professor of Pharmacology and ToxicologyCollege of PharmacyUniversity of UtahSalt Lake City, Utah

L. James Willmore, M.D.Associate Dean and Professor of NeurologySt. Louis University School of MedicineSt. Louis University HospitalSt. Louis, Missouri

Sara McCrone Winchester, M.D.Pediatric Neurology FellowDepartment of Pediatrics, Division of Child NeurologyDuke University Medical CenterDurham, North Carolina

S. Parrish Winesett, M.D.Assistant Professor of NeurosurgeryUniversity of South FloridaTampa, FloridaMedical Director, Epilepsy Monitoring UnitAll Children HospitalSt. Petersburg, Florida

Elaine Wirrell, B.Sc. (Hon.), M.D., F.R.C.P.(C.)Professor of Child and Adolescent Neurology and EpilepsyDirector of Pediatric EpilepsyMayo ClinicRochester, Minnesota

Gregory A. Worrell, M.D., Ph.D.Assistant Professor of NeurologyMayo ClinicRochester, Minnesota

Elaine Wyllie, M.D.Professor of Pediatric MedicineCleveland Clinic Lerner College of MedicineDirector of the Center for Pediatric NeurologyNeurological InstituteCleveland ClinicCleveland, Ohio

Benjamin G. Zifkin, M.D.C.M., F.R.C.P.C.Epilepsy ClinicMontreal Neurological HospitalMontreal, Quebec, Canada

xii Contributing Authors

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When I started the first edition of this book as a newly mintedepileptologist at the Cleveland Clinic, most of our currentantiepileptic medications were still on the horizon and epilepsysurgery was in the early stages of development. Each successiveedition of the book chronicled sea changes in the field, from thedevelopment of powerful neuroimaging techniques, throughapproval of many new antiepileptic medications, to the emer-gence of genetics as a force in epilepsy diagnosis. Today, with itsown neurodiagnostic procedures and plethora of effective treat-ment modalities, epileptology is one of the most rewarding andcomplex fields in medicine. And in society, epilepsy is starting toemerge from the shadows as patients and families bandtogether in support groups and gather information from theinternet. Persons with epilepsy are demanding, expecting, state-of-the-art health care at the same time that our field is growingmore complex every day.

Thats why we need this book now more than ever. Its rea-son for being is to provide health care professionals with themost up-to-date tools to care for persons with epilepsy, day inand day out. Thanks to the 144 world-renowned experts whoshared their knowledge with us, this fifth edition is a ready ref-erence for cutting-edge information about everything fromcomplex drugdrug interactions to age-related EEG manifesta-tions of focal epileptogenic lesions. Its been an honor to craftthis work for all of us to use in our clinical practice.

Elaine Wyllie, MDProfessor of Pediatric Medicine

Cleveland Clinic Lerner College of MedicineDirector of the Center for Pediatric Neurology

Neurological InstituteCleveland Clinic

www.clevelandclinic.org/epilepsy

P R E F A C E

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xiv

It is a privilege and honor to be asked to write the foreword ofthe 5th Edition of Wyllies Treatment of Epilepsy. It is also aneasy task since I know the book well. The 4th edition is fre-quently pulled from my bookshelf when I have a question abouta patient with epilepsy, and I am looking forward to replacing itwith the 5th. While the first edition, published in 1993, was out-standing, each edition has achieved new heights. Recognizingthat it is very difficult to continuously improve a legendary text,the 5th edition will not disappoint.

Advances in the treatment of epilepsy continue to evolve at arapid rate as there is increasing awareness among both health-care workers and the public of the enormity of the condition.Epilepsy does not spare age, gender, race, or ethnic group and isone of the most common neurologic disorders encountered.Increased understanding of the etiology, pathophysiology, andgenetic underpinnings coupled with advancements in the med-ical, dietary, and surgical management of patients makes this anideal time to publish the 5th edition.

Elaine Wyllie, along with her associate editors GregoryCascino, Barry Gidal, and Howard Goodkin, has recruited anoutstanding group of authors who have provided a comprehen-sive, but not encyclopedic, review of the treatment of epilepsy.Each author is well known for their work in epilepsy.

The book is crafted in a logical and educationally soundmanner. Starting with the pathologic substrates and mechanismsof epilepsy, important chapters cover epidemiology, natural his-tory, genetics, and epileptogenesis (Part I). A key tool in the eval-uation of patients with epilepsy is the electroencephalogram andPart II of the book covers the basic principles of electroen-cephalography. A wonderful bonus in this section is a remark-ably complete atlas of epileptiform abnormalities.

Epileptic seizures and syndromes are detailed in Part III of thebook. The gamut of seizures and syndromes from the neonate to

the elderly are covered in considerable detail. Nonepileptic con-ditions that mimic epileptic seizures are reviewed and there is aheavy emphasis on seizures in special clinical settings, such asseizures in neurometabolic diseases, head trauma, and neurocu-taneous disorders.

Antiepileptic medications are reviewed in Part IV andepilepsy surgery in Part V. As the books title would indicate,these topics are covered in considerable depth, either of whichwould qualify as a stand-alone monograph. Dr. Wyllie and hercolleagues understand that individuals with epilepsy frequentlyhave more issues than just seizures, and have devoted Part VI topsychosocial aspects of epilepsy.

The authors have crafted a highly integrated text, not an easytask when dealing with multiple authors. As such, the book iseasy to read and flows from one part to the other rather seam-lessly. While few readers will read the book cover to cover, theinterested student who wishes to review topics will find theprocess enjoyable as well as educationally rewarding.

While there are numerous textbooks dealing with epilepsyavailable, none do as much as Wyllie and colleagues in one vol-ume. Beautifully illustrated and attractively designed, the 5thvolume will undoubtedly retain its stature as the best book onepilepsy available. It is highly recommended for everyone inter-ested in epilepsy, from the medical student to the seasonedepileptologist.

Books like Wyllies Treatment of Epilepsy do not happenwithout a great deal of work from the editors and authors.Kudos to all.

Gregory L. Holmes, MDProfessor of Neurology and Pediatrics

Chair, Department of NeurologyDartmouth Medical SchoolLebanon, New Hampshire

F O R E W O R D

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The fifth editions terrific associate editorsDr. GregoryCascino, Dr. Barry Gidal, and Dr. Howard Goodkineachbrought their own prodigious expertise, dedication, and goodhumor to the project. Ms. Jennifer Kowalak providedimpeccable editorial assistance, Mr. Arijit Biswas meticu-lously transformed the manuscript to final printer files, and Mr. Tom Gibbons at Lippincott gracefully shepherded the

book through every stage of production. Mr. Dick Blake,master teacher of dance and etiquette, remains a constantinspiration and wellspring of creativity. And I owe everythingto Dr. Robert Wyllie, Physician-in-Chief of the ClevelandClinic Childrens Hospitalmy husband, dancing partner, andfather to our sons, Mr. Robert Wyllie and Mr. James Wyllie,who make us proud.

A C K N O W L E D G M E N T S

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xvi

Section A Epidemiology and Natural History of Epilepsy

Chapter 1 Epidemiologic Aspects of Epilepsy 2Christine Linehan and Anne T. Berg

Chapter 2 The Natural History of Seizures 11D. Ding and W. A. Hauser

Section B Epileptogenesis, Genetics, and Epilepsy Substrates

Chapter 3 Experimental Models of Seizures and Mechanisms of Epileptogenesis 20T. A. Benke and A. R. Brooks-Kayal

Chapter 4 Genetics of the Epilepsies 34Jocelyn Bautista and Anne Anderson

Chapter 5 Pictorial Atlas of Epilepsy Substrates 43Ajay Gupta, Richard A. Prayson, and Janet Reid

Chapter 6 Neurophysiologic Basis of the Electroencephalogram 60Erwin-Josef Speckmann, Christian E. Elger, and Ulrich Altrup

Chapter 7 Localization and Field Determination in Electroencephalography 73Richard C. Burgess

Chapter 8 Application of Electroencephalography in the Diagnosis of Epilepsy 93Katherine C. Nickels and Gregory D. Cascino

Chapter 9 Electroencephalographic Atlas of Epileptiform Abnormalities 103Soheyl Noachtar and Elaine Wyllie

Section A Epileptic Seizures

Chapter 10 Classification of Seizures 134Christoph Kellinghaus and Hans O. Lders

C O N T E N T S

PART I PATHOLOGIC SUBSTRATES AND MECHANISMS OF EPILEPTOGENESIS

Contributing Authors viPreface xiiiForeword xivAcknowledgments xv

PART II BASIC PRINCIPLES OF ELECTROENCEPHALOGRAPHY

PART III EPILEPTIC SEIZURES AND SYNDROMES

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Contents xvii

Appendix 10.A: Proposal for Revised Clinical and Electrographic Classification of Epileptic Seizures 137Commission on Classification and Terminology of the International League Against Epilepsy (1981)

Chapter 11 Epileptic Auras 144Norman K. So

Chapter 12 Focal Seizures with Impaired Consciousness 153Lara Jehi and Prakash Kotagal

Chapter 13 Focal Motor Seizures, Epilepsia Partialis Continua, and Supplementary Sensorimotor Seizures 163Andreas V. Alexopoulos and Stephen E. Jones

Chapter 14 Generalized TonicClonic Seizures 184Tim Wehner

Chapter 15 Absence Seizures 192Alexis Arzimanoglou and Karine Ostrowsky-Coste

Chapter 16 Atypical Absence Seizures, Myoclonic, Tonic, and Atonic Seizures 202William O. Tatum IV

Chapter 17 Epileptic Spasms 216Ingrid Tuxhorn

Section B Epilepsy Conditions: Diagnosis and Treatment

Chapter 18 Classification of the Epilepsies 229Tobias Loddenkemper

Appendix 18.A: Proposal for Revised Classification of Epilepsies and Epileptic Syndromes 235Commission on Classification and Terminology of the International League Against Epilepsy (1989)

Chapter 19 Idiopathic and Benign Partial Epilepsies of Childhood 243Elaine C. Wirrell, Carol S. Camfield, and Peter R. Camfield

Chapter 20 Idiopathic Generalized Epilepsy Syndromes of Childhood and Adolescence 258Stephen Hantus

Chapter 21 Progressive and Infantile Myoclonic Epilepsies 269Bernd A. Neubauer, Andreas Hahn, and Ingrid Tuxhorn

Chapter 22 Encephalopathic Generalized Epilepsy and LennoxGastaut Syndrome 281S. Parrish Winesett and William O. Tatum IV

Chapter 23 Continuous Spike Wave of Slow Sleep and LandauKleffner Syndrome 294Mohamad A. Mikati and Sara M. Winchester

Chapter 24 Epilepsy with Reflex Seizures 305Benjamin Zifkin and Frederick Andermann

Chapter 25 Rasmussen Encephalitis (Chronic Focal Encephalitis) 317Franois Dubeau

Chapter 26 Hippocampal Sclerosis and Dual Pathology 332Luigi DArgenzio and J. Helen Cross

Chapter 27 Malformations of Cortical Development and Epilepsy 339Ghayda Mirzaa, Ruben Kuzniecky, and Renzo Guerrini

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Chapter 28 Brain Tumors and Epilepsy 352Lara Jehi

Chapter 29 Post-Traumatic Epilepsy 361Stephan Schuele

Chapter 30 Epilepsy in the Setting of Cerebrovascular Disease 371Stephen Hantus, Neil Friedman, and Bernd Pohlmann-Eden

Chapter 31 Epilepsy in the Setting of Neurocutaneous Syndromes 375Ajay Gupta

Chapter 32 Epilepsy in the Setting of Inherited Metabolic and Mitochondrial Disorders 383Sumit Parikh, Douglas R. Nordli Jr., and Darryl C. De Vivo

Section C Diagnosis and Treatment of Seizures in Special Clinical Settings

Chapter 33 Neonatal Seizures 405Kevin E. Chapman, Eli M. Mizrahi, and Robert R. Clancy

Chapter 34 Febrile Seizures 428Michael Duchowny

Chapter 35 Seizures Associated with Nonneurologic Medical Conditions 438Stephan Eisenschenk, Jean Cibula, and Robin L. Gilmore

Chapter 36 Epilepsy in Patients with Multiple Handicaps 451John M. Pellock

Chapter 37 Epilepsy in the Elderly 458Ilo E. Leppik and Angela K. Birnbaum

Chapter 38 Status Epilepticus 469Howard P. Goodkin and James J. Riviello Jr.

Section D Differential Diagnosis of Epilepsy

Chapter 39 Psychogenic Nonepileptic Attacks 486Selim R. Benbadis

Chapter 40 Other Nonepileptic Paroxysmal Disorders 495John M. Pellock

Section A General Principles of Antiepileptic Drug Therapy

Chapter 41 Antiepileptic Drug Development and Experimental Models 506H. Steve White

Chapter 42 Pharmacokinetics and Drug Interactions 513Gail D. Anderson

Chapter 43 Initiation and Discontinuation of Antiepileptic Drugs 527Varda Gross Tsur, Christine Odell, and Shlomo Shinnar

Chapter 44 Hormones, Catamenial Epilepsy, Sexual Function, and Reproductive Health in Epilepsy 540Cynthia Harden and Robert Martinez

xviii Contents

PART IV ANTIEPILEPTIC MEDICATIONS

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Contents xix

Chapter 45 Treatment of Epilepsy During Pregnancy 557Page B. Pennell

Chapter 46 Bone Health and Fractures in Epilepsy 569Raj D. Sheth and Alison Pack

Chapter 47 Treatment of Epilepsy in the Setting of Renal and Liver Disease 576Jane G. Boggs, Elizabeth Waterhouse, and Robert J. Delorenzo

Chapter 48 Monitoring for Adverse Effects of Antiepileptic Drugs 592L. James Willmore, John M. Pellock, and Andrew Pickens IV

Chapter 49 Pharmacogenetics of Antiepileptic Medications 601Tobias Loddenkemper, Tracy A. Glauser, and Diego A. Morita

Section B Specific Antiepileptic Medications and Other Therapies

Chapter 50 Carbamazepine and Oxcarbazepine 614Carlos A. M. Guerreiro and Marilisa M. Guerreiro

Chapter 51 Valproate 622Angela K. Birnbaum, Susan E. Marino, and Blaise F. D. Bourgeois

Chapter 52 Phenytoin and Fosphenytoin 630Diego A. Morita and Tracy A. Glauser

Chapter 53 Phenobarbital and Primidone 648Blaise F. D. Bourgeois

Chapter 54 Ethosuximide 657Andres M. Kanner, Tracy A. Glauser, and Diego A. Morita

Chapter 55 Benzodiazepines 668Lazor John Greenfield, Jr., Howard C. Rosenberg, and Elizabeth I. Tietz

Chapter 56 Gabapentin and Pregabalin 690Michael J. McLean and Barry E. Gidal

Chapter 57 Lamotrigine 704Frank Gilliam and Barry E. Gidal

Chapter 58 Topiramate 710William E. Rosenfeld

Chapter 59 Zonisamide 723Timothy E. Welty

Chapter 60 Levetiracetam 731Joseph I. Sirven and Joseph F. Drazkowski

Chapter 61 Tiagabine 736Dana Ekstein and Steven C. Schachter

Chapter 62 Felbamate 741Edward Faught

Chapter 63 Vigabatrin 747Elizabeth A. Thiele

Chapter 64 Rufinamide 753Gregory Krauss and Stefanie Darnley

Chapter 65 Lacosamide 758Raj D. Sheth and Harry S. Abram

Chapter 66 Adrenocorticotropin and Steroids 763Cristina Y. Go and Orlando Carter Snead III

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Chapter 67 Newer Antiepileptic Drugs 771Deana M. Gazzola, Norman Delanty, and Jacqueline A. French

Chapter 68 Less Commonly Used Antiepileptic Drugs 779Basim M. Uthman

Chapter 69 The Ketogenic Diet 790Douglas R. Nordli Jr. and Darryl C. De Vivo

Chapter 70 Vagus Nerve Stimulation Therapy 797James W. Wheless

Section A Identifying Surgical Candidates and Defining the Epileptogenic Zone

Chapter 71 Issues of Medical Intractability for Surgical Candidacy 810Patrick Kwan and Martin J. Brodie

Chapter 72 The Epileptogenic Zone 818Anita Datta and Tobias Loddenkemper

Chapter 73 MRI in Evaluation for Epilepsy Surgery 828Ahsan N.V. Moosa and Paul M. Ruggieri

Chapter 74 Video-EEG Monitoring in the Presurgical Evaluation 844Jeffrey W. Britton

Chapter 75 Nuclear Imaging (PET, SPECT) 860William Davis Gaillard

Chapter 76 Magnetoencephalography 869Thomas Bast

Chapter 77 Diffusion Tensor Imaging (DTI) and EEG-Correlated fMRI 877Beate Diehl and Louis Lemieux

Section B Mapping Eloquent Cortex

Chapter 78 Eloquent Cortex and the Role of Plasticity 887Tobias Loddenkemper and Martin Staudt

Chapter 79 Functional MRI for Mapping Eloquent Cortex 899William Davis Gaillard

Chapter 80 The Intracarotid Amobarbital Procedure 906Rohit Das and Tobias Loddenkemper

Chapter 81 Intracranial Electroencephalography and Localization Studies 914Fernando L. Vale and Selim R. Benbadis

Section C Strategies for Epilepsy Surgery

Chapter 82 Surgical Treatment of Refractory Temporal Lobe Epilepsy 922Tonicarlo R. Velasco and Gary W. Mathern

Chapter 83 Focal and Multilobar Resection 937Paula M. Brna and Michael Duchowny

Chapter 84 Hemispherectomies, Hemispherotomies, and Other HemisphericDisconnections 948Jorge A. Gonzlez-Martnez and William E. Bingaman

xx Contents

PART V EPILEPSY SURGERY

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Contents xxi

Chapter 85 Multifocal Resections or Focal Resections in Multifocal Epilepsy 957Howard L. Weiner, Jonathan Roth, and Stephen P. Kalhorn

Chapter 86 Nonlesional Cases 964Elson L. So

Chapter 87 Hypothalamic Hamartoma 973John F. Kerrigan

Chapter 88 Corpus Callosotomy and Multiple Subpial Transection 984Michael C. Smith, Richard Byrne, and Andres M. Kanner

Chapter 89 Special Considerations in Children 993Ajay Gupta and Elaine Wyllie

Chapter 90 Outcome and Complications of Epilepsy Surgery 1007Lara Jehi, Jorge Martinez-Gonzalez, and William Bingaman

Chapter 91 Electrical Stimulation for the Treatment of Epilepsy 1021S. Matthew Stead and Gregory A. Worrell

Chapter 92 Cognitive Effects of Epilepsy and Antiepileptic Medications 1028Kimford J. Meador

Chapter 93 Psychiatric Comorbidity of Epilepsy 1037Beth Leeman and Steven C. Schachter

Chapter 94 Driving and Social Issues in Epilepsy 1051Joseph F. Drazkowski and Joseph I. Sirven

Chapter 95 Achieving Health in Epilepsy: Strategies for Optimal Evaluation and Treatment 1057Frank G. Gilliam

Appendix Indications for Antiepileptic Drugs Sanctioned by the United States Food and Drug Administration 1062Kay C. Kyllonen

Index 1064

Cover image Artists rendition of an axial colorized fiber orientation map from diffusion tensor imaging (DTI) showing displacement of white matter tracts around a grey matter heterotopia in the right posterior quadrant. The original image is shown in Chapter 77.

With thanks to Dr. Beate Diehl and Prof. Louis Lemieux for sharing thiscase, and to Mr. Jeffrey Loerch for his artistic rendition.

PART VI PSYCHOSOCIAL ASPECTS OF EPILEPSY

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PART I PATHOLOGIC SUBSTRATES AND MECHANISMS OF EPILEPTOGENESIS

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2Time

FIGURE 1.1. Prevalence bias. Each horizontal line represents a casewith active disease (i.e., a prevalent case). The length of the line repre-sents the time of the active disease, with onset to the left and offset ordeath to the right. The dashed vertical line represents the day onwhich prevalence is measured. Long-duration cases are oversampled(8 of 8 are ascertained on the prevalence day) relative to short-duration cases (2 of 7 are ascertained on the prevalence day).

SECTION A EPIDEMIOLOGY AND NATURAL HISTORY OF EPILEPSY

An estimated 40 million individuals worldwide have epilepsy.This estimate is based on epidemiological data gathered aspart of the Global Burden of Disease (GBD) Study, a studypioneered by the World Health Organisation, the World Bank,and the Harvard School of Public Health (1). Mortality datafrom GBD, a traditional measure of burden of disease, indi-cates that 142,000 persons with epilepsy die annually, equat-ing to 0.2% of all deaths worldwide. Mortality statistics,however, mask the burden of disease among those living withepilepsy. Acknowledging the need to define burden beyondmortality, the GBD study introduced a new measure of burdenof diseases, injuries, and risk factors, the DALY (disability-adjusted life year). One DALY equates to 1 year of healthy lifelost due to disability or poor health. Epilepsy is estimated tocontribute 7,854,000 DALYs (0.5%) to the global burden ofdisease.

A clear pattern emerges from the GBD data whereby overhalf of all deaths and half of all years of healthy life lost toepilepsy occur in low-income countries. Moreover, almostone in five of all deaths and almost one in four of all yearsof healthy life lost to epilepsy worldwide occur among chil-dren living in these regions. The greater burden of epilepsyobserved in these regions is multifaceted but a major con-tributor is the treatment gap, that is, the differencebetween the number of individuals with active epilepsy andthe number who are being appropriately treated at a givenpoint in time. Estimates suggest that up to 90% of peoplewith epilepsy in resource-poor countries are inadequatelytreated (2).

The burden of epilepsy, however, extends beyond physicalhealth status. Stigma and discrimination are common featuresof the condition worldwide (3). Profound social isolation (4),feeling of shame and discomfort (5), and higher risk of psychi-atric disorder (6) are among a host of variables contributing toa compromised quality of life. Poor employment opportuni-ties, lost work productivity, and out of pocket health careexpenses contribute to the economic burden of epilepsy notonly for the individual with epilepsy but also for the familyand the wider community (2,7,8). In combination, these find-ings leave little doubt regarding the substantial burden ofepilepsy.

The first epidemiological study of epilepsy was conductedin 1959 by Leonard T. Kurland and reported population-based data from Rochester, Minnesota, over a 10-year period.Kurland acknowledged that data existed from numerousreports based on proportionate hospital admission rates andselected case series, but observed that these data are notnecessarily representative of a population from which the

patients are drawn (9). This observation was to profoundlyimpact not only the future of epidemiological studies in thefield but also the prevailing view of epilepsy and its prognosis.What Kurland had observed was that studies based on institu-tionalized patients suffered an inherent bias whereby thosewith more severe levels of epilepsy were overrepresented.Those with milder forms of epilepsy were less likely to attendspecialist referral centers and were therefore less likely to beidentified in these studies. The consequence of failing toinclude those with milder forms of epilepsy in epidemiologicalstudies was that epilepsy appeared as an unremitting andchronic condition affecting a somewhat smaller proportion ofpeople with epilepsy in the population (10).

Early epidemiological studies that followed fromKurlands work contributed substantially to our currentunderstanding of epilepsy. Additional studies exploring theRochester longitudinal population-based data sets, for exam-ple, illustrated that the occurrence of epilepsy and isolatedseizures was relatively common (11). These data sets alsorevealed that the probability of being in remission, as definedby five consecutive years of seizure freedom, was also morecommon than previously thought (12), an important consid-eration for investigators determining prevalence estimates(see Fig. 1.1). These early epidemiological findings providedan evidence base of the occurrence and prognosis of epilepsy

CHAPTER 1 EPIDEMIOLOGIC ASPECTS OF EPILEPSYCHRISTINE LINEHAN AND ANNE T. BERG

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that contributed to advances in the treatment and manage-ment of seizures (10).

Epidemiological investigations since these early studiescontinue to inform and challenge our understanding ofepilepsy. This chapter aims to outline current definitions anddistinctions in epidemiological research. In addition, findingsfrom more recent studies and the challenges presented toinvestigators conducting these studies are outlined.

CURRENT DEFINITIONS AND DISTINCTIONS USED IN

EPIDEMIOLOGIC EPILEPSYRESEARCH

Epilepsy (recurrent, unprovoked seizures) must be distin-guished from many other conditions and situations in whichseizures may occur. The following definitions are generallyaccepted and are in widespread use.

Epileptic Seizure

An epileptic seizure is a transient occurrence of signs and/orsymptoms due to abnormal excessive or synchronous neu-ronal activity in the brain (13). Epileptic seizures must bedistinguished from nonepileptic seizures and from otherconditions that may produce clinical manifestations that arehighly similar to those caused by epileptic seizures.

Acute Provoked Seizure

An acute provoked seizure is one that occurs in the context ofan acute brain insult or systemic disorder, such as, but not lim-ited to, stroke, head trauma, a toxic or metabolic insult, or anintracranial infection (14).

Unprovoked Seizure

A seizure that occurs in the absence of an acute provokingevent is considered unprovoked (14).

Epilepsy

The widely accepted operational definition of epilepsyrequires that an individual have at least two unprovokedseizures on separate days, generally 24 hours apart. An indi-vidual with a single unprovoked seizure or with two or moreunprovoked seizures within a 24-hour period is typically notat that time considered to have met the criteria for labelinghim with the diagnosis of epilepsy per se (14). A recent ILAEdocument attempted to provide a conceptual definition ofepilepsy that entailed the notion of an enduring underlyingpredisposition to unprovoked seizures. The definition waspresented, however, as an operational definition and engen-dered considerable controversy and response (1517) pre-cisely because there was no way to ensure that it would beconsistently and validly applied across different settings bydifferent investigators, a quality that is a prerequisite for

meaningful research. At the same time, we must recognize thata first seizure often is the first identifiable sign of epilepsy andthat in some cases, it is possible to recognize the specificunderlying disorder (form of epilepsy) at its earliest presenta-tion (18). In the case of Dravet syndrome, the first definitivesign may be a febrile seizure and, with a genetic test, theepilepsy may be diagnosed at that early time (19). Currently inepilepsy, particularly in epidemiological settings, this is theexception rather than the rule.

Etiology

Traditionally and according to ILAE Commission reports of1989 and 1993, etiology is partitioned into two primary cate-gories. Remote symptomatic refers to epilepsy that occurs inassociation with an antecedent condition that has beendemonstrated to increase the risk of developing epilepsy.Antecedent factors include, but are not limited to, history ofstroke, brain malformation, clear neurodevelopmental abnor-mality such as cerebral palsy, history of bacterial meningitis orviral encephalitis, certain chromosomal and genetic disorders,and tumors. Epilepsy in the context of a progressive condition(e.g., neurodegenerative disease or an aggressive tumor) isoften considered a subgroup within the category of remotesymptomatic. Idiopathic refers to a group of well-characterizeddisorders whose initial onset is concentrated during infancy,childhood, and adolescence. The intent of the term is to reflecta presumed genetic etiology in which the primary and oftenthe sole manifestation is seizures. Use of the term idiopathicrequires a precise diagnosis of the form of epilepsy. A thirdterm cryptogenic is used and rightfully means that the cause ofthe epilepsy is unknown; it could be secondary to an insultthat has not yet been identified (e.g., a cortical malformation)or it could be a genetic (idiopathic) epilepsy. Both possibilitiesare realized on a regular basis as new imaging techniquesuncover previously unrecognized malformations and geneticinvestigations identify new genetic syndromes. The InternationalLeague Against Epilepsy has revised and updated the conceptsand terminology to keep them relevant in the context of increas-ing advances in genomics and neuroimaging and improvedunderstanding of the epilepsies (20).

Gray Areas

Neonatal seizures (i.e., those occurring in an infant 28 daysold) are usually differentiated from epilepsy for a variety ofreasons; however, several specific forms of epilepsy have beenreported in this age group (21). For the epidemiologist, thedifficulty is accurate diagnostic information to distinguishwell-characterized forms of epilepsy from neonatal seizuresthat may reflect chronic or transient insults to the developingbrain. Febrile seizures are a well-described and recognizedseizure disorder that, for historical reasons, has been distin-guished (both clinically and in research) from epilepsy. Forthose involved in detailed genetic investigations, this may bean inappropriate distinction; however, for the epidemiologistwho may not always have the necessary clinical and particu-larly the genetic detail, the distinction is of value. It also hasimportant clinical implications for the treatment of childrenwith such seizures.

Chapter 1: Epidemiologic Aspects of Epilepsy 3

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4 Part I: Pathologic Substrates and Mechanisms of Epileptogenesis

Epilepsy Syndromes

Epilepsy syndromes have been alluded to above and are pre-sented in greater detail in subsequent chapters of this book.Epilepsy, like cancer, is not a single disorder, and the efforts toidentify specific forms of epilepsy reflect the importance of thediversity within the epilepsies. The epilepsy syndromes repre-sent forms of epilepsy that have different causes, differentmanifestations, different implications for short- and long-termmanagement and treatment, and different outcomes. Manyepidemiological studies do not attempt to identify specificforms of epilepsy; however, in large-scale population- andcommunity-based studies, it is possible to do, provided theinvestigators have access to the necessary information and theexpertise needed to diagnose these syndromes (18,22,23).

EPIDEMIOLOGY

Epidemiological studies have provided valuable insights intothe frequency of seizures within the population and have pro-vided the initial impetus for some of the distinctions outlinedabove. However, as Kurland noted, epidemiologists need to bevigilant to potential sources of bias that threaten the validityof their findings. The ability of diagnosticians to appropriatelyidentify cases and the capabilities of epidemiologists to iden-tify those cases within the population are fundamental issueswithin the field of epidemiology.

Diagnostic Issues and Considerations in Ascertaining Cases

Seizures and epilepsy present a complex situation because thediagnosis is not based on a single source or type of information.Rather, epilepsy is a clinical diagnosis supported to a greater orlesser extent by a wide range of data obtained from severalsources: the medical history, the history (both from the patientand witnesses) of the events believed to be seizures, the circum-stances under which the events occur, a neurologic examina-tion, reliable EEG, and increasingly neuroimaging (24). To havea valid diagnosis, one must also be able to rule out many otherconditions that mimic seizures. These disorders include, but arenot limited to, movement disorders, parasomnias, attention-deficit/hyperactivity disorder, pseudo- or nonepileptic seizures,transient ischemic attacks, and syncope (see Chapters 39 and 40).

Ideally, a diagnosis of epilepsy should be undertaken bymedical practitioners with expertise in epilepsy (25).Unfortunately, access to neurologists and epilepsy specialists isgenerally poor in developing countries and often poor indeveloped countries as well. Consequently, diagnoses may bemade by those with only minimal expertise in the field(26,27). Estimates of misdiagnosis rates suggest that over onefifth of persons with a diagnosis of epilepsy may be misdiag-nosed (28,29). Re-evaluation of initial diagnosis of epilepsy inepidemiological studies report rates of 23% (30,31) with diag-nostic doubt among patients diagnosed by neurologists andnonspecialists reported at 5.6% and 18.9%, respectively (32).

Epidemiological studies that rely on medical registers forcase ascertainment provide valuable insights into levels of mis-diagnoses. Christensen et al. (33), for example, randomlyselected n 200 patients with an ICD diagnosis of epilepsy

from the Danish National Hospital Register, a national regis-ter of all discharges and outpatient cases from Danish hospi-tals. The authors reported that almost one in five (19%) of thepatients did not fulfill the ILAE criteria for an epilepsy diag-nosis. In fact, approximately 7% of patients were given anepilepsy diagnosis on the basis of one seizure. Christensenet al. (34) also noted that while the validity of epilepsy diag-nosis from the register was moderate to high, there was lowpredictive value for epilepsy syndromes.

Primary care registers, a common source of case ascertain-ment in epidemiological research, have also been found toinclude persons incorrectly diagnosed with epilepsy. Gallittoet al. (35) gathered population-based data from general prac-titioners (GPs) in the Aeolian Islands. All established or sus-pected cases of epilepsy were evaluated by epileptologists inthe local outpatient services with the support of the local GPsor, for those with additional disabilities, within the familyhome. The evaluations comprised a review of medical notesand where necessary EEG or neuroradiologic investigation.Following the epileptologic evaluation 30% of established andsuspected cases were identified as not fulfilling the diagnosticcriteria for epilepsy.

While organizations such as the UK-based NationalInstitute for Health and Clinical Excellence have proposedbest practice guidelines in diagnosis, currently no agreedcriteria exist for what constitutes an adequate diagnostic eval-uation including who should perform it. There are also nostandards in epidemiological studies for the use of routinediagnostic tests such as EEG and MRI. Unsurprisingly, therehas been a call for a gold standard diagnostic criterion to dis-tinguish epileptic seizures from other diagnoses with similarclinical features (28).

In addition to the determination of whether someone hasepilepsy, adequate information is needed to identify the specificform of epilepsy and its underlying cause. While this level ofdetail is frequently absent from traditional epidemiologicalstudies, it must be incorporated in the future if epidemiologicalstudies are to continue to inform scientific and clinical endeav-ors relevant to epilepsy as it is understood and treated today.Without a meaningful diagnostic evaluation, epidemiologicalstudies can do little more than provide an approximate headcount which previous work has shown to be rather error-prone.The lumping together of highly diverse disorders that share thediagnostic label epilepsy also limits the ability of epidemio-logical studies to provide meaningful prognostic information.

Other case ascertainment options have been employed byepidemiologists, each having its own unique challenges.Screening questionnaires, for example, are a common toolused in epidemiologic studies. Methodologies employingscreening questionnaires typically comprise two phases. In thefirst phase, a screen is used to identify positive cases. In thesecond phase, these positive cases are evaluated clinically toconfirm the presence of epilepsy. Noronha et al. (36), forexample, used a screening tool developed by Borges et al. (37)in the first phase of their study to determine the prevalence ofepilepsy in Brazil. The screening tool reported sensitivity andspecificity at 96% and 98%, respectively. Similarly, Melconet al. (38) used a modified version of a screening tool from theCopiah County study (39) to identify potential cases for inclu-sion in their prevalence estimate of epilepsy in Argentina. Thisscreening tool also reported acceptable levels of sensitivity andspecificity at 95% and 80%, respectively.

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Screening tools are also advocated by the World HealthOrganisation, whose Global Campaign against Epilepsysupports those undertaking epidemiological research inresource-poor countries. Demonstration projects managedunder this program, in addition to assessments of local knowl-edge, attitude and health service provision, undertake epi-demiological door-to-door studies to determine prevalenceestimates. Screening tools developed by WHO (40) have beenused in large-scale national epidemiological studies (41).Notwithstanding the successful application of screening toolsin many studies, the diagnostic sensitivity and specificity ofthese tools can, however, be poor and the training of physi-cians or other health care professionals charged with validat-ing positive screens may be compromised by poor access tosuch basic diagnostic tools as EEGs.

Other case ascertainment sources used in epidemiologicalstudies include prescription databases recording anti-epilepsydrug usage. By definition, these epidemiological studies esti-mate treated epilepsy and are more common in developedcountries where the treatment gap is minimal. Prescriptiondatabases have been found to offer a suitable means by whichthe prevalence of epilepsy can be determined in communitysamples (42) as the coverage of the databases is typically farbroader than medical registers. Purcell et al. (43), for example,examined rates of treated epilepsy in the United Kingdomusing the General Practitioner Research Database that pro-vided data on prescription use of over 1.4 million persons.

A potential source of bias in identifying persons withepilepsy from prescription databases is that cases cannot beclinically validated (43,44). This bias is magnified in situationswhere diagnosis is not recorded on the database and whereestimates of drug use among people with epilepsy areapplied (45,46). While anti-epilepsy drugs have been previ-ously identified as tracers of epilepsy due to their chronicand highly specific usage (46) the growing use of anti-epilepsymedication for indications other than epilepsy, such as pain,migraine, bipolar disorders, agitation, hormonal imbalance,and weight reduction must now be considered. In general,reliance on prescription data alone is an inadequate caseascertainment method for epilepsy.

A methodology for case ascertainment that is becomingmore frequently used in North American studies is the self-report survey. These studies typically include epilepsy-specificitems in large population-based health surveys (4750). Thecoverage of these surveys is extensive. The Canadian HealthSurvey, for example, was completed by over 130,000 persons,all of whom were questioned as to their health status, healthcare utilization, and determinants of health (47). TheCalifornia Health Interview Survey 2003 provided similardata on over 41,000 persons (50).

The Behavioral Risk Factor Surveillance System (51) pro-vides an example of the typical type of epilepsy-specific itemsthat can be included in these surveys; Have you ever beentold by a doctor that you have a seizure disorder or epilepsy?A distinct advantage of this methodology is the opportunity itaffords to examine not only the frequency of self-reportedepilepsy among very large representative populations but alsothe impact of epilepsy on their health-related quality of life.Issues such as employment, education, and comorbid condi-tions can be examined. Where these items are common toboth those with and without a self-report of epilepsy, impor-tant disparities can be identified. Without doubt, this method

differs from more rigorous epidemiologic studies (49). A selec-tion bias may exist whereby, despite the broad community-dwelling population from which samples are drawn, thosewho agree to participate in surveys may differ in some funda-mental way from those who decline. This method also facesthe challenge previously observed among studies examiningprescription databases whereby cases are not clinically vali-dated. Whether those who self-disclose epilepsy do in facthave the condition cannot be determined, no more so thanthose who have epilepsy but chose not to disclose it.

Each of the methods outlined above has its own benefitsand challenges. This has led some researchers to propose thatthe most valid method to identify cases of epilepsy is to accessmultiple sources of case ascertainment (52). Data linkagestudies, for example, provide opportunities simultaneously toexamine both population-based and hospital-based registers(53,54). These multicase ascertainment studies make it possi-ble not only to estimate the number of cases missed by eachsource but also to indirectly estimate the number of casesmissed by the combined dataset (55). Choice of case ascer-tainment, however, may not always be at the discretion of theepidemiologist. Resources of appropriately trained personnel,funding, and sophistication of health care services are some ofthe many factors that influence how the same study might beconducted differently in different jurisdictions.

Variations in methodology can result in highly varying esti-mates of epilepsy (56,57). A contributing factor is the lack ofharmonized definitions employed across studies. Despite theCommission of Epidemiology and Prognosis of the ILAE (14)issuing guidelines for definitions employed in epidemiologicalstudies, specific definitions of what constitutes epilepsy,active cases, and cases in remission differ markedly amongstudies. Definition of active epilepsy, for example, varies interms of their stated duration since last seizure, with some stud-ies using the ILAE-recommended definition of one seizure oruse of anti-epilepsy drugs within the previous 5 years (58) andothers truncating this duration to the previous 3 months(49,50). Harmonization of definitions is encouraged as it wouldpermit valuable comparisons of findings across studies.

FREQUENCY MEASURES OF INCIDENCE AND PREVALENCE

Incidence is expressed as the number of new cases of disease ina standard-sized population per unit of timefor example,the number of cases per 100,000 population per year.Prospective studies of incidence are advocated as they permitobservation of any changes in the incidence rate (52) and maytherefore identify risk factors that play a causal role in thedevelopment of epilepsy (33,59). Ongoing surveillance studiesof this type however are time-consuming and costly (52,60)and are therefore less common than prevalence studies (52,61)and less likely to be conducted in resource-poor countries(62). Incidence rates for epilepsy are typically between 30 and80 per 100,000 population per year in developed countriesbut have been observed to exceed these figures. Table 1.1 pre-sents a selection of studies illustrating this trend.

Worldwide, rates vary across regions, with rates being typ-ically higher in resource-poor countries (59), most especiallyin Africa and Latin America where figures can exceed 100 per100,000 population (6365). Rates also differ by age, but

Chapter 1: Epidemiologic Aspects of Epilepsy 5

59377_ch01.qxd 8/28/10 9:04 PM Page 5

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59377_ch01.qxd 8/28/10 9:04 PM Page 6

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inte

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to f

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o ch

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14 y

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of

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pile

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refe

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Mila

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blis

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prio

r to

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9.d L

iste

d as

sp

ecia

l syn

drom

e.

7

59377_ch01.qxd 8/28/10 9:04 PM Page 7

8 Part I: Pathologic Substrates and Mechanisms of Epileptogenesis

differentially in developed and resource-poor countries. Indeveloped countries, rates are highest among infants and olderpersons (6669). Although incidence rates among children havefallen over the last three decades in developed countries, thisdecrease has been offset by an increase among older persons(70). A different age-related pattern emerges in developingcountries, however, where a decrease in incidence is observedwith age (59). The larger proportion of children in developingcountries is thought to contribute to the higher overall inci-dence rates when compared with developed countries (34,59).

Prevalence studies measure the total number of personswith epilepsy at a specific moment in time. Prevalence ratesare usually expressed as the number of persons with epilepsyper 1000 population. Estimates of active epilepsy are typicallythe focus of prevalence studies, with those in remission or whoare not receiving treatment at the time of case ascertainmentbeing excluded. A plethora of studies that consistently reportprevalence estimates of active epilepsy in developed countriesof between 4 and 10 per 1000 population suggests there islittle justification for further cross-sectional studies of preva-lence (56) in these countries. Recent findings from Norway,however, of 12 per 1000 treated epilepsy and 7 per 1000active cases in a population that excluded high-risks groupssuch as older persons have led investigators to suggest that thetrue prevalence of epilepsy in developed countries may behigher than previously reported (71). Prevalence estimatestypically increase with age and are generally higher amongmales than females (52), although this difference may notalways reach statistical significance.

Prevalence estimates in resource-poor countries are gener-ally higher than in developed countries (56). Median preva-lence of active epilepsy in Latin America is reported as 12.4 per1000 population; however, this finding conceals widely vary-ing findings from individual studies ranging from 5.1 to 57 per1000 population (72). This wide variation in estimates is alsoobserved in Africa where estimates have been reported rangingfrom 5.2 to 58 per 1000 (73,74). While researchers note thatknown risk factors, such as environment, contribute to thehigh-prevalence estimates on the African continent (75), someauthors suggest that the true prevalence estimate may actuallybe higher again as disclosure of the condition is particularlyproblematic (76). Reviews of studies conducted in Asia, per-haps surprisingly, report findings aligning more closely withthose in developed countries. This has led some investigators tospeculate whether there is a specific protective factor as yetunknown in Asia or whether the finding reflects specific riskfactors in Latin America and Africa (61). Table 1.1 presentsfindings from some recent studies worldwide (7785).

Several recent studies have examined the relative frequency,if not absolute incidence, of different forms of epilepsy in well-characterized series of incident patients who were reasonablyrepresentative of the populations from which they were drawn(Table 1.2) (8688). Apart from the obvious differencebetween adults and children, there is a degree of variationamong the studies just of children as well. Whether this repre-sents real differences across populations or methodologicaldifference between studies is not clear. Certainly, patterns ofreferral to recruitment sources as well as the diagnostic abilityof the physicians who evaluate the patients, could createapparent differences between studies where none exist. Suchconcerns aside, a few generalities can be drawn. Fewer chil-dren than adults are likely to have an unclassified form of

epilepsy. In children, idiopathic focal epilepsies (largely domi-nated by Benign Rolandic Epilepsy) comprise about 5% to10% of childhood-onset epilepsy. The idiopathic generalizedepilepsies comprise 20% to 40%. Finally, between 10% and20% of childhood-onset epilepsy falls into the category of sec-ondary generalized. These are some of the most devastatingand intractable forms of epilepsy and include West andLennoxGastaut syndrome.

SUMMARY

Epidemiology has been key in demonstrating the relativelyhigh frequency of seizures in the population and in challenginglong-held beliefs about the uniformly poor seizure outcomesassociated with seizures. Research pursuits within the epidemi-ology of epilepsy have come a long way from the days of sim-ply counting how many people in a given population hadseizures. Some studies are providing estimates of the frequencyof specific t