The Treatment of Fourth edition

Edited by Simon Shorvon MA MB BChir MD FRCP Professor in Clinical Neurology and Consultant Neurologist UCL Institute of Neurology, University College London National Hospital for Neurology and Neurosurgery London, UK Emilio Perucca MD PhD FRCP(Edin) Professor of Medical Pharmacology Clinical Pharmacology Unit, Department of Internal Medicine and Terapeutics University of Pavia and Director, Clinical Trial Center C. Mondino National Neurological Institute Pavia, Italy Jerome Engel, Jr. MD PhD Jonathan Sinay Distinguished Professor of Neurology Neurobiology, and Psychiatry and Biobehavioral Sciences Director UCLA Seizure Disorder Center David Gefen School of Medicine at University of California Los Angeles, USA Tis edition frst published 2016 © 2016 by John Wiley & Sons, Ltd. Registered ofce: John Wiley & Sons, Ltd, Te Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial ofces: 9600 Garsington Road, Oxford, OX4 2DQ, UK Te Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial ofces, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell Te right of the authors to be identifed as the authors of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Designations used by companies to distinguish their products are ofen claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. Te publisher is not associated with any product or vendor mentioned in this book. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Te contents of this work are intended to further general scientifc research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specifc method, diagnosis, or treatment by health science practitioners for any particular patient. Te publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifcally disclaim all warranties, including without limitation any implied warranties of ftness for a particular purpose. In view of ongoing research, equipment modifcations, changes in governmental regulations, and the constant fow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. Te fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data are available A catalogue record for this book is available from the British Library. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Cover images: Front cover panels: top and bottom images courtesy of the authors; middle image supplied by GettyImages-172594468, courtesy of Science Photo Lib/KTSDESIGN. Set in 9/11 pt Minion Pro by Aptara, India Printed in [Country only] 1 2016 Contents

List of Contributors v 15 Management of Epilepsy in People with Intellectual Preface to the Fourth Edition ix Disabilities 193 Eylert Brodtkorb Preface to the First Edition xi 16 Management of Epilepsy in the Elderly 205 Historical Introduction: Te Treatment of Epilepsy Hiba Arif Haider and Lawrence J. Hirsch from 1857 to 2015 xiii 17 Emergency Treatment of Seizures and Status Epilepticus 221 Matthew C. Walker and Simon Shorvon Section I – Introduction 18 Management of Medical Comorbidity Associated with (Lead editor: Simon Shorvon) Epilepsy 245 1 Defnition (Terminology) and Classifcation in Epilepsy: A Gagandeep Singh Historical Survey and Current Formulation, with Special 19 Psychiatric Features of Epilepsy and their Management 259 Reference to the ILAE 1 Brent Elliott and Simon Shorvon Simon Shorvon 20 Prevention and Management of Side-efects of Antiepileptic 2 Diferential Diagnosis of Epilepsy 24 275

Mark Cook Gaetano Zaccara and Piero Perucca 3 Mechanisms of Epileptogenesis 38 21 Ketogenic Diets 288

Giuliano Avanzini and Silvana Franceschetti Eric H. Kossof and Courtney A. Haney 4 Antiepileptic Drug Discovery 52 22 Complementary and Alternative Treatments for Epilepsy 298

H. Steve White and Melissa Barker-Haliski Sallie Baxendale 5 Antiepileptic Drug Development 61 23 Reproductive Aspects of Epilepsy Treatment 311

Dieter Schmidt Torbjörn Tomson 6 Mechanisms of Antiepileptic Drug Action 75 24 Genetic Counselling in Epilepsy 323

Matthew C. Walker and Rainer Surges Federico Zara 7 Mechanisms of Drug Resistance and Tolerance 92 25 Drug Interactions 344

Wolfgang Löscher and Dieter Schmidt Edoardo Spina and Domenico Italiano 8 Epilepsy Biomarkers 103 26 Medical Treatment of Epilepsy in Resource-Poor

Jerome Engel, Jr. and Asla Pitkänen Countries 360 Patrick Adjei Section II – Principles of Medical Management (Lead editor: Simon Shorvon) Section III – Antiepileptic Drugs 9 General Principles of Medical Management 110 (Lead editor: Emilio Perucca) Emilio Perucca 27 Introduction to the Choice of Antiepileptic Drugs 365 10 Pharmacokinetic Optimization of Terapy 124 Emilio Perucca Svein I. Johannessen, Cecilie Johannessen Landmark and 28 376 Emilio Perucca Miri Y. Neufeld 11 Management of Chronic Active Epilepsy in Adults 139 29 Adrenocorticotropic Hormone and Corticosteroids 388 Simon Shorvon Federico Vigevano and Maria Roberta Cilio 12 Management of Epilepsy in Remission 148 30 Used in the Treatment of Epilepsy 398 Patrick Kwan, Howan Leung and Xiaoting Hao Eugen Trinka and Francesco Brigo 13 Management of Epilepsy in Neonates and Infants 156 31 418 Elissa G. Yozawitz and Solomon L. Moshé Joseph D’Souza and Emilio Perucca 14 Management of Childhood Epilepsy Syndromes 174 32 431 Colin D. Ferrie Torbjörn Tomson and Svein I. Johannessen

iii iv Contents

33 447 58 Invasive EEG in Presurgical Evaluation of Epilepsy 733 Meir Bialer and Christian Elger Dennis Spencer, Dang K. Nguyen and Adithya Sivaraju 34 460 59 MEG in Epilepsy Surgery Evaluation 756 Tracy A. Glauser and Emilio Perucca Hermann Stefan and Paul Boon 35 472 60 MRI in Presurgical Evaluation 764 Ilo E. Leppik and James R. White Christian E. Elger and Bernd Weber 36 479 61 PET and SPECT in Presurgical Evaluation of Epilepsy 775 Ernest R. Somerville, Andrew W. Michell and Arjune Sen Karolien Gofn and Wim Van Paesschen 37 489 62 Special Neurophysiological Techniques 787 Rajesh Sachdeo and Roopal Karia François Mauguière and Julien Jung 38 498 63 Neuropsychological Testing in Presurgical Evaluation 804 Awais Riaz and Fumisuke Matsuo Marilyn Jones-Gotman and Gail L. Risse 39 516 64 Presurgical Psychiatric Evaluation 817 Derek J. Chong and Jacqueline A. French Andres M. Kanner 40 533 65 Mesial Temporal Lobe Surgery and Other Lobar Edward Faught and Hyunmi Kim Resections 829 41 546 James Leiphart and Itzhak Fried Martin Brodie 66 Resective Surgery of Neoplasms 842 42 , and Other 555 Nicholas M. Wetjen and Gregory D. Cascino Roberto Michelucci and Elena Pasini 67 Resective Surgery of Vascular and Infective Lesions for 43 574 Epilepsy 858 Mervyn J. Eadie Christopher E. Uf and Neil D. Kitchen 44 589 68 Surgery of Developmental Anomalies Causing Epilepsy 878 Simon D. Shorvon Ahyuda Oh, Joshua J. Chern and Youssef G. Comair 45 595 69 Hemispheric Operations for Epilepsy 887 Sylvain Rheims and Philippe Ryvlin Georg Dorfmüller, Christine Bulteau and Olivier Delalande 46 606 70 Corpus Callosum Operations 895 Michel Baulac David W. Roberts 47 Rufnamide 617 71 Hypothalamic Hamartoma 903 Victor Biton John F. Kerrigan 48 628 72 Multiple Subpial Transection 916 Tapani Keränen Adriana Bermeo-Ovalle and Michael C. Smith 49 633 73 Awake Surgery for Epilepsy 922 Reetta Kälviäinen Webster H. Pilcher 50 642 74 Epilepsy Surgery in Children 931 J. Helen Cross and Catherine J. Riney Jason S. Hauptman and Gary W. Mathern 51 652 75 Complications of Epilepsy Surgery 941 Anthony G. Marson and Graeme J. Sills Charles E. Polkey 52 667 76 Anaesthesia for Epilepsy Surgery 952 Günter Krämer and Gabriele Ch. Wohlrab Barbara M. Van de Wiele 53 680 77 Vagus and Trigeminal Nerve Stimulation 959 Michel Baulac Steven C. Schachter 54 Other Less Commonly Used Antiepileptic Drugs 689 78 Brain Stimulation for Epilepsy 967 Martin Holtkamp Gregory K. Bergey and Robert S. Fisher 55 Drugs in Clinical Development 701 79 Non-Resective Approaches for Medically Intractable Norman Delanty and H. Steve White Epilepsy 980 Tomas J. Gianaris, Andrea G. Scherer and Nicholas M. Barbaro 80 Section IV – Presurgical Assessment and Epilepsy Surgery Future Focal Treatment Approaches to Epilepsy 987

(Lead editor: Jerome Engel, Jr.) Laura Mantoan Ritter and Hannah Cock 81 Epilepsy Surgery in Countries with Limited Resources 999 56 Overview of Surgical Treatment for Epilepsy 709 Andre Palmini and Kurupath Radhakrishnan Jerome Engel, Jr. 57 Scalp EEG in the Epilepsy Surgery Evaluation 723 Christine B. Baca and John M. Stern Index 1008 List of Contributors

Patrick Adjei, MBCHB MWACP Meir Bialer, PhD MBA Derek J. Chong, MD MSc PhD David H. Eisenberg Professor of Pharmacology Assistant Professor of Neurology Lecturer Institute for Drug Research Director, Epilepsy and EEG Consult Services Neurology Unit School of Pharmacy New York University Comprehensive Epilepsy Center Department of Medicine and Terapeutics Faculty of Medicine New York, USA School of Medicine and Dentistry Te Hebrew University of Jerusalem University of Ghana and David R. Bloom Center for Pharmacy Maria Roberta Cilio, MD PhD Accra, Ghana Jerusalem, Israel Professor, Neurology and Pediatrics Division of Epilepsy and Clinical Neurophysiology Giuliano Avanzini, MD Victor Biton, MD Beniof Children’s Hospital Emeritus Professor of Neurology Director of Arkansas Epilepsy Program and Clinical University of California C. Besta Foundation Trials, Inc. San Francisco, USA Neurological Institute Little Rock Milan, Italy Arkansas, USA Hannah R. Cock, BSc MD FRCP Reader in Clinical Neurology and Honorary Consultant Christine B. Baca, MD MSHS Paul Boon, MD PhD Neurologist Assistant Professor of Neurology Professor and Chairman Atkinson Morley Regional Neuroscience Centre Department of Neurology Department Neurology Ghent University Hospital St Georges University Hospitals NHS Foundation Trust University of California Belgium and St George’s University of London and VA Greater Los Angeles Health Care System and Director Research and Development London, UK Los Angeles, USA Academic Center for Epileptology Kempenhaeghe-Maastricht Youssef G. Comair, MD FRCSC Nicholas M. Barbaro, MD Te Netherlands Dean and Professor of Surgery Betsey Barton Professor and Chairman of Gilbert and Rose-Marie Chagoury School of Medicine Neurosurgery Francesco Brigo, MD Lebanese American University and Medical Director Honorary Research Associate Beirut, Lebanon Department of Neurological Surgery and IU Health Department of Neurological and Movement Sciences Neuroscience Center University of Verona Mark J. Cook, MB BS MD Indiana University School of Medicine Verona, Italy Sir John Eccles Chair of Medicine and Director of Indianapolis, USA Clinical Neurosciences Martin J. Brodie, MB ChB MD FRCP University of Melbourne and St Vincent’s Hospital Melissa Barker-Haliski, PhD Professor of Medicine and Clinical Pharmacology and Melbourne, Australia Associate Director Director, Epilepsy Unit Drug Development Program Western Infrmary J. Helen Cross, MB PhD OBE University of Utah Glasgow, UK Professor in Paediatric Neurology Salt Lake City, USA UCL Institute of Child Health Eylert Brodtkorb, MD, PhD University College London Michel Baulac, MD Senior Consultant, Professor and Great Ormond Street Hospital for Children Professor of Neurology and Neuroanatomy Department of Neurology and Clinical Neurology NHS Trust University Pierre and Marie Curie St. Olav’s Hospital London, UK Hopital de la Pitie-Salpetriere, Trondheim University Hospital Paris, France Trondheim, Norway Olivier Delalande, MD Neuorsurgeon Sallie A. Baxendale, PhD Christine Bulteau, MD Fondation Ophtalmologique Rothschild Consultant Neuropsychologist Neurological Paediatrician Paris, France UCL Institute of Neurology Fondation Ophtalmologique Rothschild University College London Paris, France Norman Delanty, BSc FRCPI London, UK Inserm U 1129 and Paris Descartes University Consultant Neurologist and Director Gif sur Yvette, France Epilepsy Programme Gregory K. Bergey, MD Beaumont Hospital, RCSI Professor of Neurology and Director Gregory D. Cascino, MD FAAN Dublin, Ireland Johns Hopkins Epilepsy Center Whitney MacMillan, Jr. Professor of Neuroscience Johns Hopkins University School of Medicine and Enterprise Director of Epilepsy Georg Dorfmüller, MD Baltimore, USA Mayo Clinic and Mayo Clinic College of Medicine Director of Neurosurgery Rochester, USA Fondation Ophtalmologique Rothschild Adriana Bermeo-Ovalle, MD Paris, France Assistant Professor Joshua J. Chern, MD PhD Inserm U 1129 and Paris Descartes University Department of Neurological Sciences Pediatric Neurosurgery Associate Gif sur Yvette, France Rush University Medical Center Neurosurgery Department Chicago, USA Emory University Atlanta, USA

v vi List of Contributors

Joseph D’Souza, PhD Tracy A. Glauser, MD Julien Jung, MD PhD Senior Director Professor Neurologist UCB Pharma Pediatrics and Neurology Lyon Neurological Hospital Smyrna, USA Children’s Hospital Medical Center C-5 Lyon Paediatric Hospital and MEG department Cincinnati, USA (CERMEP) Mervyn J. Eadie, AO MD PhD Lyon, France FRCPEd FRACP Karolien Goffn, MD PhD Emeritus Professor of Clinical Neurology and Assistant Professor Reetta Kälviäinen, MD PhD Neuropharmacology Department of Nuclear Medicine Professor of Clinical Epileptology/Neurology and Honorary Consultant Neurologist University Hospital Leuven and Director University of Queensland and Royal Brisbane Department of Imaging & Pathology Kuopio Epilepsy Center and Women’s Hospital KU Leuven University of Eastern Finland and Kuopio University Brisbane, Australia Leuven, Belgium Hospital Kuopio, Finland Christian E. Elger, MD FRCP Hiba Arif Haider, MD Professor and Director Fellow in Clinical Neurophysiology/Epilepsy Andres M. Kanner, MD Department of Epileptology Emory University School of Medicine Professor of Clinical Neurology University of Bonn Medical Center Atlanta, USA Director Bonn, Germany Comprehensive Epilepsy Center Courtney A. Haney, RD and Chief Epilepsy Section Brent Elliott, MBBS MRCPsych Registered Dietitian Department of Neurology Consultant Neuropsychiatrist Johns Hopkins University of Miami Miller School of Medicine Epilepsy Society University School of Medicine Miami, USA Chalfont St Peter, UK Baltimore, USA Roopal M. Karia, MD Jerome Engel, Jr., MD PhD Xiaoting Hao, MD Clinical Instructor Jonathan Sinay Distinguished Professor of Neurology Neurologist Department of Pediatrics Neurobiology, and Psychiatry and Biobehavioral Sciences Te West China School of Medicine Jersey Shore University Medical Center Director UCLA Seizure Disorder Center and West China Hospital Neptune, USA David Gefen School of Medicine at Chengdu, China University of California Tapani Keränen, MD PhD Los Angeles, USA Jason S. Hauptman, MD PhD Senior Medical Ofcer Staf Pediatric Neurosurgeon National Institute for Health and Welfare Edward Faught, MD Department of Neurosugery Helsinki, Finland Professor, Department of Neurology and Director, Kaiser Permanente Los Angeles Medical Center Emory Epilepsy Program Los Angeles, USA John F. Kerrigan, MD Emory University School of Medicine Associate Professor of Child Health and Neurology Atlanta, USA Lawrence J. Hirsch, MD University of Arizona College of Medicine Professor of Neurology Phoenix Colin D. Ferrie, MD FRCPCH Chief, Division of Epilepsy and EEG Barrow Neurological Institute at Phoenix Children’s Consultant Paediatric Neurologist and Co-Director Hospital Department of Paediatric Neurology Comprehensive Epilepsy Center Phoenix, USA Leeds General Infrmary Yale University School of Medicine Leeds, UK New Haven, USA Hyunmi Kim, MD PhD MPH Associate Professor Robert S. Fisher, MD PhD Martin Holtkamp, MD Division of Pediatric Neurology Maslah Saul MD Professor of Neurology Friedrich v. Bodelschwingh-Professor for Clinical and Director Stanford University School of Medicine and Experimental Epileptology Emory Pediatric Epilepsy Program Palo Alto, USA Epilepsy Center Berlin-Brandenburg Emory University Department of Neurology Atlanta, USA Silvana Franceschetti, MD PhD Charité – Universitätsmedizin Berlin Head of Department of Neurophysiology Berlin, Germany Neil D. Kitchen, MD FRCS C. Besta Foundation Consultant Neurosurgeon Neurological Institute Domenico Italiano, MD PhD Victor Horsley Department of Neurosurgery Milan, Italy Research Fellow National Hospital for Neurology and Neurosurgery Department of Clinical and Experimental Medicine London, UK Jacqueline A. French, MD University of Messina Professor Messina, Italy Eric H. Kossoff, MD New York University Comprehensive Epilepsy Center Associate Professor, Pediatrics and Neurology New York, USA Svein I. Johannessen, PhD Johns Hopkins University School of Medicine Senior Researcher Baltimore, USA Itzhak Fried, MD PhD Department of Pharmacology Professor Te National Center for Epilepsy Günter Krämer, MD Department of Neurosurgery Oslo University Hospital Neurologist University of California Oslo, Norway Neurocentre Bellevue Los Angeles, USA Zürich, Switzerland and Tel-Aviv Medical Center and Tel-Aviv University Marilyn Jones-Gotman, PhD Tel-Aviv, Israel Professor Patrick Kwan, MB BChir PhD Department of Neurology and Neurosurgery FRACP Thomas J. Gianaris, MD Montreal Neurological Institute Professor of Neurology Neurosurgeon Department of Neurological Surgery McGill University University of Melbourne Indiana University School of Medicine Montreal, Canada and Head of Epilepsy Indianapolis, USA Royal Melbourne Hospital Melbourne, Australia List of Contributors vii

Cecilie Johannessen Landmark, Andrew W. Michell, MA PhD Asla Pitkänen, MD PhD DSc PhD MRCP Academy Professor Associate Professor Consultant in Clinical Neurophysiology Department of Neurobiology Institute of Pharmacy and Biomedical Science Department of Clinical Neurosciences A.I.Virtanen Institute for Molecular Sciences Oslo and Akershus University College Addenbrooke’s Hospital University of Eastern Finland and Associate Professor Cambridge, UK Kuopio, Finland Department of Pharmacology Te National Center for Epilepsy Roberto Michelucci, MD PhD Charles E. Polkey, MD FRCS Oslo University Hospital Director of Neurology and Epilepsy Unit Emeritus Professor of Neurosurgery Oslo, Norway IRCCS Institute of Neurological Sciences Department of Clinical Neurosciences Bellaria Hospital Academic Neurosciences Centre James W. Leiphart, MD Bologna, Italy Institute of Psychiatry Neurosurgeon London, UK Inova Department of Neurosciences Solomon L. Moshé, MD Virginia Commonwealth University School of Medicine Charles Frost Chair in Neurosurgery and Neurology Kurupath Radhakrishnan, MD Falls Church, USA Professor of Neurology, Neuroscience and Pediatrics DM FAMS Vice-Chair, Department of Neurology Professor and Head Ilo E. Leppik, MD and Director Department of Neurology Professor of Pharmacy and Adjunct Professor of Pediatric Neurology Kasturba Medical College Manipal University Neurology and Director Manipal, India Epilepsy Research and Education Program Clinical Neurophysiology University of Minnesota Albert Einstein College of Medicine and Montefore Sylvain Rheims, MD PhD and MINCEP Epilepsy Care Medical Center Assistant Professor of Neurology Minneapolis, USA New York, USA Department of Functional Neurology and Epileptology Hospices Civils de Lyon and Lyon 1 University Howan Leung, MB BS MRCP Miri Y. Neufeld, MD Epilepsy Institute (IDEE) and Lyon’s Neuroscience Clinical Assistant Professor Clinical Professor of Neurology and Director EEG and Research Center Chinese University of Hong Kong and Epilepsy Unit Lyon, France Prince of Wales Hospital University of Tel-Aviv Hong Kong, China and Tel-Aviv Sourasky Medical Center Awais Riaz, MD PhD Tel-Aviv, Israel Chief, Epilepsy Division Wolfgang Löscher, DVM PhD Dang K. Nguyen, FRCPC Department of Neurology Professor and Chair University of Utah School of Medicine Neurologist Department of Pharmacology, Toxicology and Salt Lake City, USA University of Montreal Pharmacy Montreal, Canada University of Veterinary Medicine Hannover Catherine J. Riney, FRACP PhD Hannover, Germany Ahyuda Oh, DDS MBA DrPH Senior Lecturer University of Queensland School of Medicine Pediatric Neurosurgery Associate Laura L. Mantoan Ritter, MD and Paediatric Neurologist and Epileptologist Neurosurgery Department Lady Cilento Children’s Hospital MRCP PhD Children’s Healthcare of Atlanta Brisbane, Australia Honorary Research Associate and Neurology Specialty Atlanta, USA Registrar Atkinson Morley Regional Neuroscience Centre André Palmini, MD PhD Gail L. Risse, PhD St Georges University Hospitals NHS Foundation Trust Associate Professor of Neurology Director and University College London Faculty of Medicine and Service of Neurology Psychology and Neuropsychology London, UK Pontifcia Universidade Catolica do Rio Grande do Sul Minnesota Epilepsy Group and Hospital São Lucas St Paul, USA Anthony G. Marson, MB ChB MD Porte Alegre, Brazil FRCP David W. Roberts, MD Professor of Neurology and Honorary Consultant Elena Pasini, MD Professor of Surgery (Neurosurgery) and Neurology Neurologist Neurology Fellow Geisel School of Medicine University of Liverpool and Walton Centre NHS Department of Biological and Neuromotor Sciences Dartmouth College Foundation Trust University of Bologna Dartmouth-Hitchcock Medical Center Liverpool, UK Bologna, Italy Lebanon, USA

Gary W. Mathern, MD Emilio Perucca, MD PhD Philippe Ryvlin, MD PhD Professor in Residence FRCP(Edin) Professor of Neurology Departments of Neurosurgery and Psychiatry and Professor of Medical Pharmacology Department of Clinical Neurosciences Biobehavioural Medicine Department of Internal Medicine and Terapeutics Te Lausanne University Hospital (CHUV) David Gefen School of Medicine at University of Pavia and C. Mondino National Lausanne, Swizterland University of California Neurological Institute Los Angeles, USA Pavia, Italy Rajesh Sachdeo, MD Clinical Professor of Neurology Fumisuke Matsuo, MD Piero Perucca, MD Neuroscience/Epilepsy Center Professor of Neurology Clinical Epilepsy Fellow Jersey Shore University Medical Center University of Utah Departments of Medicine and Neurology Neptune, USA School of Medicine Royal Melbourne Hospital and University of Melbourne Salt Lake City, USA Melbourne, Australia Steven C. Schachter, MD Professor of Neurology François Mauguière, MD PhD DSci Webster H. Pilcher, MD PhD Harvard Medical School Professor of Neurology Chair and Professor, Boston, USA Department of Functional Neurology and Epilepsy Department of Neurosurgery University Lyon 1 and Lyon Neurological Hospital University of Rochester Lyon, France Rochester, USA viii List of Contributors

Andrea G. Scherer, MD Edoardo Spina, MD PhD Matthew C. Walker, MA MB BChir Neurosurgery Resident Professor of Pharmacology PhD FRCP Indiana University School of Medicine Department of Clinical and Experimental Medicine Professor in Clinical Neurology and Consultant Indianapolis, USA University of Messina Neurologist Messina, Italy UCL Institute of Neurology Dieter Schmidt, MD PhD University College London and National Hospital for Epilepsy Research Group Hermann Stefan, MD Neurology and Neurosurgery Berlin, Germany Professor of Neurology London, UK University Hospital Erlangen Arjune Sen, BM BCh MA (Oxon) Neurological Clinic – Biomagnetism Bernd Weber, MD PhD FRCP Erlangen, Germany Professor of Neuroimaging Consultant Neurologist Department of Epileptology and BRC Senior Research Fellow in Epileptology John M. Stern, MD University of Bonn Medical Center Oxford Epilepsy Research Group Professor of Neurology Bonn, Germany National Institute of Health Research Biomedical Department of Neurology Research Centre University of California Nicholas M. Wetjen, MD FAANS Te John Radclife Hospital Los Angeles, USA FACS FAAP Oxford, UK Associate Professor of Neurosurgery and Pediatrics Rainer Surges, MD Mayo Clinic Simon Shorvon, MA MB BChir Lead Consultant Rochester, USA MD FRCP Department of Epileptology University Hospital Bonn Professor in Clinical Neurology and Consultant James R. White, MD Bonn, Germany Neurologist Epileptologist UCL Institute of Neurology Minnesota Epilepsy Group University College London Torbjörn Tomson, MD PhD St Paul, USA National Hospital for Neurology and Neurosurgery Professor of Neurology and Epileptology London, UK Department of Clinical Neuroscience H. Steve White, PhD Karolinska Institutet Professor of Pharmacology and Toxicology Stockholm, Sweden Graeme J. Sills, BSc PhD Director of Anticonvulsant Drug Development Senior Lecturer in Pharmacology Program University of Liverpool Eugen Trinka, MD MSc Department of Pharmacology and Toxicology Liverpool, UK Chair of Department of Neurology University of Utah Paracelsus Medical University Salzburg Salt Lake City, USA Gagandeep Singh, DM Christian Doppler Klinik and Centre for Cognitive Neuroscience Gabriele Ch. Wohlrab, MD (Neurology) Salzburg, Austria Professor and Head Epileptologist and Pediatric Neurologist Department of Pediatric Neurology Department of Neurology Christopher E. Uff, PhD FRCS Dayanand Medical College Epilepsy Center, Children’s Hospital Consultant Neurosurgeoon Ludhiana, India University of Zurich Head of Neurotrauma and Neurovascular Surgery and Institute of Neurology, Queen Square, Zurich, Switzerland Department of Neurosurgery London, UK Royal London Hospital Elissa G. Yozawitz, MD London, UK Adithya Sivaraju, MD MHA Assistant Professor Department of Neurology and Pediatrics Epilepsy Fellow Barbara M. Van de Wiele, MD Yale University and Director, Neonatal Neurology Clinical Professor New Haven, USA Albert Einstein College of Medicine Department of Anesthesiology and Perioperative and Montefore Medical Center Medicine New York, USA Michael C. Smith, MD David Gefen School of Medicine at Professor and Director of Rush Epilepsy Center University of California Gaetano Zaccara, MD Department of Neurological Sciences Los Angeles, USA Rush University Medical Center Director of the Unit of Neurology Chicago, USA Department of Medicine Wim Van Paesschen, FRCP PhD San Giovanni di Dio Hospital Professor Florence, Italy Ernest R. Somerville, MB BS FRCP Department of Neurology Associate Professor of Neurology University Hospital Leuven Federico Zara, PhD and Director Comprehensive Epilepsy Service Head of Laboratory for Epilepsy Research Professor Prince of Wales Hospital Department of Neurosciences Department of Neuroscience and University of New South Wales KU Leuven Laboratory of Neurogenetics Sydney, Australia Leuven, Belgium G. Gaslini Institute Genoa, Italy Dennis Spencer, MD Federico Vigevano, MD Harvey and Kate Cushing Professor and Chair Director of Neuroscience Department Department of Neurosurgery Bambino Gesù Children’s Hospital Yale University Rome, Italy New Haven, USA Preface to the Fourth Edition

Te frst edition of this book was published in 1996, the second in from 17 countries, to refect this global reach. Te regulatory and 2004, the third in 2009, and this edition, the fourth, in 2016. In the administrative frameworks governing pharmaceutical and clinical 20 years that have passed since the appearance of the frst edition, activity continue to change and one thing complained about by all therapy in epilepsy has evolved perhaps not in quantum leaps but is the enormous growth in administrative oversight. Too much bu- certainly incrementally. Te additive efect of these incremental reaucracy is the enemy of innovation, and one wonders whether changes has been very considerable and this is refected in these vol- the balance is currently correctly struck. In the book, these aspects umes. Furthermore, over the course of the four editions, the editors too are covered. have tightened their grip on the quality of chapters and of writing, Te purpose of the book has not changed over the four editions and tried progressively to ensure that the text provides accurate and and, as in the preface of the third edition, I here quote what was well-grounded information. Troughout all four editions, the basic written in the second edition: format of the book has not changed. Te same section structure Te primary objective is unaltered [from the frst edition] – namely to has been maintained, and all aspects of clinical medical therapy provide a systematic review of the whole feld of contemporary therapy are covered. Te number of chapters has grown from 63 in the frst in epilepsy. Te emphasis is, as before, on a text that provides practical edition to 81 in this. An historical introduction has been added to information, useful for the clinician but which is comprehensive, accu- provide a synoptical overview of the evolution of the treatment of rate and concisely given. We [the editors] have asked the contributors epilepsy between 1860 and the present day. Te focus of the en- to examine the evidential basis of both conventional and experimen- tire book is on treatment, and we have endeavoured to produce a tal therapies and have attempted to cover all therapeutic options . . . thoroughly up-to-date and detailed, independent and authoritative It remains the basic purpose of the book to guide clinical practice account of all aspects of modern clinical therapy. Te authorship and rational therapy, and to be a source of reference for clinicians at has been changed in crucial ways, and each of our authors, new every level. and old, have been urged to sif information carefully and to take a I here wish also to record my gratitude to my two co-editors. considered and defnitive view of their topic. Tabulated information All three of us edited the last edition, and my co-editors have un- has been included where possible, and summary tables have been dertaken the task of producing a new edition with undiminished drawn up at the head of each chapter on individual drugs. One ma- enthusiasm and expertise. Tey possess unparalleled skill in both jor change to the format has been the introduction of full colour to book editing and in epileptology, and the mixture of the two is the text, which we feel improves the readability and clarity as well as unbeatable. Extensive editing has been carried out in parts of the the aesthetic aspects of the book. Tere is also an enhanced online book to ensure a consistency of approach and style and to ensure presence. clarity and accuracy, and this job has been superbly done. Of Te passage of 20 years is a good time to refect on the changes course, also, enormous thanks from all three of us go to all the of treatment that have occurred during this time. Over this peri- chapter authors. Many are new to the book, some have contributed od, perhaps the most important advances have been in the under- before, and some indeed have been called upon for all four edi- standing of the molecular and neurophysiological bases of epilepsy, tions. All have produced superb chapters, and dealt with our tire- and discoveries in these areas are beginning to feed through into some editing queries and suggestions with universal good humour. clinical therapeutics. Te impact of clinical genetics on treatment Te timetable imposed on the book was very tight, with chapters remains relatively marginal, but neuroimmunology is changing written within 8 months of commissioning and production with- clinical practice and carries the promise of quite fundamental in 9 months of receipt of the completed draf manuscript. Despite changes in approach to therapeutics in epilepsy. Over this period, this, the book kept to schedule. Te standard of the writing is high too, 11 new drugs have been introduced into global clinical prac- and a tribute to the commitment and work of all the authors; the tice for epilepsy and also a variety of new approaches to the treat- world of epileptology is lucky to have such a talented group of writ- ment of acute seizures and status epilepticus. On the surgical side, ers. I also would like to thank Wiley Blackwell for suggesting the most of the advances have been technical rather than theoretical, new edition, and for producing it to such a high standard. It has and perhaps the biggest change has been the various forms of brain been a particular pleasure to work with Claire Bonnett who is a stimulation now entering clinical practice. All of these develop- delightful person and who became our publisher half way through ments are included in this volume. We have also tried to keep the the project. She has provided excellent advice, ideas and guidance book at the cutting edge, by including details of what we predict throughout on the intricacies of book publication. Te production will be the next changes in clinical practice. We have taken a global aspects were outsourced to PM-Bookpublishing, with the project view, hoping to cover the variations in practice in the many dif- led by Kathy Syplywczak, who has been an extraordinarily efcient ferent settings around the world, and have chosen our authorship, colleague, extremely responsive to all the detailed requests for

ix x Preface to the Fourth Edition amendments by the editors and authors, and a joy to work with; the privilege of medicine to be able to gain experience and knowl- the book has been greatly improved by her expertise, and that of edge in this way. Our book refects our clinical experience, and we her colleagues, and it would not be possible to have had a better hope will improve our own and our readers’ therapeutic knowl- team running the production aspects. Te book is embedded in edge and practice. our clinical practices, and our fnal thanks must go to our patients. A thorough understanding of epilepsy is gained best by listening Simon Shorvon, for the editors to, and discussing with, those whom we see in our clinics, and it is London, 2015 Preface to the First Edition

Epilepsy is one of the oldest recorded diseases. Troughout its histo- in the investigation of epilepsy, much more efective and ambitious ry strange and varied methods of therapy have been employed. Me- surgical treatment. Tis expansion in the options for efective treat- dicaments, potions, ointments, amulets, enemas, exorcism, magic, ment, both medical and surgical, is enormously welcome, but brings spiritualism, magnetism, galvanism, dietary regimens, surgical and its own problems. Te physician now has to make much more dif- physical and moral and behavioural therapies have all been pop- fcult decisions about treatment because of the greater range of ular; reputations have been made (less ofen broken) and are still therapeutic choices and also because the evidence on which to base being made by therapeutic manoeuvres, yet none has provided rational therapy is more complex, at times contradictory, and not the cure. Within this compass have been some efective therapies all readily accessible. In this book we have addressed these issues. but others which are ill-directed, useless, misleading, and at times Our principal objective is to provide a systematic review of the frankly fraudulent. Epilepsy is, of course, a difcult taskmaster for whole feld of contemporary therapy. We have included individu- the inquisitive. Its fuctuating nature, its ready infuence by environ- al chapters on all licensed medications, on drugs in an advanced mental factors, its easy confusion with hysterical disorders, its multi stage of clinical trial, on all specifc surgical therapies of value in factorial causation and its tendency to spontaneous remission, all epilepsy, and also chapters on treatment in specifc clinical situa- render judgements of treatment difcult. Such confounding factors tions. Te contributors were asked to examine the evidential basis allowed inefective and fashionable therapies to fourish in the past, of both conventional and experimental therapies, and to provide a and today marketing and commercial pressures add to the difcul- clear assessment of this. We have attempted, therefore, to encom- ties of evaluation. pass all therapeutic options, and their relative values in the varied Tis book is an attempt to catalogue the contemporary treatment clinical circumstances of the person with epilepsy. In this sense, the of epilepsy in the late 1990s, both medical and surgical, in a com- book should be a useful platform for all doctors treating epilepsy. prehensive, concise, balanced and practical manner. Each chapter Although the book is primarily about the treatment of epilepsy, we has been commissioned from an acknowledged authority, known have also included an initial section of six chapters, the purpose of personally to the editors as knowledgeable, intellectually honest which is to place therapy in context. In these chapters we have also and capable of clear communication. We have covered all matters highlighted those areas in which rapid advances are being made, of importance to those treating patients with epilepsy, and provide for herein will the context of treatment also change (the chapters on clear clinical advice on these issues. We have avoided unsupported pathophysiology, the developmental basis of epilepsy, diagnosis and speculation and highly biased opinion, but have asked our contrib- prognosis, and on economic cost, for example). utors to be as up-to-date as is compatible with our evidence-based Te information contained within the pages of this book is suf- exigencies. Tese are difcult and challenging requirements, which, ciently comprehensive to act as a reference for specialists, and con- I hope, have been largely realized. cise enough for more general clinical usage. It is very much a hands- What are the boundaries of the volume? When was in- on text, and, we hope, a constant companion. Te aim of the book troduced in 1857, a new era can be said to have been entered, with is to guide clinical practice and rational therapy and to be a source a treatment that was indubitably efective. Ironically, one can note of reference. It has been designed for doctors in adult and paedi- that similar claims had been made many times before in earlier and atric medicine, both generalists and also specialists in the felds of less competitive times, and the single most important lesson of his- neurology, neurosurgery, psychiatry, paediatrics, alienist medicine tory is surely scepticism. In our historical chapter, we have surveyed and in learning difculty. It will also appeal to practitioners of the treatment from the time of the introduction of to the out- paramedical specialties who are involved in the management of break of World War II, a fascinating period which provides the con- epilepsy. text for today’s therapeutic approaches. From about 1940 onwards, One remarkable fact about modern epileptology is its interna- more scientifc methods were adopted to devise and assess therapy, tionalism. In countries all around the world, the same issues about and more rigid standards were set for proof of efectiveness. Various the treatment of epilepsy arise, the same therapeutic questions are new therapies were introduced, but most have not stood the test of debated, and there is a large and surprising measure of agreement time. Even as recently as 1970, the orthodox practitioner in most on specifc points. Te international nature of epilepsy is in no small countries could still ofer only phenytoin and phenobarbitone as part due to the endeavours of the International League Against Ep- efective options for most epileptic patients. ilepsy (ILAE) which has chapters now in 48 countries and nearly Tere has been, however, in the past decade or so, a sea change, 10 000 members, and whose meetings are a forum for the dissem- almost a revolution in the feld, and a wide range of highly efective ination of information about epilepsy and its treatment. Te in- new therapeutic possibilities has become available. Not only has a fuence of the league has lef no area of epilepsy untouched. We series of new medicaments been introduced, but new approaches are therefore greatly honoured, in this book, to Dr E.H. Reynolds, to drug therapy have become possible, and also with improvements the current president of the ILAE, for contributing a foreword.

xi xii Preface to the First Edition

A distinguished and accomplished physician, Dr Reynolds is also text easy to follow and readily accessible to the reader, ofen a busy a mentor and a friend, and a person whose infuence on modern clinician. Also, we have tried to provide a uniform style, and a high British and international epileptology has been benevolent and quality of writing. To assemble chapters on such a disparate subject all-embracing. Our contributors are from four continents and pro- from authorities around the world, to edit and to produce a pleas- vide a truly international perspective. Almost all are active in the ing and useful book has been a major task. In this, the editors have ILAE, and the text refects to a great extent the current interest and been expertly helped by Dr Stuart Taylor from Blackwell Science, research of ILAE members. Matching this internationalism, nearly the publishers, whose skill and expertise were the essential ingredi- half of the chapters are by contributors (from various countries and ents of the successful completion of our work. We are enormously continents) whose training was partly at the National Hospital for grateful to Dr Taylor, not least for his humour and forbearance in Neurology and Neurosurgery at Queen Square in London. Our pre- executing (a seemingly, at times, well-chosen word) the task, also to liminary historical chapter looks at the history of epilepsy therapy Lorna Dickson, our production editor who has worked absolutely (from 1857 to 1939) using the National Hospital as an historical tirelessly on this project, and other members of the design and pro- mirror, and as epilepsy is still an important area of contemporary duction team at Blackwells; they have all been pre-eminent in their neurology at Queen Square, subsequent chapters also refect cur- work. Finally, we would like to thank the chapter authors for their rent practice at the National Hospital. Tis is another thread which outstanding contributions, their patients for providing the experi- runs through the book and gives to the volume, at least in part, a ence on which our current therapeutics is based, and epileptologists specifc favour which I hope provides the text with an interesting around the world, ILAE members and others, who have stimulated perspective. our thoughts and actions in the feld of epilepsy treatment. A book of 63 chapters will always pose a challenge for its editors Every efort has been made in the preparation and editing of this and its publisher. In this volume, we have heavily edited some indi- book to ensure that the details given (for instance of drug dosag- vidual contributions, and worked assiduously in conjunction with es and pharmacokinetic values) are correct, but it is possible that the authors to avoid repetition or overlap. Where overlap has been errors have been overlooked. Te reader is advised to refer to pub- permitted between chapters, this is because individual authors have lished information from the pharmaceutical companies and other taken difering (and occasionally conficting) approaches which reference works to check accuracy. are, in the editors’ view, sufciently instructive to allow inclusion. We have also added editorial tables in places to ease comprehen- Simon Shorvon, for the editors sion and in particular to make the information contained in the London, 1996 Historical Introduction The Drug Treatment of Epilepsy from 1857 to 2015 Simon Shorvon

In the historical introductions to the three previous editions of this has been because of an erroneous theoretical basis, an only modest book, therapeutic developments in three periods were covered, each impact on seizure control — if any impact at all — or the develop- from a diferent historical viewpoint: 1857–1939, 1938–1955, 1955– ment of sometimes serious side-efects, some of which took years 1989 [1,2,3]. In this, the fourth edition, I decided not to produce a to be recognized. It is not so much that the many adulatory claims further update (from 1989), judging this to be too close to garner an made for medicaments, now discarded, were deliberate deception, appropriate perspective. In its place, I have attempted to provide a but more that they refected the theoretical mores and fashions of timeline of antiepileptic drug therapy, listing pharmaceutical devel- the day. However, they do induce a sense of déjà vu — and should opments in mainstream clinical practice for the treatment of epilep- encourage a degree of skepticism when presented with assertions sy since 1857. A second timeline is also provided, in which surgical about contemporary therapies which are themselves based on an and other non-drug epilepsy therapies are listed, with events of im- equally transient state of knowledge. portance for epileptology. Both are accompanied by a commentary Secondly, the pace of new drug introductions varied considerably providing a brief contextual narrative. Finally, in the appendix, a over time. Tere has been a clear ‘concertina efect’ with bursts of snapshot of drug use at diferent times during this period is given activity followed by fallow periods. Tese periods of activity have as a series of tables. Te purpose of this introductory chapter is to ofen been due, afer the discovery of a new class of drug, to the provide a synoptical overview of epilepsy therapeutics since 11 May development of close structural derivatives (‘me-too’ drugs; this 1857. Tis date was chosen as it was then that bromides, the frst happened for bromides, barbiturates, , oxalozolidine modern therapy, were introduced into epilepsy practice, and as we diones, iminodibenzyls, pyrrolidones). Sometimes the derivatives pass the sesquicentennial of this momentous therapeutic advance, it have fared better than the parent drug, as has been the case with seems an appropriate topic to introduce this edition. ethosuximide and levetiracetam, for instance, but sometimes the Now, in the early twenty-frst century, and for most of the past reverse has been the case (e.g. with phenytoin and phenobarbital). 150 years, the treatment of epilepsy has been dominated by phar- Tirdly, the introduction of the most efective drugs has depend- maceuticals. Almost all the most signifcant advances in therapy ed on new technology, new models or new scientifc paradigms, have revolved around medicinal treatment. Although much efort albeit ofen laced with a large element of serendipity. Te introduc- has been devoted to surgical treatment, the number of patients re- tion of phenytoin thus depended on the new maximal electroshock ceiving surgery is still extremely small when compared with those model, the introduction of pregabalin, gabapentin, vigabatrin, ti- treated with drugs, and it remains a therapy largely of last resort. agabine on the ‘GABA’ wave of experimental work, of perampanel Other non-drug, non-surgical therapies are also mainly confned to on the glutamate wave, and of lamotrigine on the now abandoned the margins of clinical therapeutics, at least in contemporary hospi- ‘folate theory’ and so on. Te underpinning of drug discovery by tal practice. Pharmaceutical developments have dwarfed all others, physiology and biochemistry shows how science leads and com- and in relation to treatment and outcome most other clinical devel- mercialism follows, but the infuence of chance and of providence opment have been of marginal importance (it is striking how rela- can never be underestimated. Epilepsy therapeutics has never been tively little impact all the work on clinical description, classifcation entirely rationally based. and clinical investigation has had on drug therapy). Perhaps only Fourthly, the theoretical underpinning of drug introductions was developments in relation to the social aspects of epilepsy (reducing ofen also based on concepts of aetiology of epilepsy. Tus, at the stigma, reforms of marriage and employment law, etc.) have had as beginning of this period, therapy was devised on theories of nu- much impact as drug therapy on the lives of those with epilepsy. tritional balance, vascular congestion, autointoxication, masturba- Te evolution of therapy for epilepsy, however, is not a simple tion and hereditary degeneration, and therapies based on restoring linear trajectory of constant progress, but more an erratic journey, balance, reducing congestion, cleansing the bowel, castration and full of false starts and dead ends. It is striking to observe how sim- eugenics rose in and out of fashion. In recent times, the concept that ilar have been the claims made for past and current drugs, even epilepsy is caused by a loss of the normal balance between excita- though these claims have ofen turned out to be overblown, and tion and inhibition, of specifc molecular or biochemical defects, how much therapy is dictated by fashion as much as science. Tese of reducing infammation or infuencing specifc genetic pathways facts alone emphasize the need for historical perspective, for with- are not altogether dissimilar. Te relativism of our current scientifc out a knowledge of history the same mistakes made in the past are orthodoxies should not be underestimated, and current theories are inevitably repeated. likely to fall out of fashion as the restless focus of science shifs. Over these 150 or so years, a few general themes have emerged Finally, the social, commercial and political contexts have an which are worth enumeration. First, it is clear that most of the drugs enormous infuence, and this infuence is realized through such introduced over this period have not stood the test of time, despite processes as regulation and commercial practice. Te rapid devel- exaggerated claims made at the time. Tere have been various rea- opment of drugs in the 1940s in the USA and in the 1950s–1960s sons for this, but usually their failure to make long-term impact in Europe were a result of light-touch regulation, and the dearth of

xiii xiv Historical Introduction drugs in the 1960s–1970s in the USA was due in part to a regulatory sinapisms or leeches to the temple, removal of all restraint, avoid- reaction to the thalidomide tragedy. Te current lack of new com- ance of sedatives, cool air, carotid compression, cold applications, pounds is partly due also to the increasing bureaucracy and regu- Galvanism, avoidance of ammonia and volatile stimulants and lation of recent years. Another notable development has been the . He then considered the treatment of the premonito- transfer of drug discovery from the hospital or university setting, ry stage and chronic epilepsy and recommended ligatures to the typical in the frst half of the period, to the situation now where extremities, counter-irritation (e.g. setons, blisters), dry cupping drugs emerge mainly from the hidden interstices of the pharma- and the abstraction of blood (by various means), trephining, moral ceutical industry in a heavily commercialized context. Te rise in treatment, purgatives, mineral tonics (‘heroic antiphlogistic treat- power and proftability of the pharmaceutical industry is one of the ments should be eschewed’), nitro-muriatic acid, gentian, decoc- striking features of the post-war therapeutic scene and of epilepsy tion of bark and sulphuric acid, olcum morrhuae (in other words, treatment. Epilepsy has interested the pharmaceutical industry also cod liver oil!), as well as bromide, which he thought of only mod- as the most successful drugs have been found to have uses in other erate beneft, and potassium iodide for epilepsy due to secondary indications (e.g. pain, depression) as well as in epilepsy, and these syphilis and lead poisoning. Sieveking remained skeptical about the indications are ofen larger and more proftable than epilepsy itself. use of specifcs, as he put it: I make these remarks not only as an apology for not entering Commentary more fully into the consideration of a host of drugs that may be used in the course of the treatment of epilepsy with more or less advantage; but also as a protest against that specialism, 1857–1911 fostered by the public as well as the profession, which converts At the start of our period, 150 years ago, there were, by general every disease into a separate entity, breaks up the unity of the agreement, few if any ‘specifcs’ for the treatment of epilepsy. Tis science of medicine, and, in its extremes, does more harm was the point made by Dr Edward Henry Sieveking, soon to become than any extra-professional quackery. physician at the National Hospital for the Paralysed and Epileptic in London, the frst hospital providing outpatient treatment of epilep- He listed therapies which in general he had found unhelpful: opi- sy, and later physician to Queen Victoria, at a celebrated meeting of ates and narcotics, hyoscine, conium, belladonna, hydrocyanic acid, the London Royal Medical and Chirurgical Society on 11 May 1857 belladonna, digitalis, mistletoe, cotyledon umbilicus and indigo. [4]. In his paper, he dismissed specifc remedies and recommended He ended his long chapter on treatment by referring readers to the a more rounded approach with the use of counter-irritants, the pro- complete lists of therapies in the works of Tissot, Fraser, Cooke, Co- motion of healthy action of the secernent organs (secreting organs), pland and others, and by his now famous remark: and the toning up of the constitution by vegetable and metallic rob- In fact, there is not a substance in the material medica, there is orants (tonics). Delasiauve, in his book Traité de l’épilepsie of 1854, scarcely a substance in the world, capable of passing through made the same point, dividing therapy into: the gullet of man, that has not at one time or other enjoyed a 1 Debilitating therapies, such as bleeding, tepid baths; reputation of being an anti-epileptic. 2 Evacuant therapies, including emetics and purgatives; 3 Sedative therapies, including ether; Hughlings Jackson also took a negative view of drug therapy, 4 Specifcs, including valarian and opiates; the latter being not very writing in 1888: ‘It is notorious that our treatment of epilepsy is successful. deplorably unsatisfactory’ (cited in [6]), and he recommended Tis was indeed the orthodoxy of the day. Te 1857 meeting was for the frst time, consideration of surgical treatment. Despite the celebrated though, not for Sieveking’s paper — excellent though it pessimism of these leading doctors, it was nevertheless quite clear was – but for the remarks in the discussion that followed. In this, that bromide had changed the way physicians approached therapy the royal obstetrician Sir Charles Locock, chairman of the meet- in epilepsy. Tese drugs ushered in the modern age of antiepi- ing, reported his use of in hysterical catamenial leptics, with its emphasis on efcacy, side-efects, mechanism of epilepsy. Tus, on this rainy evening in London, the frst modern action and clinical therapeutics. Tis revolution started with bro- medical treatment for epilepsy, and the frst really efective ‘specifc’ mide in its formulation as a potassium salt, but was soon followed (or at least near-specifc), was launched. Tere were further reports by other formulations (notably as sodium, ammonium, strontium by Wilks, Radclife, Ramskill and Hughlings Jackson over the next or lithium salt, and by combination products) but no consensus few years, and by 1864 bromides had began to be very widely used. was ever reached about their relative merits. Tis was the start of In passing, it is interesting to note that at the meeting Locock also a trend for the production of ‘me-too’ drugs which has continued recommended removing over-crowded teeth and the cessation of to this day. masturbation. In the same vein, Webster remarked afer Sieveking’s In this period, medicaments fell into three categories (Table 1): paper that onanism was a frequent cause of epilepsy especially in plant derivatives, animal derivatives and simple chemicals. Ter- southern climates, but Sieveking said he had not referred to the apy also was ofen divided into therapy for the acute seizures (or practice as ‘it was difcult to arrive at the truth in regard to this’, impending seizures) and chronic therapy. Te plant and animal and that ‘he did not know how to proceed to determine it in the extracts were produced largely in local pharmacies and dispensa- case of females’. ries, but the chemicals were increasingly the province of the grow- Sieveking had also in that year published a book Epilepsy and ing chemical industry, particularly in those companies involved in Epileptiform Seizures: Teir Causes, Pathology and Treatment [5] making dyes. Tese were the birth pangs of the pharmaceutical in- which was a landmark in epilepsy therapeutics. Te second edition dustry which was to so dominate therapy in the next century. was completed in 1861 and in this Sieveking divided treatment into William Gowers was the most celebrated writer on epilepsy ther- that of the ‘acute paroxysm’, for which he recommended the preven- apeutics in the late nineteenth century. His superb text Epilepsy tion of injury, counter-irritation by terebinthenate fomentations or and Other Chronic Convulsive Disorders [7] contained 50 pages on Historical Introduction xv

Drug treatment for epilepsy Other treatments for epilepsy

1857 Sir Charles Locock reported the efectiveness of bromide 1854 Publication of Traité de l’épilepsie by Louis Delasiauve in hysterical catamenial epilepsy 1857 Publication of On Epilepsy and Epileptiform Seizures: Teir 1861 Samuel Wilks reported the efectiveness of bromide (com- Cases, Pathology and Treatment by E.H. Sieveking bined with iodide) in ordinary epilepsy 1859 Publication of On the Origin of Species by Charles Darwin 1865 Chloroform and ether used for acute seizures and modern theories of inheritance of disease were born 1871 Amyl nitrite and later nitroglycerin used for acute con- 1860 Foundation of the National Hospital for the Relief and vulsions Cure of Epilepsy and Paralysis in London 1872 Cannabis recommended for the headache and restlessness 1866 Gregor Mendel published his theory of inheritance, wide- afer an epileptic ft ly recognized only in 1902 when his work was translated into English by William Bateson 1873 Ergot reported to be useful in epilepsy Cliterodectomy reported to be efective in epilepsy 1874 Chloral used for acute seizures 1881 Ligation of carotid artery reported to be efective in epi- 1880 Borax introduced for epilepsy by Sir William Gowers lepsy Strychnine reported to be useful in epilepsy Publication of frst edition of Epilepsy and Other Chronic Con- vulsive Disorders by Sir William Gowers 1884 Coal tar products used in epilepsy 1883 Cervical sympathectomy described for use in epilepsy Beta-naphthol used to cleanse the bowel in epilepsy 1886 Sir Victor Horsley carried out frst cortical resective sur- 1887 used for epilepsy (the drug was entered into gery for epilepsy, an operation that opened the modern era of the formulary in 1874) epilepsy surgery, and published work on cerebral localization and brain mapping 1892 Sulphonmethane (Sulphonal) used in epilepsy 1889 Francis Galton proposed his law of ancestral inheritance 1893 Paul Gibier recommended injection of extract of sheep whereby ofspring receive half of their inherited characteristics cerebrum from each parent 1895 Adonis vernalis recommended for epilepsy by Bernard 1899 Low salt diet recommended for epilepsy and to reduce the Sachs and Vladimir Bekhterev dose of bromides 1898 Erysipelas antiserum used to treat epilepsy by Hessler 1904 Publication of Epilepsy and its Treatment by William Spratling 1901 Ceni recommended injection of serum from other epilep- tic patients on the basis that this contained autocytotoxin 1905 William Bateson coined the term genetics 1906 First Food and Drug Act in the USA 1906 First Food and Drug Act in the USA 1908 Sir Victor Horsley and Robert Clarke designed a stereo- tactic frame 1907 Indiana became the frst US state to enact a eugenic com- pulsory sterilization law for persons with mental defciency and included patients with epilepsy Publication of Epilepsy: a Study of the Idiopathic Disease by W. Aldren Turner 1909 Foundation of the International League Against Epilepsy (ILAE) in Budapest Launch of frst series of Epilepsia which continued publication until 1914 1910 Eugenic record ofce opened at Cold Spring Harbor un- der the leadership of Charles Davenport and engaged in genetic studies of epilepsy 1911 First report that fasting improves epilepsy xvi Historical Introduction treatment, and his recommendations for drug therapy are summa- in the stage of stupor what was needed was careful nursing, abun- rized in Table 2. He wrote in the second edition in 1901 that apart dance of light nourishment and tonics. from therapies aimed at the underlying cause, and general and sur- By the end of the nineteenth century, the side-efects of bromides gical measures: were recognized (‘bromism’), and much of the therapeutic eforts were focused on reducing these. Tis included the use of low salt di- Te treatment of epilepsy is purely medicinal. It has always ets to reduce the requirement for bromide (so that the body would been so, but in a far more pronounced degree since the replace chloride with bromide; dechloridization), the use of com- almost accidental discovery, more than forty years ago, of bination therapies and the use of lower doses. With the advent of the infuence on the disease exerted by the combinations of bromides many previously widely used compounds fell from favour bromine. (including most herbal and many chemical remedies such as Gowers considered all other therapies as ‘adjuncts’ to bromide, and and iron) and the range of therapies greatly narrowed. he also criticized many of the medicaments used in contemporary therapy as being of little if any value. One adjunct though that did 1912–1988 impress him was borax, which Gowers himself frst introduced in In 1912, the hegemony of bromides was challenged for the frst his Goulstonian lecture of 1879, and this continued to have a place time by a totally new medicament. Tis newcomer, a new chemi- in therapy right up until the 1950s. cal compound manufactured in the laboratories of Bayer, the Ger- Bromide dominated therapy until the 1920s, but it was clear man pharmaceutical company, was phenobarbitone (Luminal). It that, by 1890, enthusiasm for medicinal therapies was waning. No been synthesized in 1904, and joined a group of barbiturates then new efective therapies were launched in the next 20 years and the being used as sedatives and hypnotics. Its antiepileptic properties transient nature of improvement on therapy was also recognized. were discovered in 1912 by chance by Alfred Hauptmann, a young As Gray wrote in 1895: psychiatrist in Freiburg, who wrote a long and detailed account of its actions. Te importance of this discovery was not initially Epileptics, are very readily infuenced by slight changes in widely recognized, partly because of its publication in an obscure the environment and in … treatment … [they] do well for a German language journal and also the greater medical priorities of time upon any change in treatment, whether that treatment the 1914–1918 war. However, by 1920 its use was being reported in be medical or surgical, whether it consists of cutting of the England and a year later in the USA, and very rapidly afer this it prepuce, removing the clitoris, extirpating the ovaries … entered general prescribing. using the hot iron ... cutting the eye muscles … or etherizing Until about 1940, bromide and phenobarbital remained the frst- the patient and cutting a piece of skin out of the buttock. I line drugs for epilepsy, with some authorities favouring each. It is have even seem improvement efected in a patient for months curious to see how opinion was divided about their relative merits, by mere change of locality. (cited in [7]) but what it does seem clear that when bromide therapy was used In 1907, the next major fgure in epilepsy therapeutics, William skillfully, it matched the outcomes of phenobarbitone in the eyes of Aldren Turner, published his classic book Epilepsy: A Study of the many of the leading neurological fgures. Kinnier Wilson [11], for Idiopathic Disease [8]. Tis was a text that defned advanced think- instance, could still write in the late 1930s in his standard neuro- ing of the time. In the book, he considered that only a few drugs logical textbook that: ‘although phenobarbital was at frst thought were of defnite beneft and his lists of efective and inefective drugs likely to supplant bromides as a remedy of choice’, it was ‘not its are shown in Table 3. equal in general applicability’, and bromide ‘remains the drug of William Philip Spratling, the leading US epileptologist of the frst choice – the sheet-anchor on which everyone relies’. Wilson time, published his book Epilepsy and its Treatment in 1904 [9]. listed other drugs that he found helpful (Table 4) but wrote that His recommendations regarding drug treatment were very similar ‘no useful purpose would be served by further comment on the list to those of Gowers. He expounded in detail on the bromides, and of drugs vaunted at one time or another: all must stand the test of their various formulations, and also recommended their combina- experience, and … those which have successfully done so can be tion with opium or codein. Other drugs he thought efcacious, in numbered on the fngers of one hand’. line with Gowers and Turner, were borax, chloral, amylene hydrate, In the 1950s, the absorption, distribution, metabolism and ex- nitroglycerin, zinc, iron and chloroform. He also recommended cretion of phenobarbital was frst clearly identifed when serum chloretone (trichloro-2-methyl-2-propanol, a hypnotic similar to phenobarbital levels were possible to measure in clinical practice chloral), urethan, solanum carolinense, simulo, trional (a GABAe- (in 1952). Tis improved its therapeutic efectiveness and pheno- rgic sedative), serum therapy of Ceni and the coal tar derivatives barbital remains today one of the most prescribed medications for (antipyrin, phenacetin and acetanilide). epilepsy globally, with a high uptake especially in the developing Te therapy of status epilepticus also evolved during these years world because of its remarkable cheapness. Furthermore, its efca- (for sources see [10]). In 1874, Bourneville, in his classic account of cy has never been shown to be signifcantly worse than any other status epilepticus, related the case of Marie Lamb who was treated at drug, and its fall in popularity in contemporary Western medicine the Salpêtrière with sinapisme (a topical remedy with a base of mus- is largely because of its side-efect profle, and its lack of marketing tard four), lavement purgative and quinine sulphate – to no efect. backing by any of the major players in the pharmaceutical industry Amyl nitrite was introduced in 1876, and Gowers in 1881 recom- who see little proft in the promotion of such an inexpensive drug. mended morphia. Other drugs used were apomorphine, hyoscine Intravenous phenobarbital was introduced in 1926 for status hydrobromate and chloroform. In 1903, Clark and Prout advocated epilepticus, and was sometimes mixed with chloroform, enemata chloroform, bromide and chloral. Turner suggested at the onset of and bromides. Other drugs recommended for status epilepticus at status epilepticus that the dose of bromide salt should be doubled, the time [10] included scopolamine and atropine, amyline hydrate and chloral hydrate, but that at the height of an episode ‘nothing (‘Alt’) and paraldehyde (frst used in 1914). Non-pharmacological will arrest the seizures except the inhalation of chloroform’ and that therapies included irrigation of the bowel. Kinnier Wilson [11] Historical Introduction xvii

Drug treatment for epilepsy Other treatments for epilepsy

1912 Discovery of the anticonvulsant efects of phenobarbitone 1912 Fedor Krause reported 96 operated patients with focal ep- by Alfred Hauptmann ilepsy and brain mapping by electrical stimulation 1914 ILAE went into hibernation with the outbreak of the First 1913 Publication of a large series of epileptic patients treated World War with crotalin – rattlesnake venom – by Ralph Spangler 1915 William Shanahan stated that irrigation of the bowel was the most urgently indicated procedure to treat status epilepticus 1914 Paraldehyde frst used for status epilepticus 1916 Bacillus epilepticus isolated from stools of epileptic pa- tients and identifed as the cause of epilepsy and the theoretical justifcation of colectomy 1915 William Shanahan stated that irrigation of the bowel was the most urgently indicated procedure to treat status epilepticus 1917 Publication of an infuential series of cases of right-sided colectomy for the control of epilepsy from Boston 1920 Positive efect of the ketogenic diet on epilepsy was frst 1918 Air ventriculography devised by Walter Dandy documented critically 1919 Air encephalography frst carried our via the lumbar route by Dandy Borotartrate introduced by Pierre Marie 1921 Ketogenic diet proposed as a possible treatment for epi- lepsy 1922 Introduction of allobarbital with allylparacetaminophenol 1922 Resection of adrenal gland used as treatment for epilepsy (Dialacetin; Ciba) for epilepsy (approx. date) 1923 Dandy carried out the frst hemispherectomy in a human patient 1926 Intravenous phenobarbital reported to be used in status 1924 Hans Berger recorded the frst human EEG epilepticus Publication of the frst edition (in Dutch) of L.J.J. Musken’s book Epilepsy: Comparative Pathogenesis, Symptoms and Treatment 1926 Cerebral angiography frst attempted by Egas Moniz 1927 Buck v. Bell case in US Supreme Court ruled in favour of forced sterilization of epileptic patients 1929 Penfeld’s frst ‘temporal lobectomy’ (a cortical resection) Berger published a recording of human EEG 1930 Foester and Penfeld’s paper on the surgical treatment of post-traumatic epilepsy published in Brain 1931 Dandy carried out the frst corpus callosal section to re- move a congenital cyst 1934 Adrian and Matthews published their renowned paper in Brain corroborating Berger’s EEG fndings J.D. Bernal and Dorothy Hodgkin developed X-ray crystallog- raphy 1935 Gibbs, Davis and Lennox described the interictal spike waves and the 3/s pattern of absence seizures Te frst intraoperative electrocortigram carried out by Foester and Altenburger A group of neurologists met at Lingfeld Epilepsy Centre and relaunched the ILAE 1936 First clinical EEG laboratory was set up at Massachusetts General Hospital Moniz published the frst human frontal lobotomy xviii Historical Introduction realized that status was ofen caused by too rapid drug withdrawal was a vogue for institutionalization and the establishment of epilep- and in these cases large doses of bromide and chloral per rectum sy colonies for promoting good health. Indeed, the promotion of re- every 4–6 hours should be used. Other methods of treatment in- search into institutional care was one of the main reasons proposed cluded the hypodermic injection of Luminal sodium, bromide (in- for the establishment of the International League Against Epilepsy cluding intrathecal bromide), repeated drainage of the spinal fuid (ILAE) in 1909 [14]. Surgical therapy was also made possible by the by lumbar puncture, hyoscine hydrobromide, paraldehyde and, he introduction of Listerian antisepsis, general anaesthesia with ether also commented, ‘venesection and saline injections may also be (1846) and especially chloroform (1847) and local anaesthesia (ini- used in the robust’. tially with cocaine, 1877). Horsley introduced resective cortical sur- In 1910–1939, many of the other traditional herbal, animal and gery on the basis of meticulous brain mapping in primates, and his simple chemical remedies still continued to be widely used, al- pioneering work, with Jackson and Ferrier, on cerebral localization. though one senses from the literature that these were applied with His frst epilepsy operations were carried out in 1886 to interna- little hope of success. A small number of other novel therapeutic op- tional acclaim. Other operations also performed around this time, tions were also launched in this period. Perhaps the most important almost certainly totally inefectively, included ligation of the carotid of these was the ketogenic diet, and although not strictly speaking a artery (1881), cervical sympathectomy (1883), circumcision, clit- ‘drug’ it is included here as it was thought to exert its efects through eridectomy (1866), oophorectomy, testectomy, adrenalectomy and biochemical changes similar to those induced by drugs. Te diet bilateral vertebral artery occlusion. Oophorectomy, orchidectomy was frst mooted in 1921, based on the observations that starvation, and castration were used as eugenic methods, especially in the early and also the ‘water diet’, improved epilepsy (frst made in 1911). Af- twentieth century. Interest waned in cortical resection in the frst ter a few years of experimentation with diferent fat : carbohydrate four decades of the twentieth century, which was proving less suc- and protein ratios, the standard diet was in widespread use in the cessful than initially hoped, and the number of surgeries performed 1930s with many reports of its value. Another introduction was that worldwide fell considerably. At the same time there developed a of borotartrate, frst mentioned by Marie in 1926. Tis was notable widespread vogue for colectomy and other bowel resections, on the for the fact that it was antiepileptic without being sedative (a prop- basis that these would reduce autointoxication (for a consideration erty not shared with bromide or phenobarbital) but its efectiveness of the historical infuences of aetiology on therapy see [15]). seems to have been modest at best. In the early 1930s, especially in the USA, there was a new inter- A snapshot of the most popular drug treatments in the period est in trying novel compounds for epilepsy. Tese included the use was given by the Dutch neurologist Muskens in his book of 1926 of vital dyes – notably brilliant vital red and methyl blue – and for [12]. He divided therapy according to the stage of the disease. He a time there was a vogue for these treatments. Vasodilator therapy emphasized prophylaxis in the prodromal stage, where therapy was also being tried with a variety of substances, including acetyl- should be aimed at preventing the development of epilepsy by elab- choline, amyl nitrite, carbaminoylcholine (one of the most powerful orate social hygiene methods and good nutrition but without med- parasympathomimetic drugs known), and the ‘fourth substance of ication. In early epilepsy he used bromide, phenobarbital and borax the arteriolenstaf’, refecting the then current interest in alterations as the three main therapies, and also zinc oxide, nitroglyerine and in cerebral blood fow as a pathogenic mechanism of epilepsy. Other cannabis indica; in inveterate cases, he prescribed iodide of mercu- new medicinal therapies included thyroid extract, pancreatic extract, ry, according to a method ‘very similar to the mercurial treatment vitamin B, strychnine, boric acid, pyridine, ammonium chloride, used for lues’. ethyl phenyl sulphone and . Benzedrine and cafeine Although this survey is primarily concerned with drug therapy, were widely used to counteract the sedative efects of the barbitu- a brief word on non-drug approaches to the treatment of epilep- rate, bromide and drugs. Other physical treatments were sy needs to be added, as from the mid-nineteenth century right up explored including insufation of the cerebrospinal fuid space with until the 1950s there was also a strong emphasis on what was ini- air, X-irradiation, metrazol-induced or electrically induced convul- tially included broadly under the designation of hygiene and advice sions. Paraldehyde too, introduced into clinical practice in 1882, was on other broad aspects. Tese included the importance of regular frst recognized to be have useful anticonvulsant action in 1940. habits, enough sleep, sufcient exercise, massage, attention to bowel Te big news of the period though of course was the discovery habits, the avoidance of masturbation, the avoidance of stress and of phenytoin, by Merritt and Putnam, who were given the chemi- the use of tonics. Hydrotherapy and detoxication were frequently cal by the US pharmaceutical company, Parke Davis, and who for proposed. Turner wrote in 1910: ‘We have, therefore, in every case the frst time used an animal model for systematically screening of epilepsy to treat the individual and not solely the disease’ [13]. chemicals for their antiepileptic action. Te use of experimental Turner recognized six headings under which the treatment of ep- models was not new, and camphor- and metrazol-induced models ilepsy should be considered: prophylaxis, management and treat- had been in use for many years, but the systematic use of screening, ment of young epileptics, hygiene, education of epileptic children, using an electrical convulsant model, was a novel step. Te clinical care of confrmed epileptics (epileptic colonies) and surgical treat- development of phenytoin was impressively fast. It was frst tried ment. Tere was great attention paid to diet, with emphasis on bal- experimentally in the cat in 1936, eight patients had been treated ance, ofen with low protein and or low salt diets promoted, and the by August 1937, the frst clinical trial was reported in June 1938 and omission of a seemingly random selection of foods and drinks by by September 1938 the results in 200 patients were published. In diferent authorities. Lengthy dissertations on these various meas- 1939, the drug was added to the ‘New and Nonofcial Remedies list ures were to be found in the texts of the period. Physical therapies of the American Medical Association’, on the basis of 13 diferent included counter-irritation with cautery, blistering or setons, for trials in 595 patients for ‘epileptic patients who are not beneftted example. Tis was popular too in the nineteenth century although by Phenobarbital or bromides and in those in whom these drugs seems to have faded from fashion in the early twentieth century, as induced disagreeable side reactions’. By 1940, it was in widespread did galvanism, magnetism and other electrical therapies. Another use as a frst choice medication and remained so in epilepsy treat- interesting trend in the late nineteenth and early twentieth centuries ment worldwide at least until the late 1980s, when it was slowly Historical Introduction xix

Drug treatment for epilepsy Other treatments for epilepsy

1937 First report of the anticonvulsant efects of the vital dyes 1937 Second series of Epilepsia was launched and continued (Brilliant Red) in epilepsy publication until 1950

1938 Amendment to the Food and Drugs Act in the USA J.B.S. Haldane and Julia Bell published the frst evidence of ge- netic linkage in humans First use of phenytoin in epilepsy (Dilantoin, Epanutin; Parke, Davis) 1938 McKenzie carried out the frst human hemispherectory 1939 Action T4 – the mass murder of handicapped persons 1941 Acetazolamide (Diamox; Lederle) introduced for the with epilepsy began in Nazi Germany treatment of epilepsy Hodgkin and Huxley published their frst paper on the mem- 1946 (Tridione; Abbott) introduced into clinical brane theory of nerve transmission practice 1940 First corpus callosectomy for epilepsy was reported by 1947 (Mesantoin; Sandoz) introduced into clin- William van Wagenen and Yorke Herren ical practice Publication of three-volume textbook Neurology by S.A. Kinnier First randomized controlled trial carried out – the Medical Re- Wilson search Council study of streptomycin in tuberculosis 1941 Principle that one gene codes for one enzyme established 1949 (Paradione; Abbott) introduced into by George Beadle and Edward Tatum clinical practice 1942 ECT used in the treatment of epilepsy Intravenous paraldehyde frst used in status epilepticus 1947 George Dawson recorded cerebral evoked potentials for the frst time 1950 First use of corticosteroids and ACTH in epilepsy Stereotactic methods introduced into neurosurgery by Spiegel Phenthenylate (Tiantoin; Lilly) introduced into clinical prac- et al. tice 1948 Around this time, the frst temporal lobectomy with re- 1951 (Phenurone; Abbott) introduced into clin- moval of the mesial structures was performed, by either Arthur ical practice Morris in Georgetown or Wilder Penfeld in Montreal

1952 (Gemonil; Abbott) introduced into clinical Gibbs et al. described the anterior temporal EEG spike practice 1949 First video and EEG monitoring introduced Benzchlorpropamide (Hibicon; Lederle) introduced into clini- GABA identifed in the brain by Roberts and Fraenkel cal practice and then withdrawn Video-tape and EEG recorded simultaneously 1953 (Milontin; Parke, Davis) introduced into 1950 Second series of Epilepsia ceased publication clinical practice 1951 Stereotactic radiosurgery introduced by L. Leksell 1954 Primidone (Mysoline; ICI) introduced into clinical practice 1952 Volume 2 of the Atlas of Electroencephalography, devoted to epilepsy, was published 1956 Intravenous phenytoin frst used in status epilepticus Tird series of Epilepsia inaugurated but ceased publication in 1957 (Peganone; Abbott) introduced into clinical 1956 practice Measurement of phenobarbital serum levels frst achieved Methsuximide (Celontin; Parke, Davis) introduced into clinical 1953 James Watson and Francis Crick identifed the helical practice structure of DNA 1958 Ethosuximide (Zarontin; Parke, Davis) introduced into 1953 Fourth series of Epilepsia launched and continues to be clinical practice published 1960 Intravenous lignocaine reported to be efective in status 1960 Publication of Epilepsy and Related Disorders by William epilepticus G. Lennox First description of the sodium amytal (Wada) test xx Historical Introduction displaced in most countries from its pinnacle by carbamazepine compounds had been synthesized and of these 50 com- and valproate. pounds were marketed, of which phenobarbital was the most fre- Te promise of phenytoin was recognized early, as shown by an quently used for epilepsy. Te third drug that impressed Lennox article in 1940 in which the history of drug treatment in epilepsy was (mephobarbital) which he pronounced was said to be divisible into three epochs: the frst of bromide, the to be ‘the only barbiturate besides phenobarbital efective against second of phenobarbital and ‘the third era is very recent in origin epilepsy’ and the fourth was phenytoin. He rated the ffh drug, me- and is characterized by the introduction in 1938 of Dilantin Sodi- phenytoin, as better than phenytoin in several situations, and in- um’. Within a few years it had displaced bromide from the front deed he favoured their combined use. Te next drug was ethotoin line of therapy, and although phenobarbital continued to be wide- which Lennox noted was one of the 1500 compounds screened by ly used, bromide became a peripheral therapy, although a furry of Abbott Laboratories in the previous 8 years. new papers on aspects of bromide; were published in the 1980s. Te next decade, 1958–1968, was the most productive in the his- In the two decades that followed the discovery of phenytoin, new tory of epilepsy therapeutics, and in these 10 years a crop of truly chemical derivatives began to be explored for their antiepileptic ac- efective and novel new drugs was developed. First of was ethosux- tion on a massive scale by the burgeoning pharmaceutical industry. imide (α-ethyl-α-methylsuccinimide; PM 671), a drug that was very Putnam and Merritt screened a further 700 compounds, provided similar in structure to phensuximide and methsuximide which had to them by Parke Davis and other companies, and listed the results been introduced by Parke Davis in the previous years; in this sense on 618 of these chemicals in a paper in 1945. Seventy-six com- this was a drug of the old school. It was licensed in 1958 for petit pounds were given a 4+ rating. Tey could be grouped into seven mal, and remains a drug of frst choice to this day. It acts by block- categories on the basis of their structure: barbiturates, benzoxaz- ing the low-voltage T-type calcium channel, a mechanism that was oles, hydantoins, ketones and phenyl ketones, oxazolidine diones, identifed only in 1984, some 16 years afer licensing. phenyl compounds with sulphur and phenyl glycol. Of these drugs, Further developments were of drugs originating almost entirely phenytoin and four others were selected for clinical trial. None of from Europe and not the USA, and which were not chemical deriv- the other four (5-phenyl-5-isopropoxymethylhydantoin, ethyl-phe- atives of known antiepileptics. Te frst was carbamazepine, initially nylsulphone, 5-methyl-5-phenylhydantoin, 5,5-diphenylenehydan- known as G32883, a compound developed in the Swiss pharmaceu- toin) showed clinical benefts greater than phenytoin and so were tical company Geigy in 1953. It had a tricyclic structure, and was not pursued afer the initial trials. However, a further 13 new an- frst investigated for depression and psychosis and then licensed for tiepileptic drugs were introduced into practice in 1940–1958, by trigeminal neuralgia in 1962. Its antiepileptic efects were investi- six pharmaceutical companies, fve of which were American and gated clinically in 1959 and frst reported in 1963. Te drug was the sixth, ICI, from England. Te drugs were produced mainly by licensed as an anticonvulsant in Britain in 1965, then in Europe and manipulating the structure of the barbiturates and hydantoins us- in 1974 in the USA. Its principal mechanism of action, the blockade ing the newly refned principles of medicinal chemistry linked to of sodium channels, was not recognized until 1983 but by then car- methods of large-scale industrial production. Clinical testing was bamazepine had become the most prescribed antiepileptic drug in perfunctory and the drugs were introduced with minimal safety Europe, consigning barbiturate to the therapeutic periphery, and it testing and as a result many were subsequently withdrawn because remains the gold standard for comparative studies of antiepileptics of severe side-efects. and the drug to beat for any new compounds. An international list of antiepileptic drugs was published in 1955 Sodium valproate was the next antiepileptic to be introduced and by the ILAE (a total now of 23 licensed drugs) and this demon- a drug that, like carbamazepine, completely changed the scope of strates the extent of structural manipulation (Table 5) comprising prescribing. Te frst report of the antiepileptic efect of sodium four barbiturates, four oxazolidines diones, six hydantoins and sev- valproate was published in 1964. Tis was discovered serendipi- en other types. In addition, there were eight combination tablets tously in a small laboratory in Rennes where valproate was being which were mainly combinations of hydantoins and barbiturate. used as the solvent for other experimental drugs, but its potential Although a large number of medicines, these were largely ‘me-too’ was quickly realized. In 1967 it was approved in France for epilepsy, drugs and none were a major advance. Tis period, following the and then over the next few years in other European countries (and discovery of phenytoin, was essentially arid and little fundamental in 1976 in the USA, albeit initially only for absence seizures). Val- improvement was achieved. proate and carbamazepine have since become the most prescribed A striking feature of the post-war period, initially in the USA and drugs worldwide. Valproate is highly efective in many types of epi- then in Europe, was the enormous rise in the power of the pharma- lepsy, and was recognized early to be the drug of choice in idiopath- ceutical industry and the intense commercialization of the pharma- ic generalized epilepsy, but is also a drug with signifcant adverse ceutical market. Tis was a period of great optimism; drugs devel- efects, in particular teratogenicity. oped in the 1950s and 1960s included the frst oral contraceptives, Another enormous development in the epilepsy pharmaceutical corticosteroids, antihypertensives, monoamine oxidase inhibitors, landscape of the 1960s was the introduction into clinical practice of new antibiotics, antipsychotics (chlorpromazine, ) and the drugs. Te frst licensed was chlordiazepoxide the benzodiazepines (Valium became the most prescribed drug in in 1960 and then in 1963. Over the next 15 years, over history). 4000 related compounds were synthesized and screened, and by In the 1950s, in the feld of antiepileptic drugs there was no really 1978 23 diferent compounds had been licensed. Although the main major advance, and epilepsy drug therapy in this period can best be focus of these drugs was on their anxiolytic and hypnotic properties, ascertained from William Lennox’s defnitive textbook Epilepsy and the anticonvulsant efect of chlordiazepoxide (Librium; Ro 5-0690) Related Disorders published in 1960 [16]. Lennox listed 16 drugs was frst reported in 1960 and in 1962, a series of cases of epilepsy (his ‘therapeutic arsenal’) licensed for epilepsy in the USA (Table 6). treated with chlordiazepoxide and diazepam (Valium; Ro 5-2807) Te frst places were given to bromides, which he noted were ‘lit- were presented. In 1965, Gastaut reported the efects of tle used today’, and to phenobarbital. Lennox mentioned that 2500 (Rivotril; Ro 05-4023) and, in 1977, the frst double-blind study Historical Introduction xxi

Drug treatment for epilepsy Other treatments for epilepsy

1962 Sulthiame (Ospolot; Bayer) launched in Europe into clin- 1961 First routine method for measuring blood levels of antie- ical practice pileptic drugs introduced in clinical practice, and the beginning of therapeutic drug monitoring and intensive pharmacokinetic and interaction studies which continue to the present day Intravenous urea used in status epilepticus with excellent results International Bureau Against Epilepsy (IBE) formed Francis Crick and Sydney Brenner discovered that the genetic 1963 Kefauver–Harris amendments to FDA regulations code is a triplet code (the sequence hypothesis was predicted by Crick in 1957)

Benzodiazepines — in the form of diazepam (Valium; Roche) Francis Crick and Sydney Brenner proposed that RNA is the and chlordiazepoxide (Librium; Roche) — introduced into clin- messenger, transmitting code from DNA ical practice and diazepam also used in status epilepticus 1962 First congress devoted entirely to status epilepticus (Marseilles Colloquium)

Chlormethiazole (Heminevrin; AstraZeneca) introduced into 1964 Gastaut produced the frst draf of the ILAE Classifcation clinical practice of Seizure Type 1965 Talairach, Bancaud and coworkers published La stéréoélectroencéphalographie dans l’épilepsie 1965 Carbamazepine (Tegretol; Geigy) introduced as an antiep- ileptic, with frst licensing in the UK 1966 Epilepsy section formed at NIH with J. Kifn Penry as chief 1967 Computerized X-ray tomography (CT scanning) devised 1966 First randomized controlled trial in epilepsy published – by Godfrey Hounsfeld (later awarded a Nobel Prize) of carbamazepine Microneurosurgical techniques (and the operating microscope) introduced by Mahmut Yaşargil 1967 Valproate (Epilim; Sanof) approved for use frst in France 1968 Laboratory of Prince in Stanford began to elucidate many of the electrophysiological characteristics of experimental ep- ilepsy 1968 Clonazepam (Rivotril; Roche) licensed for treatment of epilepsy in Europe First Gamma Knife introduced by Leksell 1969 ILAE Classifcation of Seizure Type approved 1971 Gastaut reported excellent results of intravenous clonaze- 1970 Establishment of the ILAE Commission on Antiepileptic pam in status epilepticus Drugs 1972 First CT scan carried out on a patient with epilepsy 1972 Publication of Efectiveness and Efciency: Random Refec- First edition of Antiepileptic Drugs published. Te ffh and last tions on Health Services and start of Cochrane collaboration by edition was published in 2002 Archie Cochrane 1975 Ed Southern developed Southern blotting 1977 First MRI scan in vivo in man (of a fnger) carried out in 1975 (Frisium; Roche) licensed in Europe for the Nottingham by Peter Mansfeld (later awarded a Nobel Prize) treatment of epilepsy A method for sequencing DNA developed by Frederick Sanger (later awarded a Nobel Prize) 1978 Antimyoclonic efect of piracetam demonstrated 1978 Publication of Commission for the Control of Epilepsy and Its Consequences, Plan for Nationwide Action in Epilepsy, First published reports of the advantages of antiepileptic drug by the US government monotherapy – and the beginning of the ‘monotherapy age’ First clinical MRI brain scans carried out First published reports of the use of PET scanning in epilepsy 1980 Beginning of a period of intense study of frst GABAergic and then glutaminergic mechanisms ( ‘GABA wave’ and ‘gluta- 1979 Recognition that barbiturates act by modulating GABA mate wave’) reception function

1985 licensed in France, but not elsewhere xxii Historical Introduction comparing clonazepam and ethosuximide in absence seizures was fully documented. In the 1960s, too, the measurement of serum published. Te mechanism of action — agonist action at the GABA levels of drugs entered clinical practice (known as therapeutic drug receptor — was discovered. Clobazam was then licensed in Europe monitoring), and soon laboratories were routinely measuring lev- in 1975, but not until 2012 in the USA. els. By the early 1980s, the characterization of the hepatic enzyme Amongst the more minor discoveries of the period was sulthi- systems was largely complete, and the relevant factors, both envi- ame, frst launched in Europe in the early 1960s, but never licensed ronmental and genetic, were intensively studied. A veritable indus- in the USA. Soon afer its launch, its major interaction with pheny- try arose, related to drug interactions, led by the study of phenytoin toin was recognized and it was postulated that its efects were due (a drug with uniquely complex interactions), in the mid-1960s. simply to the increasing levels of phenytoin when used in come- Te emphasis on single-drug therapy (monotherapy) was an dication. Because of this, in 1986 sulthiame was withdrawn from infuential change in treatment strategy dated from the late 1970s. the market in the UK and then in other European countries. Te Monotherapy became feasible, paradoxically, because of the intro- ownership was transferred to Desitin in 1993 and it is available now duction of a wider choice of new efective drugs, especially carba- in a few European countries. Progabide was licensed in France in mazepine and valproate, and also because of the adoption of the 1985 and by 1992 used in over 2500 persons, where it remains to therapeutic drug monitoring which refned and improved individ- this day on the Gallic fringe of therapy. It was never licensed in any ual dosing. Tere rapidly followed a marked swing to monotherapy other European country nor in the USA. protocols in patients with epilepsy, and the nearly universal rec- Corticosteroids and particularly adrenocorticotrophic hormone ommendation that antiepileptic monotherapy be initiated in new (ACTH) were introduced into clinical epilepsy practice in 1950. In patients. By the late 1980s, the regulatory authorities had began to 1958 the dramatic efect of these drugs in infantile spasms was frst request monotherapy trials. reported, and they have remained frst-line therapy for this indi- cation. ACTH and cortisone were shown in the 1950s also to have 1989–2014 value in occasional cases of other types of childhood epilepsy and Te impact of molecular medicine began to be felt in this period, in status epilepticus. Te frst report of the use of chlormethiazole in initially particularly in relation to studies of inhibitory GABAergic status epilepticus was in 1963 and it became a standard second-line brain function (the ‘GABA wave’) and then excitatory brain func- therapy in the treatment of epilepsy in 1970s and of acute seizures tion (the ‘glutamate wave’). Between 1989 and 1994, fve major an- and status epilepticus. tiepileptic drugs were licensed in Europe and introduced into clini- Te treatment of status epilepticus (Table 7) [10] was also greatly cal practice. Vigabatrin, a product of the ‘GABA wave’ was the frst. infuenced by the introduction of intravenous phenytoin, frst used It was a designer drug, produced to be a ‘suicidal inhibitor’ of GABA in 1956. Intravenous paraldehyde had also become popular afer the transaminase. Te frst trials were in 1983 and it was launched frst report of its use in 1949, and was favoured by many above phe- frst, in the UK, in 1989 and then in Europe but not in the USA. nytoin. Intravenous lignocaine was frst reported in 1960 and intra- In 1997, severe visual side-efects were frst reported and the drug, venous urea was reported in 1962 to be highly efective in severe sta- once widely prescribed, is now used in a very small number of pa- tus epilepticus. All these drugs were eclipsed by the benzodiazepines. tients. Lamotrigine was developed, in the UK, as an antifolate drug In 1965, Gastaut said of diazepam in status epilepticus, that it was: and found to have antiepileptic efects by chance. It was licensed in Britain in 1991 and then in Europe, and in 1994 in the USA, and is Outstanding for the reliability and rapidity of action, which now a frst-line medication. Felbamate, a drug developed by Carter together make it a more efective drug than others we have Wallace Laboratories, was launched in the USA in 1993. It was not used in the past, amongst which have been: injectable licensed in Europe and in 1994 was withdrawn because of the risk of Phenobarbital, Somnifene, Chloral hydrate, Eunoctal, hepatic failure. It has since been reintroduced to be used as a last-re- , Rectanol, Novocain and Hemineurin … sort therapy with special precautions, and has a very small place in We have never obtained such results in the past, although we contemporary prescribing. Gabapentin was developed as a GABA have used a variety of drugs, including: Tridione, Pentothal, analogue to act at the GABA receptor as a GABA agonist. In fact, it Eunoctal, Hemineurin, ACTH and aldosterone. has no action at the GABA receptor and its mechanism of action is Ten, in 1971, Gastaut reported the use of clonazepam (Rivotril; due to binding to the α2δ subunit of the neuronal voltage-dependent Ro 5-4023): calcium channel (a fact discovered a decade or more afer licensing). It was licensed in 1994 in the USA and UK and by 2003 was one of ‘a new benzodiazepine – more active than diazepam … we the 50 most-prescribed drugs in the USA (its sales of nearly $2.7 bil- do not hesitate to afrm that Ro 05-4023 is by far the most lion in 2003) due largely to non-epilepsy indications. It is still used efective agent which we have at present for the treatment of as a second-line drug in epilepsy. Oxcarbazepine was licensed in status epilepticus of whatever form or aetiology’. Denmark in 1990 and then in most EU countries in 1999 and in the Te application of pharmacokinetic principles to epilepsy thera- USA in 2000. It is now widely used as a frst or second-line therapy. py was a most important clinical advance in the 1960s and 1970s. Between 1995 and 2014, a further 10 antiepileptic drugs were Te measurement of antiepileptic drug serum levels began to be licensed — topiramate, tiagabine, levetiracetam, zonisamide (al- studied systematically only in the late 1950s, although the technol- though earlier licensed in Japan), pregablin, stiripentol, rufnamide, ogies had been available for some years before. Tis early devel- lacosamide, retigabine and perampanel. Of these, topiramate and opment was both methodology-driven and also stimulated by the levetiracetam are widely used as frst-line agents, retigabine and regulatory requirement for pharmacological information. Exten- tiagabine have been largely abandoned, and stiripentol and rufna- sive studies of bromide, ethosuximide, phenytoin and phenobarbi- mide licensed only for niche indications (in Dravet and the Lennox– tal were conducted initially, and within a decade or so the clinical Gastaut syndromes, respectively). In addition, buccal pharmacokinetic properties of all the antiepileptic drugs — their has been licensed for emergency therapy, initially as midazolam absorption, distribution, metabolism and excretion — were quite hydrochloride in a preparation approved under a special licence in Historical Introduction xxiii

Drug treatment for epilepsy Other treatments for epilepsy

1989 Licensing of a furry of new drugs begins (third generation 1981 Revision of the ILAE Classifcation of Epileptic Seizures drugs) initially with vigabatrin in Europe and zonisamide in Japan approved Vigabatrin (Sabril; Marion Merrell Dow) licensed in the UK for epilepsy 1982 Morrell and Whisler reported the frst case treated by mul- tiple subpial transection Zonisamide licensed in Japan and South Korea (Excegran; Dainippon) and then in 2000 relicensed for epilepsy in the USA and Europe in (Zonegran; Elan) First investigations of SPECT scanning in epilepsy 1990 Lamotrigine (Lamictal; Burroughs Wellcome) licensed frst in Ireland and a year later in the UK Clinical MRI introduced and frst large published series of neu- rological patients, some with epilepsy Oxcarbazepine (Trileptal; ) licensed frst in Denmark, then in EU generally in 1999 and in the USA in 2000 1984 MRS studies of epilepsy initiated 1992 First biannual Eilat Conference on New Antiepileptic Drugs held 1993 Discovery of micro RNAs 1993 Felbamate (Felbatol; Carter-Wallace) licensed in the USA, but not in Europe, and then rapidly withdrawn 1995 First epilepsy gene published 1994 Gabapentin (Neurontin; Parke-Davis) licensed in the USA and UK 1997 Launch of the Global Campaign Against Epilepsy (entitled 1995 Topiramate (Topamax; Johnson & Johnson) licensed in Out of the Shadows) the UK and subsequently in Europe and USA Foundation of European Agency for the Evaluation of Medici- Vagal nerve stimulation received a US regulatory approval as a nal Products (EMEA). Name changed to European Medicines treatment for partial onset epilepsy Agency in 2004 1996 Tiagabine (Gabatril; Novo Nordisk) licensed frst in 2000 First draf of the human genome published France and then widely in Europe and the USA 2002 HapMap project launched Cochrane epilepsy group registered in the Cochrane collabo- ration 2008 RCT of trigeminal nerve stimulation in epilepsy initiated 1999 Levetiracetam (Keppra; UCB) licensed as a treatment for epilepsy in the USA and in Europe a year later 2010 TMS trial reported favourable results in epilepsy 2004 Pregabalin (Lyrica; Pfzer) licensed in Europe for epilepsy

Buccal midazolam, as midazolam maleate (Epistatus; Special Publication of SANTE trial (bilateral anterior thalamic stimu- Products) permitted under special license in the UK lation) 2007 Stiripentol (Diacomit; Biocodex) licensed for use in se- vere myoclonic epilepsy of infancy in Europe EMA approved Medronics Deep Brain Stimulation Terapy for Rufnamide (Inovelon (Europe) and Banzel (USA); Eisai) li- treatment of epilepsy censed for use in Lennox–Gastaut syndrome in Europe 2011 Publication of the NeuroPace trial (responsive cortical 2008 Lacosamide (Vimpat; UCB) licensed in Europe, and in the stimulation) USA in 2009 2010 Retigabine (ezogabine) (Trobalt; Glaxo Smith Kline in 2012 EMA approved NeuroSigma external Trigeminal Nerve Europe, and Potiga; Valeant in USA) licensed in 2010 in USA Stimulation (eTNS) system in epilepsy and 2011 in Europe

2011 Buccal midazolam in the form of midazolam hydrochlo- 2013 Publication of seizure prediction studies using implanted ride (Buccolam; ViroPharma) licensed in Europe under PUMA Neurovista device scheme

2012 Perampanel (Fycompa; Eisai) licensed in Europe and USA NeuroPace RNS stimulator approved by FDA for treatment of in 2012 epilepsy xxiv Historical Introduction

Britain, and then as midazolam maleate in a preparation approved clinical trials than the older drugs, nor generally has there been a by the European Medicines Agency (EMA) under the PUMA (pae- paradigm shif in side-efect profle, although most (but not all) of diatric use marketing authorization) scheme in September 2011, for the newer drugs have some pharmacokinetic advantages. use in patients under the age of 18 years; in fact this is the only Te regulatory environment has grown pari passu with the pow- antiepileptic drug ever to be licensed in children but not in adults. er of the pharmaceutical industry. In the USA, for instance, the frst Tere have been, in addition, a range of further drugs under de- major legislation was the Federal Pure Food and Drugs Act, enact- velopment. Te drugs discussed at the Eilat conferences on New ed in 1906. Tis required accurate labelling and was in response Antiepileptic Drugs are a rough guide to those that were closest to public concern about excessive misbranding and adulteration of to licensing and these are listed in Table 8. Other drugs in earlier food, but this had little practical efect in the feld of antiepileptics. clinical trials were listed in various periods between 1992 and 2014 Te next signifcant development was the 1938 Food, Drug and and in Table 9 other additional drugs in early clinical development, Cosmetic Act, framed in response to public anger over the deaths listed in the various editions of this book, are given. Although the of more than 100 people caused by ‘elixir of sulfanilamide’. Tis re- number of drugs is large, as will be very evident, many do not pro- quired evidence of safety to be submitted to the FDA prior to mar- gress to licensing even though clinical trials have been undertaken. keting. Many of the raf of new drugs that were licensed following It is clear that the most important scientifc developments in this the discovery of phenytoin were then shown to be quite toxic, and period have not been in the discovery of these novel drugs, but in it seems, at least in the feld of antiepileptics, that this legal dog the basic science of pharmaceutical medicine. Te enormous de- had little teeth. Ten, in 1962, the Drugs Amendment Act, the Ke- velopments in molecular science in the past three decades are out- fauver–Harris Amendment, was signed into law, in response to the side the scope of this chapter, but sufce to say that the advances thalidomide tragedy in Europe. Tis totally changed the regulatory in knowledge about the molecular mechanisms and regulation of environment. For the frst time, evidence of efcacy was required brain function and epilepsy are the key to future drug development, as well as safety, and a retrospective programme of evaluation of and these hold the promise of new drugs specifcally targeted at pre- drugs introduced between 1938 and 1962 was undertaken. Te Act viously unknown molecular processes. Tis is an exciting prospect, also required the disclosure of accurate information about side-ef- but one not yet realized in clinical practice, or indeed in most drugs fects and efcacy in drug advertising, and also placed on the FDA currently under clinical investigation (Table 8). In this sense, epi- an obligation to establish guidelines for testing all classes of drugs, lepsy therapeutics is lagging behind therapeutics in other areas such including antiepileptics. A new system of licensing was devised as immunology and oncology. A clinical area in which there has by which the FDA required each company to obtain an IND be- been particular disappointment in that of pharmacogenetics. Te fore it was permitted to use the drug in human subjects. Complete promise of individualized ‘tailored drug therapy’ has been trumpet- chemical and manufacturing information, preclinical screening ed, and over-hyped, for the last 15 years, but has singularly failed to and animal investigation, including toxicology, teratogenicity and materialize. Perhaps this is not surprising given the complexity of safety, had to be submitted before the IND was granted. Clinical cerebral mechanisms, the importance of brain maturation and the testing was divided into three phases and only afer the comple- inherent limitations of the approach, but it nevertheless is disap- tion of this battery of studies could a drug be licensed. Tese new pointing. Tis topic too has to date wasted large amounts of money regulations no doubt protected the public from dangerous com- and time, and whether more will be delivered in the future remains pounds, but there were also immediate negative consequences. Te to be seen. Currently, the only practical result, in the routine epilep- cost of developing antiepileptic drugs increased greatly because of sy clinic, has been the ability to identify patients at increased risk the huge increase in the number of animals and procedures need- of a Stevens–Johnson reaction (which is a very small risk anyway), ed in preclinical testing, and in the complexity and scope of this in certain populations although there are diferent genetic bases testing. Large controlled clinical trials were also required, and the for diferent populations (this is an immunological mechanism; immediate efect was a rapid fall-of in the number of drugs being cerebral epilepsy mechanisms have remained untouched in any developed. practical sense by pharmacogenetics). Tis fnding resulted in the Carbamazepine and valproate and some benzodiazepine drugs over-reaction of the US Food and Drug Administration (FDA), and were licensed in Europe for many years before being given a US its main consequence in practice has been to limit carbamazepine licence and patients in the USA were therefore disadvantaged. Te prescribing to the detriment of most patients, and to drive up costs US epilepsy community became very concerned and, in 1972, the for very little gain. US NINDS set up an Ad Hoc Committee on Anticonvulsant Drugs One of the striking phenomena of the post-war years, and par- in conjunction, and with the ILAE and FDA, formulated a proce- ticularly in the last 50 years, has been the rise in the size, profts and dure in 1973 for design, patient selection and protocols for new power of the pharmaceutical industry. As a result of the proftability drug trials which has been the framework for drug development of the pharmaceutical section, drug discovery moved in large part right up until the present day. from a university environment to in-house company laboratories, In 1980, the FDA further tightened clinical trial methodology and drug development has become a commercial enterprise kept and made randomized controlled trials a necessary prerequisite of under conditions of tight secrecy to protect commercial interests. licensing. Tey also made the momentous decision that the new Particularly since the mid-1980s, the value of the antiepileptic drug drugs had to demonstrate superiority over a comparator compound market has increased dramatically and the total sales of antiepilep- rather than equivalence, and so almost all the studies compared the tic drugs in the USA, for instance, rose from $400 million in 1990 to new drug with placebo rather than a conventional therapy. Tis de- $3 billion in 2000. Tis is in part due to increased numbers of treated cision resulted in a lamentable lack of head-to-head randomized persons (for reasons that are not entirely clear) and also the greatly controlled trials, and the existing pattern of studies with small num- increased cost of medication and the use of the drugs in non-epi- bers of patients in a cross-over design had to be replaced by the lepsy indications. Despite this, none of the newer expensive antiep- early 1990s by the requirement to carry out parallel group studies in ileptics have proven to be strikingly more efcacious in controlled increasingly large numbers of patients. Over the past decades, the Historical Introduction xxv laws have been interpreted with mounting stringency, and higher to perform randomized controlled trials (uniquely in epilepsy sur- levels of evidence of efcacy and lack of toxicity are required now gery) and several systems have been licensed by the EMA and FDA. than even 20 years ago. In the past decade, a further layer of bu- It must be admitted though, the results of stimulation generally on reaucracy has been added in many countries, which assesses the epilepsy control have been modest. cost-efectiveness of therapy. Whether, in the light of all these new Much of the current emphasis of surgery is fuelled by economic regulatory hurdles, the balance between protecting the public and factors in market-driven medical systems, where surgical activity stimulating new therapies is appropriate is a matter of opinion but brings in large monetary reward, rather than on clinical factors. Te there is a strong sense that the development of AEDs is now being current reality is that although epilepsy surgery is a fashionable and hampered by over-regulation. much-promoted topic, it remains a marginal treatment, unsuitable Although this survey focuses on drug treatment, a brief note on for the vast majority of patients and with ofen suboptimal out- non-pharmaceutical approaches in this period is in order. Tere has comes. in the past 30 years been great interest in surgical therapy. Tis has Non-pharmaceutical, non-surgical approaches to treatment (i.e., been fuelled by the advent of CT and particularly MRI, which pro- lifestyle, nutrition, socio-psychological factors, etc.) have been al- vides a method of identifying structural defects as the target of re- most totally ignored in orthodox medicine in the post-war years, as spective surgery. Te increased sensitivity of MRI has demonstrated the technologies of modern medicine and surgery and of pharma- lesions such as hippocampal sclerosis, small cavernoma and devel- ceutical science have dominated thought. Tis perhaps is the big- opment disorders which were previously not possible to visualize gest change in the past 100 years. directly. Other investigatory modalities also (see Section 4) have Te drug treatment in common use in 1996–2014, as refected improved surgical selection. Surgical technique has also improved in the four editions of this book, are shown in Table 9. As can be in the last 50 years, with better anaesthesia and postoperative care, seen, one very obvious development in the past 50 years has been and surgical morbidity has fallen. Te technology of surgery has im- the narrowing of treatment options in professional practice to only proved, and in relation to epilepsy surgery the two most important those drugs that have been assessed in blinded and randomized developments were the introduction of the operating microscope, in trials and that have shown superiority over placebo (i.e. have bi- 1967, which has allowed microsurgical techniques to be developed ological action). Patients are ofen not satisfed with this, and al- and, more recently, improved computerized stereotactic methods. ternative and complementary medicines are widely sought (for the However, the theoretical basis of surgery has not changed at all. common remedies used see Chapter 22) as well as other physical Te fundamental basis of most surgery is the ‘resection of epilep- non-medicinal approaches. Furthermore, orthodox medicine has tic tissue in focal ’ in the hope that this will halt seizures removed its focus from consideration of diet, hygiene and modes of without leaving large cerebral defcits. Tis is exactly the same basis living which were so much part of conventional therapy, and which of surgery that was expounded by Horsley and others in the 1880s. were a large component of the medical consultation at least until Indeed, the types of operation have also not changed fundamentally the period of the Second World War. It is interesting to speculate in the last 50 years (e.g. temporal lobectomy, lesionectomy, tailored on the degree to which the much more evidence-based approach of resections, collosotomy, hemispherectomy, awake craniotomy). today has improved overall outcome (there is little synoptical study Te non-resective approaches (e.g. cortical stimulation, ablation of this) or alleviated sufering. Terapy has undoubtedly improved, of pathways) also have a long history stretching back to the early but the focus on drugs and surgery, to a signifcant extent commer- twentieth century, and although technology has changed, the prin- cially fuelled, has tended to protocolize medicine and to dehuman- ciples and, indeed to a large degree, the outcomes of non-resective ize therapy. What has been gained on one hand might have been operations have not. Nevertheless, in the last 10 years or so, the ma- lost on the other, and I suspect the picture is more complicated than jor focus of surgical research has been on stimulation both invasive ofen believed. and external. Te frst therapy to gain wide acceptance has been vagal nerve stimulation, on the basis of trials which have been crit- icized in various ways, and certainly the routine clinical experience Acknowledgement of vagal nerve stimulation is less positive than the trials have indi- Some of the tables and text are adapted from the historical intro- cated. More recently, a series of invasive stimulation technologies ductions in previous editions of this book [1,2,3] and from the au- have been studied; divided into ‘scheduled stimulation’ (e.g. bilat- thor’s contributions to the pubilcations around the ILAE centenary eral stimulation of the anterior thalamus and hippocampal stimu- and other works [10,14,17,18,19,20]. Te sources of unreferenced lation) and ‘responsive stimulation’ (e.g. of the cortical epileptic fo- material in this chapter are found in references [6,10,15,19,20]. Tis cus or hippocampus). External non-invasive stimulation methods work was undertaken at UCLH/UCL which receives a proportion through the trigeminal nerve, and via transmagnetic cranial stimu- of its funding from the Department of Health’s NIHR Biomedical lation, have also been explored. In these areas, it has been possible Research Centre’s funding scheme. xxvi Historical Introduction

Table 1 Non-bromide medicinal products used in the treatment of epilepsy 1857–1910.

Plant-based (herbals) Aconite (wolf’s bane), adonis vernalis, bryonia, cannabis, calabar bean, conium (hemlock), cotyledon umbilicus (penny wort), ergot, digitalis, gelseminum sempervirens (yellow jasmine), hydrastine, indigo, mistletoe, opium (and codeia), picrotoxin (from connulus indicus), piscidia erthrina (fshfuddle) rue, santonin (artemisia), selenum (marsh parsley), simulo (hyssop), strophanthus, strychnine, valerian. Extracts of the solanaceae (nightshade) family were also widely used: atropine, belladonna, hyoscine, stromonium

Animal-based extracts Bufo rana crotalin (rattlesnake venom), curare, thyroidin, toxins and antiserum

Simple chemicals amylene hydrate, borax, caustium, coal tar (acetanilide, phenacetin, acetophenetidin), chinolin (quinoline), copper, copper sulphate, chloral hydrate, chloralamide, chloretone, iron, lead, nitroglycerine, osmic acid, pepto-mangan, potassium iodide, resorcin, sodium eosinate, silver nitrate, sulphonal, urethane, zinc (oxide, sulphate, acetate, valerianate, lactate, nitrate)

Source: Lists derived from [1,5,6,7,8,9,19]. Most of the above were used for chronic therapy. For the treatment of acute seizures in the nineteenth century, various compounds were widely used such as amyl nitrite, atropine, chloral, chloroform, ether, nitroglycerine, paraldehyde. Others less frequently recommended included some by inhalation: , ammonia, assafoetida (inhalation or enema), camphor, curare (by injection), hydrocyanic acid, lavender, musk, turpentine, veratrum (American hellebore).

Table 2 Antiepileptic drugs listed by Gowers in 1881 and 1901.

Drugs of ‘defnite beneft’ Drugs of ‘doubtful value’

Bromide (ammonium, potassium, sodium, lithium, strontium) Camphor Digitalis Aconite Belladonna Hydrocyanic acid Atropine Iodide of potassium Stramonium Mistletoe Cannabis indica Turpentine Gelsemium sempervirens Cocculus indicus (picrotoxin) Opium Choral Nitroglyerine Amylene hydrate Zinc Nitrate of silver Borax (sodium biborate) Sulphate of copper Iron Benzoate of soda Hyoscine Piscidia erthrina Strophanthus Codeia (Of this list, bromide was seen by Gowers as the primary treatment, Calabar bean and all the others ‘adjuncts’) Ergot Sclerotic acid Nitrite of amyl Bromide of aluminium, nickel, camphor, rubidium and ammonium, iodine, chorine, bromaline (bromine and formaldehyde derivatives), bromapin (bromine and sesame oil), hydrobromic acid Osmic acid Curare Hydrastin Chinolin Resorcin Antipyrine Acetanilide Thyroidin

Source: Data from Gowers 1881 [7]. Gowers also notes that zinc and opium were generally of not much use but good in hysteroid convulsions; digitalis, cannabis, belladonna, atropine were thought useful only in combination with bromide. Historical Introduction xxvii

Table 3 Therapy in 1907: drugs recommended by William Aldren Turner.

Drugs of defnite beneft Drugs of limited beneft Drugs of no special beneft

Bromide — sodium and potassium primarily Zinc salts (oxide, valerianate, lactate) Monobromate of camphor or Gélineau’s formula Opium Eosinate of sodium Other synthetic formulations (e.g. bromipin, Strychnine Chloretone bromaline, bromocarpine) or salts Chloride of calcium Antipyrin (e.g. strontium or ammonium) had, in Atropine Atropine Turner’s view, little advantage Glycerophosphatesa Intestinal antisepticsb Chloral hydrate Borax Belladonna

Source: Data from Turner 1907 [8]. For status epilepticus, Turner recommended chloral, chloroform, morphia and bromides (including intrathecal bromide solutions). a For neurasthenic symptoms. b In view of the theories of autointoxication (which Turner found unconvincing). Other drugs that Turner found of no value included sulpho-carbonate of soda, salol (phenyl salicylate), beta naphthol, salicylate of bismuth and ‘a host of other remedies of this character’.

Table 4 Drugs listed in the treatment of epilepsy by SAK Wilson in 1940.*

Drugs of defnite beneft Bromide (in any of the following salts: sodium, potassium, ammonium, lithium, calcium, calcium bromine galactogluconate) Bromide combinations Phenobarbitone (Luminal) N methylethylphenylmalonyl urea (Prominal) Borax Belladonna (sometimes with bromide or bromide and caffeine) Nitroglycerine (sometimes with strychnine and bromide) Dialacetin (a mixture of the hypnotic allobarbital (Dial) with allylparacetaminophenol)

Source: Data from Wilson 1940 [11]. *Although Wilson [11] was published in 1940, this was after his death and the draft manuscript was completed (in 1937), edited and published posthumously. xxviii Historical Introduction

Table 5 The drugs used in the treatment of epilepsy in 1955, derived from the international list of antiepileptic drugs published in Epilepsia.

Chemical composition Common or trade name

Barbiturates Phenylethyl barbituric acid Gardenal Phenylethyl malonylurea Luminal, Phenobarbital, Phenobarbitone Methylphenyl barbituric acid Mephebarbital, Rutonal Methylphenylethyl barbituric acid Isonal, Meberal, Prominal Methyldiethyl barbituric acid Gemonil Combinations with barbiturate Phenylethyl barbituric acid, belladonna and caffeine Alepsal Phenylethyl barbituric acid and amphetamine Ortenal Oxazolidine diones Trimethyl oxazolidine dione Absentol, Epidione, Minoaleviatin, Petilep, Trimethadione, Tridione Dimethylethyl oxazolidine dione Paramethadione, Paradione Diphenyl oxazolidine dione Epidon Allylmethyl oxazolidine dione Malidone Hydantoins Diphenyl hydantoin (or diphenyl hydantoin sodium) Alleviatin, Alepsin, Antipil, Antisacer, Comitiona, Convulsin, Dihydan, Dilantin, Diphentoin, Ditoinate, Epamin, Epanutin, Eptoin, Phenytoine, Solantyl Methyldiphenyl hydantoin Melantoine Methylphenylethyl hydantoin Mesantoin, Phenantoin, Sedantoinal Methyldibromophenylethyl hydantoin Anirrit Dimethyldithio hydantoin Thiomedan Sodium phenylthienyl hydantoin Thiantoin, Phethenylate Methylphenyl hydantoin Nuarone Combinations with hydantoins Diphenyl hydantoin and phenobarbital Hydantoinal, comitoina compound Diphenyl hydantoin, phenobarbital and caffeine Antisacer compound, Apilep Diphenyl hydantoin, phenobarbital and desoxyephedrine Isosolantyl, Phelantin Methylphenylethylhydantoin and phenobarbital Hydantal Diphenyl hydantoin and methylphenylethyl barbituric acid Comital, Mebaroin Diphenyl hydantoin, methylphenylethyl barbituric acid and Comital L phenobarbital Other types Phenylacetylurea Epiclase, Fenilep, Phenacemide, Phenurone Phenylethylhexahydropyrimidine dione Mysoline, Primidone Benzchlorpropamide Hibicon, Posedrine Methylalphaphenyl Lifene, Milontin Acetazolamide Diamox Alkaline borotartrates Several preparations Glutamic acid (or glutamic acid-HCl) Acidulin, Glutan-HCl, Glutamicol Bromides Large numbers of preparations (in three categories: alkaline bromides and alkaline earths: polybromide; organic bromides; bromide in combination with other agents) Source: Epilepsia 1955; 4: 121–123. Reproduced with permission from John Wiley & Sons. Historical Introduction xxix

Table 6 Lennox’s ‘therapeutic arsenal’: drugs in common use in the USA around 1960.

Non-commercial offcial name Patented trade name Grand mal and psychomotor seizures Bromides Bromides Phenobarbitala Luminal Methobarbital Mebaral Diphenylhydantoina Dilantin Mesantoin Mesantoin Ethotoin Peganone Primidonea Mysoline Phenacemide Phenurone Methsuximidea Celontin Acetazolamideb Diamox Petit mal Trimethadioneb Tridione Paramethadionea Paradione Phensuximidea Milontin Ethylmethylsuccinimide Zarontin Quinacrine hydrochloride Atabrine Metharbital Gemonil

Source: From Lennox 1960 [16]. Reproduced by permission of Wolters Kluwer Health. aDrugs of initial choice. bDrugs of second choice. Phenurone and Diamox were noted to be often effective against petit mal as well, and phensuximide to be often effective against grand mal.

Table 7 Drug treatments reported to be used in status epilepticus 1857–1973.

ACTH Hyoscine hydrobromate Aldosterone Lignocaine Amyl nitrate Morphia/apomorphine Amylene hydrate Oxygen inhalation Amyline choral Paraldehyde Amylobarbital Atropine sulphate Phenobarbital Bromide of potassium Phenytoin Bromide salts (various) intrathecal Procaine Camphor (subcutaneous) Quinine sulphate Chlordiazepoxide Scopolamine (hydodermic) Chlomethiazole Sinapismes Chloral hydrate Strophanthus Chloroform Suxamethonium Clonazepam Tribromethanol Diazepam Tridione Diethyl barbituric acid D-Tubocuraine Digitalis Urea Donath’s solution

Source: Data from Neligan and Shorvon 2009 [10]. In addition to these drugs, physical treatments were also strongly recommended including: cold douches or baths, darkened room, rest and quiet, lumbar puncture/ CSF drainage, multiple enemata and irrigation of the bowel, saline infusions and venesection. xxx Historical Introduction

Table 8 Drugs in clinical trial development (presented at the biannual Eilat Conference on New Antiepileptic Drugs 1992–2014).

Eilat II, 1992 Eilat II, 1994 Eilat III, 1996 Eilat IV, 1998 Eilat V, 2000 Eilat VI, 2002 CGP33 101 Clobazam 534U87 (a lamotrigine AWD 131–138 () Carabersat (SB- Felbamate (rufnamide) Dezinamide derivative) DP-VPA (DP16) 204269) Gabapentin Desinamide Felbamate ADCI Harkeroside (lacosamide: -G (CGX- e 1007) Lamotrigine Fluzinamide AWD 131–138 SPM 92 7) (imepitoin) Fluorofelbamate Oxcarbazpine Gabapentin Gabapentin LY 300164 () DP16 (DP-VPA) Lacosamide (SPM Lamotrigine Lamotrigine NPS 1776 a Ganaxolone (CCD 927) hydrochloride Losigamone Levetiracetam NW-1015 1042) Pregabalin Stiripentol Oxcarbazepine (UCB L059) Pregabalin (CI-1008) Levetiracetam (UCB Retigabine Tiagabine Remacemide Oxcarbazepine Remacemide LO59) Safnamide Topiramate hydrochloride Remacemide Retigabine (D-23129) Losigamone SPD421 (DP-VPA) Vigabatrin Stiripentol hydrocholride Rufnamide Pregabalin (CI-1008; Tiagabine Retigabine (D-23129) Talampanel isobutyl GABA) Valrocemide (TV 1901) Topiramate Ralitoline Valrocemide (TV Remacemide 1901) UCB L059 Rufnamide (CGP hydrochloride (levetiracetam) 33101) Retigabine (D-29129) Vigabatrin Tiagabine Rufnamide (CGP Valrocemide 33101) (TV 1901O) Soretolide (D2916) Valrocemide (TV 1901)

Source: Data from Eilat Conferences [21,22,23,24,25,26,27,28,29,30]. Drugs highlighted in green are those that were subsequently licensed. aLosigamone was mentioned in programme but not the publication. bRWJ-333369 was mentioned in programme but not the publication. cNS1209 was mentioned in the publication but not the programme. dSection on ‘Emergency therapy’ for drugs used in the frst time; details from programme, not yet published. eHarkeroside was sold on in various steps eventually to UCB and renamed lacosamide. fImepitoin is licensed for use in veterinary medicine for dogs. Historical Introduction xxxi

Eilat VII, 2004 Eilat VIII, 2006 Eilat IX, 2008 Eilat X, 2010 Eilat XI, 2012 Eilat XII, 2014d Atipamezole Brivaracetam 2-Deoxy-glucose D-deoxy-glucose D-deoxy-glucose D-deoxy-glucose BIA 2-093 (eslicarbazepine (UCB 34714) Brivaracetam (UCB Brivaracetam Brivaracetam Adenosine-releasing acetate) Eslicarbazepine 34714) Carisbamate Ganaxolone silk acetate (BIA Fluorofelbamate Carisbamate (RWJ- Ganaxolone ICA-105665 Allopregnanolone 2-093) 333369) SAGE547) NPS 1776 Imepitoinf Fluorofebamate CSC700-008 AMP-X-0079 Pregabalin ICA-105665 NAX-810-2 Ganaxolene Eslicarbazepine BGG492 Retigabine NAX-5055 Perampanel Huperzine A acetate (BIA 2-093) Brivaracetam RWJ-333369 Perampanel Propylisopropyl (carisbamate)b JZP-4 Fluorofebamate Bumetamide Propylisopropyl acetamide (PID) Lacosamide Ganaxolene Safnamide acetamide (PID) Tonabersat Butylpropylacetamide NS1209c Huperzine (SPD) SPM 927 (lacosamide) Retigabine VK-765 Propylisopropyl JZP-4 Stiripentol T2007 (sodium Valnoctamide acetamide (PID) Talampanel Lacosamide (SPM 5,5-diphenylbarbiturate) (VCD) and sec- Cannabidivarin (GWP Retigabine 927) 420006) UCB 34714 (brivaracetam) Valnoctamide (VCD) Butylpropylacetamide Rufnamide NAX 5055 (SPD) Everolimus Valrocemide YKP3089 RWJ-333369 Propylisopropyl YKP3089 Ganaxolone (carisbamate) acetamide (PID) Huperzine A Seletracetam Retigabine Imepitoinf (UCB 44212) T2000 Micocycline Stiripentol Tonabersat NAX-810-2 Talampanel Valrocemide Pitolisant (tiprolisant) Valrocemide Valnoctamide Propofol YKP3089 hemisuccinate Propylisopropyl acetamide (PID) PRX 0023 (naluzotan) SAGE-217 Valnoctamide (VCD) VLB-01 YKP3089 xxxii Historical Introduction

Table 9 Drugs used in the treatment of epilepsy 1996–2014 as taken from the four editions of the Treatment of Epilepsy.

First edition, 1996 Second edition, 2004 Third edition, 2009 Fourth edition Clobazam Acetazolamide Acetazolamide Acetazolamide Clonazepam Carbamazepine ACTH and corticosteroids ACTH and corticosteroids Other benzodiazpines Clobazam Benzodiazepines used primarily Benzodiazepines used in epilepsy (, diazepam, Clonazepam for chronic treatment (clobazam, clonazepam, , midazolam, Short-acting and other (clobazam, clonazepam, clorazepate, diazepam, ) benzodiazepines (diazepam, clorazepate, nitrazepam) lorazepam, midazolam, Carbamazepine and lorazepam, midazolam, Benzodiazpines used primarily nitrazepam) oxcarbazepine clorazepate, nitrazepam) for emergency treatment Brivaracetama Ethosuximide and methsuximide Ethosuximide (diazepam, lorazepam, Carbamazepine Felbamate Felbamate midazolam) Eslicarbazapine acetate Gabapentin Fosphenytoin Brivaracetama Ethosuximide Lamotrigine Gabapentin Carisbamatea Felbamate Phenobarbitone Lamotrigine Carbamazepine Gabapentin Phenytoin Levetiracetam Eslicarbazapine acetatea Lacosamide Piracetam Oxcarbazepine Ethosuximide Lamotrigine Topiramate Phenobarbital, primidone and Felbamate Levetiracetam Valproate other barbiturates (metharbital, Gabapentin Oxcarbazepine Vigabatrin methylphenobarbital, Lacosamide Perampanel Other drugs used in the ) Lamotrigine Phenobarbital, primidone and treatment of epilepsy Phenytoin Levetiracetam other barbiturates (acetazolamide, ACTH, Piracetam Oxcarbazepine Phenytoin allopurinol, ethotoin, Pregabalin Phenobarbital, primidone and Piracetam bromides, mephenytoin, Rufnamide other barbiturates Pregabalin paraldehyde, phenacemide, Tiagabine Phenytoin Retigabine trimethadione) Topiramate Piracetam Rufnamide Valproate Pregabalin Stiripentol Vigabatrin Retigabinea Tiagabine Zonisamide Rufnamide Topiramate Other drugs more rarely used Stiripentol Valproate in the treatment of epilepsy Tiagabine Vigabatrin (ACTH, allopurinol, bromide, Topiramate Zonisamide ethotoin, mephenytoin, Valproate Other drugs rarely used (bromide, paraldehyde, phenacemide, Vigabatrin lidocaine, methsuximide, trimethadione) Zonisamide paraldehyde, sulthiame) Other drugs rarely used (allopurinol, bromide, ethotoin, , mephenytoin, phenacemide, trimethadione — oral use)

Source: Lists derived from Shorvon [1,2,3] and the current book. In addition to the above licensed drugs, each edition of the book has listed drugs in early clinical development: 1st edition: eterobarb, levetiracetam, losigamone, ralitoline, remacemide, stiripentol, taltrimide, tiagabine, zonisamide. 2nd edition: AWD 131-138, carabersat (SB-204269), conantokin-G (CGX-1007), ganaxolone, harkoseride (SPM 927; ADD 234037), NPS 1776, retigabine (D-23129), safnamide (NW-1015; PNU-151774E). SPD421 (DP16; DP-VPA). talampanel (LY300164; GIKY 53773), valrocemide (TV 1901). 3rd edition: 2-deoxy-o-glucose, fuorofelbamate, ganaxolone, JZP-4, safnamide, seletracetam, T2000, talampanel, tonabersat, valrocemide, YKP3089. 4th edition: allopregnanolone (SAGE-547), cannabinoids, 2-deoxy-D-glucose, everolimus, ganaxolone, huperzine A (INS-001), NAX 810-2, pitolisant, PRX00023 (naluzotan), selurampanel, tonabersat, YKP3089. aDrug not licensed but in late-stage clinical development. References xxxiii

References 17. Weiss G, Shorvon SD. International League Against Epilepsy – the second period: 1. Shorvon SD, Sander JWAS. Te treatment of epilepsy at the National Hospital 1953–1992. In Shorvon SD, Weiss G, Avanzini G, et al. (eds). International League Queen Square, 1857–1939: a mirror of the frst phase of the modern history of Against Epilepsy: A Centenary History. Oxford: Wiley Blackwell, 2009; 45–96. medical and surgical therapy. In Shorvon SD, Dreifuss F, Fish D and Tomas D 18. Avanzini G, Engel J, Reynolds E, Shorvon S, Weiss G, Wolf P. International League (eds). Te Treatment of Epilepsy. Oxford: Blackwell Science, 1996; xvii–xliv. Against Epilepsy – the third period: 1993–2008. In Shorvon SD, Weiss G, Avanzini 2. Shorvon SD. Te drug treatment of epilepsy between 1938 and 1955. In Shorvon G, et al. (eds). International League Against Epilepsy: A Centenary History. Oxford: SD, Dodson E, Fish DR, Perucca E (eds). Te Treatment of Epilepsy, 2nd edition. Wiley Blackwell, 2009; 97–132. Oxford: Blackwell Science, 2004, xiv–xxxiii. 19. Shorvon SD. Drug treatment of epilepsy in the century of the ILAE: the frst 50 3. Shorvon SD. History of the treatment of epilepsy 1955–1989. In Shorvon SD, Pe- years, 1909–1958. Epilepsia 2009; 50(Suppl 3): 69–92. rucca E, Engel J (eds). Te Treatment of Epilepsy, 3rd edition. Oxford: Blackwell 20. Shorvon SD. Drug treatment of epilepsy in the century of the ILAE: the second 50 Science, 2009, xxi–xxxvi. years, 1959–2009. Epilepsia 2009; 50(Suppl 3): 93–130. 4. Anon. Medical Societies: Te Royal Medical and Chirurgical Society, Tuesday 11 21. Stables JP, Bialer M, Johannessen SI, et al. Progress report on new antiepileptic May 1857: Sir Charles Locock, president in the chair. Analysis of ffy-two cases of drugs: a summary of the Second Eilat Conference. Epilepsy Res 1995; 22: 235–246. epilepsy observed by the author. By Edward H. Sieveking, MD, FRCP. Lancet 1857; 22. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress 70: 527–528. report on new antiepileptic drugs: a summary of the Tird Eilat Conference. Epi- 5. Sieveking E. On Epilepsy and Epileptiform Seizures, Teir Causes, Pathology and lepsy Res 1996; 25: 299–319. Treatment. London: Churchill, 1857. 23. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress 6. Friedlander WJ. Te History of Modern Epilepsy – the beginning, 1865–1914. West- report on new antiepileptic drugs: a summary of the Fourth Eilat Conference (EI- port,CT and London: Greenwood Press, 2001. LAT IV). Epilepsy Res 1999; 34: 1–41. 7. Gowers WA. Epilepsy and Other Chronic Convulsive Disorders. London: Churchill, 24. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress 1881 (second edition in 1901). report on new antiepileptic drugs: a summary of the Fifh Eilat Conference (EI- 8. Turner WA. Epilepsy: A Study of the Idiopathic Disease. London: Macmillan, 1907. LAT V). Epilepsy Res 2001; 43: 11–58. 9. Spratling W. Epilepsy and its Treatment. Philadelphia: WB Saunders & Co, 1904. 25. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress 10. Neligan A, Shorvon SD. Te modern history of status epilepticus and its treat- report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EI- ment. Epilepsia 2009; 50(Suppl. 3): 56–58. LAT VI). Epilepsy Res 2002; 51: 31–71. 11. Wilson SA. Neurology. London: Edward Arnold, 1940. 26. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T. Progress 12. Muskens LJJ. Epilepsie: Vergelijkende Pathogenese, Verschijnselen, Behandeling. report on new antiepileptic drugs: a summary of the Seventh Eilat Conference Amsterdam: Van Rossen, 1924. (EILAT VII). Epilepsy Res 2004; 61: 1–48. 13. Turner WA. Tree lectures on epilepsy. Being the Morrison lectures delivered be- 27. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T. Progress fore the Royal College of Physicians of Edinburgh in 1910. Edinburgh: Mackenzie, report on new antiepileptic drugs: a summary of the Eighth Eilat Conference (EI- 1910. LAT VIII). Epilepsy Res 2007; 73: 1–52. 14. Shorvon SD, Weiss G. International League Against Epilepsy – the frst period: 28. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress re- 1909–1952. In Shorvon SD, Weiss G, Avanzini G, et al. (eds). International League port on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT Against Epilepsy: A Centenary History. Oxford: Wiley Blackwell, 2009; 1–44. IX). Epilepsy Res 2009; 83: 1–43. 15. Shorvon SD. Historical introduction: the causes of epilepsy in the pre-molecular 29. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress re- era (1860–1960). In Shorvon SD, Andermann F, Guerrini R. (eds). Te Causes port on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT of Epilepsy. Common and Uncommon Causes in Adults and Children. Cambridge: X). Epilepsy Res 2010; 92: 89–124. Cambridge University Press, 2011; 1–20. 30. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress 16. Lennox WG. Epilepsy and Related Disorders. Boston: Little Brown, 1960. report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res 2013; 103: 2–30.