Epilepsy and Movement Disorders

Epilepsy and Movement Disorders

The boundaries between epilepsy and movement disorders are often difficult to define. Many symptoms of epilepsy present themselves as movement disorders and, conversely, movement disorders may be observed that are not dissimilar to epileptic seizures. In this unique book, a distinguished international team of specialists examine the clinical, neurophysiological, genetical, pharmacological and molecular factors that underlie the relationships and differences between these two disorders. They examine methods for investigating motor cortex excitability and the electrophysiological and chemical characteristics of epilepsies resembling movement disorders, and present schemes for the neurophysiological classification of myoclonic epilepsies and myoclonus. Included is an innovative, up-to-date review of the genetic syndromes that associate epilepsy and paraoxysmal dyskinesias, and a review of the drugs used to treat, or which may precipitate, epilepsy and movement disorders. This is essential reading for all neurologists and neuroscientists. Renzo Guerrini is Professor of Paediatric Neurology at the Institute of Child Health and Great

Ormond Street Hospital, University College London. Jean Aicardi is Honorary Professor at the Service de Neurologie Pédiatrique at l’Hôpital Robert

Debré in Paris. Frederick Andermann is Professor at the Epilepsy Center of the Montreal Neurological Institute

and Hospital. Mark Hallett is Chief of the Human Motor Control Section at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in Bethesda.

From the first description of myoclonus in the medical literature by Dr. Angelo Dubini (1846. Primi cenni sulla Corea Elettrica. Annali Univerali di Medicina, 117; 349: 5–50). . . . scosse muscolari succedentesi a piu’ o men brevi intervalli, e sempre identiche a se’ stesse, quasi fossero prodotte da ripetute scariche elettriche: le quali, preso dapprima un dito, un arto, (. . .) od una meta’ della faccia, (. . .) si estendono in brevi giorni a tutta la meta’ corrispondente del corpo . . . . . . muscular jerks, relapsing at variable intervals and each one always indentical to the other, as if they were generated by repeated electrical shocks, which, after first seizing a finger, a limb, (. . .) or a hemiface, (. . .) progress over the whole hemibody in a matter of a few days . . .

Epilepsy and Movement Disorders Edited by

Renzo Guerrini Institute of Child Health and Great Ormond Street Hospital, University College London, UK

Jean Aicardi Service de Neurologie Pédiatrique, l’Hôpital Robert Debré, Paris, France

Frederick Andermann Montreal Neurological Institute and Hospital, Quebec, Canada

and Mark Hallett National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA

                                                     The Pitt Building, Trumpington Street, Cambridge, United Kingdom    The Edinburgh Building, Cambridge CB2 2RU, UK 40 West 20th Street, New York, NY 10011-4211, USA 10 Stamford Road, Oakleigh, VIC 3166, Australia Ruiz de Alarcón 13, 28014 Madrid, Spain Dock House, The Waterfront, Cape Town 8001, South Africa http://www.cambridge.org © Cambridge University Press 2002 This book is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 2002 Printed in the United Kingdom at the University Press, Cambridge Typeface Minion 8.5/12pt System QuarkXPress™ [  ] A catalogue record for this book is available from the British Library Library of Congress Cataloguing in Publication data Epilepsy and movement disorders / edited by Renzo Guerrini . . . [et al.]. p. ; cm. Includes bibliographical references and index. ISBN 0 521 77110 2 (hardback) 1. Epilepsy. 2. Movement disorders. I. Guerrini, Renzo. [DNLM: 1. Epilepsy. 2. Movement Disorders. WL 385 E6038 2001] RC372.5.E623 2001 616.8′53–dc21 2001025799 ISBN 0 521 77110 2 hardback

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

This book is in memoriam of Professor Henri Gastaut and Professor C. David Marsden, who promoted epilepsy and movement disorders from ancillary disciplines to leading areas of modern neurology. Many concepts developed in this book stem from their seminal work.

Contents

List of contributors Preface and overview

page x xix

Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett

1

Epilepsies as channelopathies

1

Guiliano Avanzini and Louis J. Ptàcek

2

Epilepsy and movement disorders in the GABAA receptor 3 subunit knockout mouse: model of Angelman syndrome

15

Richard W. Olsen and Timothy M. DeLorey

3

Genetic reflex epilepsy from chicken to man: relations between genetic reflex epilepsy and movement disorders

29

Robert Naquet and Cesira Batini

4

Functional MRI of the motor cortex

47

Raphaël Massarelli, Angelo Gemignani, Michela Tosetti, Domenico Montanaro, Raffaello Cannapicchi and in memoriam Claudio Munari

5

Neuromagnetic methods and transcranial magnetic stimulation for testing sensorimotor cortex excitability

59

Paolo M. Rossini, Alfredo Berardelli and Roberto Cantello

6

Motor dysfunction resulting from epileptic activity involving the sensorimotor cortex

77

Renzo Guerrini, Lucio Parmeggiani, Alan Shewmon, Guido Rubboli and Carlo A. Tassinari

7

Nocturnal frontal lobe epilepsy

97

Paolo Tinuper, Elio Lugaresi, Federico Vigevano and Samuel F. Berkovic

8

Motor cortex hyperexcitability in dystonia

111

Mark Hallett

9

The paroxysmal dyskinesias Nardo Nardocci, Emilio Fernández-Alvarez, Nicholas W. Wood, Sian D. Spacey and Angelika Richter

vii

125

viii

10

Contents

Normal startle and startle-induced epileptic seizures

141

Peter Brown, David R. Fish and Frederick Andermann

11

Hyperekplexia: genetics and culture-bound stimulus-induced disorders

151

Andrea Bernasconi, Frederick Andermann and Eva Andermann

12

Myoclonus and epilepsy

165

Renzo Guerrini, Paolo Bonanni, John Rothwell and Mark Hallett

13

The spectrum of epilepsy and movement disorders in EPC

211

Hannah R. Cock and Simon D. Shorvon

14

Seizures, myoclonus and cerebellar dysfunction in progressive myoclonus epilepsies

227

Roberto Michelucci, José M. Serratosa, Pierre Genton and Carlo A. Tassinari

15

Opercular epilepsies with oromotor dysfunction

251

Javier Salas-Puig, Angeles Pérez-Jiménez, Pierre Thomas, Ingrid I. E. Scheffer, Bernardo Dalla Bernardina and Renzo Guerrini

16

Facial seizures associated with brainstem and cerebellar lesions

269

A. Simon Harvey, Michael Duchowny, Alexis Arzimanoglou and Jean Aicardi

17

Neonatal movement disorders: epileptic or non-epileptic

279

Cesare T. Lombroso

18

Epileptic and non-epileptic periodic motor phenomena in children with encephalopathy

307

Giuseppe Gobbi, Antonella Pini and Lucia Fusco

19

Epileptic stereotypies in children

319

Thierry Deonna, Martine Fohlen, Claude Jalin, Olivier Delalande, Anna-Lise Ziegler and Eliane Roulet

20

Non-epileptic paroxysmal eye movements

333

Emilio Fernández-Alvarez

21

Shuddering and benign myoclonus of early infancy

343

Christa Pachatz, Lucia Fusco and Federico Vigevano (with appendix by Natalio Fejerman and Roberto Caraballo)

22

Epilepsy and cerebral palsy

353

John Stephenson and Charlotte Dravet

23

Sydenham chorea

359

Marjorie A. Garvey and Fernando R. Asbahr

24

Alternating hemiplegia of childhood

379

Jean Aicardi

25

Motor attacks in Sturge–Weber syndrome Alexis Arzimanoglou

393

ix

Contents

26

Syndromes with epilepsy and paroxysmal dyskinesia

407

Renzo Guerrini, Lucio Parmeggiani and Giorgio Casari

27

Epilepsy genes: the search grows longer

421

Antonio V. Delgado-Escueta, Marco T. Medina, Maria Elisa Alonso and G. C. Y. Fong

28

Genetics of the overlap between epilepsy and movement disorders

451

Nicholas W. Wood, Lucy Kinton and M. G. Hanna

29

Seizures and movement disorders precipitated by drugs

465

Olivier Dulac and Ubaldo Bonuccelli

30

Steroid responsive motor disorders associated with epilepsy

511

Brian G. R. Neville

31

Drugs for epilepsy and movement disorders

517

Lucio Parmeggiani, Renzo Guerrini and Brian Meldrum

Index Colour plates between p. 68 and p. 69

548

Contributors

Jean Aicardi, Department of Child Neurology, l’Hôpital Robert Debré, 48 Boulevard Serurier, 75019 Paris, France Maria Elisa Alonso, Department of Genetics, National Institute of Neurology and Neurosurgery, Mexico City, Mexico Eva Andermann, Department of Neurology, Montreal Neurological Hospital and Institute, McGill University, 3801 University Street, Montreal, Québec H3A 2B4, Canada Frederick Andermann, Department of Neurology, Montreal Neurological Hospital and Institute, McGill University, 3801 University Street, Montreal, Québec H3A 2B4, Canada x

Alexis Arzimanoglou, Department of Child Neurology, l’Hôpital Robert Debré, 48 Boulevard Serurier, 75019 Paris, France

Fernando R. Asbahr, Laboratório de Investigaçâo Médico (LIM-23), Medicina da Universidade de São Paulo, Rua Ovidio Pires de Campos, CEP 05403-010, Caiza Postal: 8091, São Paulo, Brazil Guiliano Avanzini, Department of Neurophysiology, Istituto Nazionale Neurologico C. Besta, Via Celoria 11, 20133 Milano, Italy Cesira Batini, National Centre of Scientific Research, Université Pierre et Marie Curie, CHU Pitié Salpêtrière, 91 Boulevard de l’Hôpital, 75634 Paris, France

xi

List of contributors

Alfredo Berardelli, Dipartimento Scienze Neurologiche, Università La Sapienza, Viale dell’ Università 30, 00185 Roma, Italy Samuel F. Berkovic, Department of Neurology, Austin and Repatriation Medical Centre, University of Melbourne, Studley Road, Heidelberg, Victoria 3084, Australia Bernardo Dalla Bernardina, Neuropediatric Department, Borgo Roma Hospital, University of Verona, 37134 Verona, Italy Andrea Bernasconi, Department of Neurology, Montreal Neurological Hospital and Institute, McGill University, 3801 University Street, Montreal, Québec H3A 2B4, Canada Paolo Bonanni, Institute of Child Neurology and Psychiatry, University of Pisa, IRCCS Stella Maris, Via dei Giacinti 2, 56018 Pisa, Italy

Ubaldo Bonuccelli, Department of Neuroscience, University of Pisa, Pisa, Italy Peter Brown, MRC Human Movement and Balance Unit, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK Raffaello Cannapicchi, Department of Neuroradiology, S. Chiara Hospital, Pisa, Italy Roberto Cantello, Clinica Neurologica, Università del Piemonte Orientale, A. Avogadro, Novara, Italy Roberto Caraballo, Servicio de Neurologia, Hospital de Pediatria ‘Prof. Juan P. Garrahan’, Buenos Aires, Argentina Giorgio Casari, Department of Human Molecular Genetics, IRCCS San Raffaele Hospital, Milan, Italy

xii

List of contributors

Hannah R. Cock, University Department of Clinical Neurology, Room 617, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK

Michael Duchowny, Department of Neurology, Miami Children’s Hospital, Solomon Klein Pavilion, 3200 SW 60 Court, Room 302, Miami, FL 33155-4079, USA

Olivier Delalande, Department of Pediatric Neurosurgery, A de Rothschild Foundation, 25–29 rue Manin, 75940 Paris, Cedex 19, France

Olivier Dulac, Department of Pediatric Neurology, Hôpital Saint Vincent de Paul, 82 avenue Denefert Rocherau, 75674 Paris Cedex 14, France

Antonio V. Delgado-Escueta, Comprehensive Epilepsy Program, UCLA and VA Greater Los Angeles Healthcare System, West Los Angeles, CA 90073, USA

Natalio Fejerman, Servicio de Neurologia, Hospital de Pediatric ‘Prof. Juan P. Garrahan’, Buenos Aires, Argentina

Timothy M. DeLorey, Molecular Research Institute, Mountain View, CA 94943, USA

Emilio Fernández-Alvarez, Servicio de Neuropediatria, Hospital de San Juan de Dios, Avda San Juan de Dios, 08950 Esplugues Barcelona, Spain

Thierry Deonna, Department of Neuropediatrics, CHUV Cantonal Hospital, University of Lausanne, 1010 Lausanne, Switzerland

David Fish, MRC Human Movement and Balance Unit, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK

Charlotte Dravet, Centre Saint Paul, 300 Boulevard de Sainte Marguerite, 13009 Marseille, France

Martine Fohlen, Service de Neurochirurgie, Fondation Rothschild, 25 rue Manin, 75019 Paris, France

xiii

List of contributors

G. C. Y. Fong, Division of Neurology, University Department of Medicine, Queen Mary Hospital, Hong Kong Lucia Fusco, Section of Neurophysiology, Bambino Gesù Children’s Hospital, IRCCS Piazza Onofrio 4, 00165 Roma, Italy Marjorie A. Garvey, Pediatric and Developmental Neuropsychiatry Branch, NIM, 10 Center Drive, Room 4N208, MSC 1255, Bethesda, MD 20892-1255, USA Angelo Gemignani, Department of Physiology and Biochemistry, University of Pisa, 56100 Pisa, Italy Pierre Genton, Centre Saint Paul, 300 Boulevard de Sainte Marguerite, 13009 Marseille, France Giuseppe Gobbi, Infancy and Childhood Neuropsychiatry Service, Maggiore C.A. Pizzardi Hospital, Largo Nigrisoli 2, 40123 Bologna, Italy

Renzo Guerrini, Neurosciences Unit, Institute of Child Health and Great Ormond Street Hospital for Children, University College London, The Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK Mark Hallett, Human Motor Control Section NINDS, NIH, Building 10, Room 5N226, 10 Center Drive, MSC 1428, Bethesda, MD 20892-1428, USA Michael G. Hanna, Department of Clinical Neurology, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK A. Simon Harvey, Department of Neurology, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3050, Australia Claude Jalin, Service de Neurochirurgie, Fondation Rothschild, 25 rue Manin, 75019 Paris, France

xiv

List of contributors

Lucy Kinton, Department of Clinical Neurology, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK

Roberto Michelucci, Department of Neurology, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy

Cesare T. Lombroso, c/o Seizure Unit and Division of Neurophysiology, Harvard Medical School, Children’s Hospital, 319 Longwood Avenue, Boston, MA 02115, USA

Domenico Montanaro, Department of Neuroradiology, S. Chiara Hospital, Pisa, Italy

Elio Lugaresi, Institute of Clinical Neurology, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy Raphaël Massarelli, CNRS UMR 5542, Faculty Laënnec, University C. Bernard, 69372 Lyon 08, France Marco T. Medina, Department of Neurology, Autonomous University, Tegucigalpa, Honduras Brian Meldrum, Institute of Psychiatry, King’s College Hospital, De Crispigny Park, London SE5 8AF, UK

†

Claudio Munari, Department of Neurological Sciences, Niguarda Hospital, 20126 Milano, Italy Robert Naquet, Institut Alfred Fessard, CNRS-UPR 2212, 91198 Gif-sur-Yvette, France Nardo Nardocci, Department of Child Neurology, Instituto Neurologico C. Besta, Via Celoria 11, I-20133 Milano, Italy Brian G. R. Neville, Neurosciences Unit, University College of London Medical School, The Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK

†

deceased.

xv

List of contributors

Richard W. Olsen, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, 10833 Le Conte Avenue, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA

Louis J. Ptàcek, Department of Neurology and Human Genetics, Howard Hughes Medical Institute, University of Utah Bld 533, Suite 2260, Salt Lake City, UT 84112, USA

Christa Pachatz, Section of Neurophysiology, Bambino Gesù Children’s Hospital, IRCCS Piazza Onofrio 4, 00165 Roma, Italy

Angelika Richter, Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Bunteweg 17, D-30559 Hannover, Germany

Lucio Parmeggiani, Institute of Child Neurology and Psychiatry, University of Pisa, IRCCS Stella Maris, Via dei Giacinti 2, 56018 Pisa, Italy Angeles Pérez-Jiménez, Department of Clinical Neurophysiology, Hospital Niño Jesús, Madrid, Spain Antonella Pini, Infancy and Childhood Neuropsychiatry Service, Maggiore C.A. Pizzardi Hospital, Largo Nigrisoli 2, 40123 Bologna, Italy

Paolo Maria Rossini, Department of Neurology, CRCCS AFaR Ospedale Fatebenefratelli, Isola Tiberina 39, 00186 Roma, Italy John Rothwell, MRC Human Movement and Balance Unit, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK Eliane Roulet, Paediatric Department, CHUV, Rue du Bugnon 46, 1011 Lausanne, Switzerland

xvi

List of contributors

Guido Rubboli, Department of Neurology, Bellaria Hospital, University of Bologna, Via Altura 3, 40139 Bologna, Italy Javier Salas-Puig, Department of Neurology, Hospital General de Asturias, Oviedo, Spain Ingrid I. E. Scheffer, Department of Neurology, Austin and Repatriation Medical Centre, University of Melbourne, Studley Road, Heidelberg, Victoria 3084, Australia José M. Serratosa, Departamento de Neurologia, Unidad de Epilepsia, Fundación Jiménez Diaz, Madrid, Spain Alan Shewmon, Department of Pediatric Neurology, UCLA Medical Center, Rm 22-474 MDCC, Box 951752, Los Angeles, CA 90095-1752, USA

Simon D. Shorvon, Department of Clinical Neurology, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK Sian D. Spacey, Neurogenetics Section, Department of Clinical Neurology, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK John Stephenson, Department of Neurology and Child Development, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK Carlo Alberto Tassinari, Department of Neurology, Bellaria Hospital, University of Bologna, Via Altura 3, 40139 Bologna, Italy Pierre Thomas, Department of Neurology, CHU, Nice, France Paolo Tinuper, Institute of Clinical Neurology, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy

xvii

List of contributors

Michela Tosetti, MR Department, Stella Maris Scientific Institute, Calambrone, Pisa, Italy Federico Vigevano, Section of Neurophysiology, Bambino Gesù Children’s Hospital, IRCCS Piazza Onofrio 4, 00165 Roma, Italy

Nicholas W. Wood, Neurogenetics Section, Department of Clinical Neurology, Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK Anna-Lise Ziegler, Paediatric Department, CHUV, Rue du Bugnon 46, 1011 Lausanne, Switzerland

Preface and overview

The boundary between epilepsy and movement disorders may sometimes be difficult to define. Clinical semiology, unbiased description of phenomena, is the first tool clinicians use in order to classify their patients. For many years the main task has been one of differential diagnosis. It was either epilepsy or a movement disorder. Yet, this is a biased approach as it implies that they cannot coexist. Not only can epilepsy masquerade as movement disorders, but movement disorders may be observed which are not easily differentiated from epileptic seizures; syndromes or diseases may associate both epilepsy and movement disorders occurring in the same patient or the same family. This is because a structural or genetic abnormality may determine both conditions. But if we need to break barriers which have been set for nosological purposes, we need to validate clinical semiology with clinical and experimental neurophysiology, functional neuroimaging, genetics and molecular biology. The purpose of this book is to present innovative information on the nosology and pathophysiology of motor epilepsy, myoclonus, paroxysmal dyskinesias and syndromes associating epilepsy and movement disorders in children and adults. Chapter 1 examines the development of the concept of channelopathies as a crucial mechanism in the genetically determined epilepsies. Starting with benign familial neonatal convulsions, evidence for this has also been shown in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), and in generalized epilepsy with febrile seizures plus (GEFS). Interestingly, several different channelopathies may result in a similar, if not an identical, clinical picture, often due to mutations of different subunits of the same ion channels, or of different ion channels. Recent evidence suggests that additional epileptic disorders such as severe myoclonic epilepsy of infancy (SMEI – Dravet syndrome) may also be due to a specific channelopathy. The autosomal dominant focal epilepsies show clinical and, whenever known, molecular evidence for genetic heterogeneity. Although these syndromes appear to be limited in numbers, they may not be all that rare, since some sporadic focal epilepsies may have the same genetic basis. Recognition of channel dysfunction has been an important step in our understanding of the nature of these disorders. xix

xx

Preface

This window on our understanding of the genetics of the epilepsies represents an enormous advance, but for the moment the inheritance of the idiopathic generalised epilepsies is still considered to be polygenic or complex, and current attention is focused on identification of polymorphisms or susceptibility genes. Chapter 2 An area in which there has been impressive recent progress is our understanding of the genetic mechanism of Angelman syndrome. The epileptic disorder and the electroencephalographic findings have been well delineated and this chapter now presents a knockout mouse model, which shares with the human condition many features of the epilepsy, the coordination and the electrographic abnormalities. This approach also shows the potential of using such knockout models for therapeutic purposes and represents a prototype of how molecular techniques can be used to clarify developmental abnormalities and retardation syndromes in the human. In Chapter 3 the reflex activation of epileptic seizures, one of the earliest epileptic phenomena described in man, is contrasted with the reflex activation of movement disorders. The authors rightly raise the question as to whether this division is an artefact of our classification systems depending on the level within the central nervous system which is activated by the stimulus. These reflex disorders continue to generate fascination, and their neurophysiological and genetic dissection should result in further improvements in the treatment of the human conditions. Chapter 4 presents a critical review of fMRI, one of the most promising approaches to the study of cortical organization, complementing all other techniques available so far. The discussion contains important questions on the interpretation of functional MRI findings, a technique which raises many questions. One of the major ones is that localization findings may be obtained by this technique in some individuals and not in others. In epilepsy, triggering of functional MR images by epileptic spike discharges promises to be effective in the localization of the epileptic generator. Chapter 5 presents physiological methods that are valuable in addition to clinical assessment in the differential diagnosis of patients with a motor disorder. The methods are based on studies of basic pathophysiology that promote understanding of the disorder and suggest therapeutic approaches in addition to developing diagnostic testing. Physiological tools are constantly under development, and, in recent years, the use of magnetism has been added to the standard use of electricity. Magnetoencephalography (MEG) can record the magnetic fields of the brain and is a helpful supplement to electroencephalography (EEG). Transcranial magnetic stimulation (TMS) allows stimulation of the brain non-invasively, something that is possible with electrical stimulation, but not widely used because it is so painful. Applications of these methods are described in the chapter. Chapter 6 includes an extensive up-to-date bibliography and review of recent neurophysiological analyses, which have conclusively shown that myoclonus may

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be either positive or negative. Negative myoclonus ranges in severity from the mild and hardly noticeable, to the severely incapacitating. It occurs in a wide range of epileptic conditions involving the frontal and central areas and appears to be due to an inhibitory mechanism. Whether antimyoclonic agents are equally effective in both negative and positive myoclonus is as yet not clearly established. Inhibitory epilepsy with ictal paresis or paralysis has been debated since the days of Hughlings Jackson; however, patients reported are few, diagnosis is difficult and, as the authors rightly stress, ictal EEG recording remains essential in order to establish the diagnosis. To complicate this further, spiking has also been described during a classical migraine aura rendering a distinction of migraine from inhibitory epilepsy even more difficult. The third part of this chapter discusses increased motor impairment due to frequent paroxysmal discharges involving the sensorimotor cortex. This disorder is closely related, if not identical, with continuous spike-and-wave discharge during sleep or with the Landau–Kleffner syndrome. Thus it may be the localisation, rather than the mechanism, which results in the cognitive, language or motor dysfunction which characterises this group of disorders. Chapter 7 Probably no other neurological disorder presenting with seizures and movement abnormalities has been as difficult to clarify as nocturnal frontal lobe epilepsy. The absence of electrographic epileptogenic abnormalities in many of the patients has been a major reason for this, and the fact that most of the patients have no generalized seizures has been an additional factor. The Bologna School which has expertise in both epilepsy and sleep disorders, was ideally placed to finally clarify this problem. Paroxysmal nocturnal dystonia no longer exists as a specific movement disorder and the patients previously so diagnosed are now shown to have nocturnal frontal lobe epilepsy. This revised concept has been difficult to accept by many, but is now generally recognized. Nocturnal frontal lobe epilepsy does, however, remain heterogeneous, both in its clinical manifestations, electrographic features and response to treatment. Localization within the frontal lobe remains a major problem and in patients with intractable attacks surgical treatment is difficult in the absence of a structural lesion. The spectrum of this type of epilepsy has been further enlarged by the recognition of autosomal dominant nocturnal frontal lobe epilepsy. This syndrome is also heterogeneous genetically as well as in severity and in response to antiepileptic medication. The genetic findings in this syndrome have been a milestone in our understanding of the autosomal dominant familial epilepsies, as well as the first example of epilepsy as a channelopathy. This chapter illustrates the range of the nocturnal frontal lobe epilepsies and provides a solid framework for the understanding and management of patients with such attacks.

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Chapter 8 Dystonia is a relatively common movement disorder with somewhat mysterious pathophysiology. A number of physiological studies have now begun to solve the mystery, although it is clear that much more needs to be done. Interestingly, motor cortex excitability is increased in dystonia as it is in epilepsy so the question arises as to what are the similarities (and what are the differences). The chapter details our current understanding of dystonia. Chapter 9 The paroxysmal dyskinesias are one of the hottest areas of neurological research these days. This comes about because of the rapid strides in the genetics of these disorders, and the recognition that many of them appear to be channelopathies, disorders of membrane channels. This chapter outlines the different disorders which are frequently confused with each other, and discusses what is known about their pathogenesis. Their paroxysmal nature makes the distinction between them and epilepsy often tricky, and, indeed, some of them may well have some epileptic features. Chapters 10 and 11 These address the normal physiology of startle and describe a variety of pathological conditions in which abnormal startle is an important feature. Considerable evidence has shown that the startle response is of lower brainstem origin. There is, in addition, a tonic inhibitory effect exercised by cortical structures and this probably explains the presence of startle abnormalities in patients with a frontal or central abnormality, usually of developmental nature. The localization of the cortical abnormalities has been well characterized by Chauvel and his group. Resection of the abnormal cortex has been shown to abolish startle epilepsy, which may be a particularly malignant seizure pattern and lead to frequent falls. This interaction between the brainstem representation of the startle reflex and the cortical abnormality interacting with it, is delineated in Chapter 10. Hyperekplexia or startle disease has been well described in recent decades and most of the patients have an obvious family history. The sporadic cases probably have the same disorder, either with an occult family history or represent new mutations. Hyperekplexia has been shown to be due to a mutation of the alpha or beta subunits of the GLRA1. There are, however, patients in whom a mutation has not been demonstrated. This requires further investigation. Whether the minor form of startle disease or hyperekplexia represents merely an increased awareness of abnormal startle in family members or whether an underlying genetic abnormality is present in this form as well has not been fully clarified. The neonatal form of startle disease is the most malignant and death brought on by the tonic attacks is not uncommon in small infants. Some of the manifestations of hyperekplexia, such as the prolonged clonus of the legs or the falling attacks, may be misinterpreted as functional in nature. Finally, Chapter 11 also briefly discusses the culturebound syndromes such as jumping, latah, imu and others. These are probably identical from a pathophysiological point of view but have a widely varied cultural overlay. They probably rep-

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resent an unusual form of tic disorder. They are however, surprisingly still considered by some to be entirely psychogenic, thus repeating the archaic view held for many years in an attempt to explain the more common tic disorders. Chapter 12 Myoclonus is one of the most critical topics for this book. What is a movement disorder and what is epilepsy is perhaps most confusing for myoclonus. One of the principal reasons for the confusion is that one of the major types of myoclonus is an epileptic fragment. When myoclonus is seen in the setting of a well-defined epileptic disorder, it is very likely to be an epileptic fragment. This chapter reviews the situations where myoclonus occurs, pointing out how to recognize an epileptic fragment. A high point of the chapter is a review of those disorders in pediatric epilepsy that include myoclonus Chapter 13 The review of electrophysiological evidence in patients with Epilepsia partialis continua (EPC) provides an excellent overview of the diverse reports in the literature. There is considerable variation in the etiology of EPC encountered in different settings, depending on the referral base and experience of the authors. In this chapter the multiplicity of causes is stressed, and these are contrasted with what in many centres is the most common cause, namely Rasmussen’s syndrome. The mechanisms of EPC and, in particular, the evidence for cortical as well as subcortical origin document the age-old discussion fuelled by the absence of scalp EEG abnormality in some of the patients. It has been recognized recently that movement disorders may coexist with epilepsy or even antedate it in patients with Rasmussen’s syndrome. The finding is not unexpected considering the pathology but was, until recently, ignored. Recognition of this clinical pattern has important diagnostic implications. Chapter 14 There has been great progress in the last decade in unravelling the molecular basis of the progressive myoclonus epilepsies. The challenge now is to explain how the molecular defects are responsible for the fairly stereotyped clinical pattern in this group of disorders, including particularly the myoclonus, the epileptic seizures and the cerebellar dysfunction. The concept that the same anatomical systems are involved in this group of disorders with widely divergent causes has been present for some time. These structures include the dentate, other parts of the cerebellum, olives and thalamus, but there is still remarkably little pathological evidence for this intuitively appealing view. In most of the rare causes of progressive myoclonus epilepsy, progress in molecular diagnosis is yet to come. There are still patients whose specific form of PME cannot be diagnosed, despite awareness of all the described entities, although such patients represent a minority. Recognition of the fact that myoclonus and epilepsy are not necessarily responding in parallel to available medication and recent emphasis on antimyoclonic treatment promises improved quality of life for the patients incapacitated by the myoclonus.

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Chapters 15 and 16 deal with rare epilepsy syndromes of great clinical and theoretical interest. The opercular syndrome (Chapter 15) can be permanent, resulting from congenital – cortical malformations – or acquired – hypoxic or infectious damage. The clinical features of the bilateral perisylvian syndrome are distinctive. A similar syndrome may occur without detectable brain lesions, apparently in relation with intense bilateral epileptic discharges – with or without seizures – in some forms of epilepsy including benign ones. The latter type may require corticosteroid treatment. The syndrome of congenital cerebellar/brainstem tumours (Chapter 16) is manifested, often from the neonatal period by facial attacks mimicking hemifacial spasms. Direct recording from the vicinity of the tumour has shown the attacks are associated with focal epileptic discharges, thus realizing a form of subcortical epilepsy. Chapters 17 and 21 are concerned with the special difficulties in separating seizures from movement disorders in newborn infants. Chapter 17 points out the frequency at this age of abnormal motor phenomena which are not true seizures and emphasizes the fact that differentiation can be extremely difficult, as even EEGs may not show paroxysmal discharges in clinically overt seizures. The chapter also discusses current classifications of abnormal movements in neonates with special emphasis on nonepileptic attacks for which treatment with antiepileptic agents is useless and may even be contraindicated. Chapter 21 reviews two types of abnormal movements in neonates and young infants: benign neonatal sleep myoclonus and benign infantile myoclonus. The former is often mistaken for epileptic seizures and some infants receive unjustified treatment sometimes for long periods despite the fairly straightforward features described in this chapter. The latter syndrome mainly raises a diagnostic problem with infantile spasms but also has suggestive clinical features and a normal EEG. Paroxysmal phenomena in children with encephalopathies also pose the problem of separating epilepsy from other motor phenomena, as highlighted by Chapters 18 and 19. Until recently, as the definition implies, infantile spasms associated with hypsarrhythmia were described as starting in the first year of life. It eventually became apparent that very similar spasms, occurring in salvos or in bursts could continue in children with encephalopathy or, indeed, develop later. This seizure pattern was described as periodic spasms. Periodic spasms appear to be a variant of infantile spasms observed in children with usually extensive brain lesions and are clearly of epileptic nature. Their EEG and clinical peculiarities are described. In this chapter the clustering of hypnagogic jerks or hypnagogic myoclonus in children with encephalopathy is also described. These jerks usually occurring singly, may also be

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clustered in other situations. Sleep starts are a non-epileptic phenomenon that may occur in normal individuals. Their repetition in the infantile period in infants with neurological problems raises diagnostic difficulties, but their clinical and EEG characteristics are distinctive. Even in older children, the distinction of epilepsy from other non-epileptic manifestations may be difficult. Chapter 19 shows that apparently simple stereotypies may represent an epileptic phenomenon. Their true nature can be uncovered by careful attention to clinical features and their occurrence in children with overt epileptic seizures and/or neurological or psychiatric problems. In one remarkable case, the focal epileptic origin of stereotypies could be demonstrated by intracranial monitoring combined with videorecording and confirmed by disappearance following focal resection. Chapter 20 discusses the diagnostic problems posed by abnormal eye movements. Tics and rarer disorders such as tonic upgaze or downgaze are sometimes mistaken for palpebral myoclonias or epileptic eye deviations, although their clinical presentation is quite distinctive. The syndrome of opsoclonus–myoclonus is a unusual cause of error. Its features and treatment are briefly reviewed. Chapters 22 and 25 underline that a diagnosis of epilepsy is often too easily made in patients with fixed neurologic abnormalities or dysfunctions, who also have other paroxysmal events. Imitators of epilepsy in children with cerebral palsy (Chapter 22) include such phenomena as vasovagal syncope, tonic seizures, exaggerated startles and dystonic movements due to basal ganglia damage. The presence of confirmed epileptic seizures is of prognostic significance, as it has been shown that epilepsy tends to be associated with more severe motor and cognitive difficulties. In children with Sturge–Weber syndrome (Chapter 25), all paroxysmal attacks need not be of epileptic nature. Attacks of paralysis not preceded by obvious seizures are not rare, even though they are not frequently mentioned. They often present with some migrainous features. The chapter gives a detailed description, reviews their possible mechanisms and emphasizes the probable importance of vascular/circulatory changes in the pial angioma, as recently shown by interictal and ictal SPECT studies. Chapter 23 The antibiotic era and the development of pediatrics have brought about changes which lulled the medical world into the belief that Sydenham Chorea was extinct. Despite reduction in the number of patients in many parts of the world, this is by no means the case and there has been ongoing research in the different aspects of this immune mediated disorder. The authors review the increasing literature on behavioural and psychiatric disorders, particularly obsessional behaviour, associated with Sydenham Chorea. There is a tantalizing analogy between obsessional disorder in chronic patients with this disorder and those with tics. Sydenham

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Chorea is not as benign as was originally thought, and after a long lag there is again a move towards improved treatment by immunomodulation. The differential diagnosis of chorea has gained renewed importance. Thus, 300 years after its original description, Sydenham Chorea is still with us and continues to present a challenge in management. Chapter 24 reviews the syndrome of alternating hemiplegia of childhood, which in many cases is misdiagnosed as epilepsy as the hemiplegias often follow tonic seizures and are regarded as Todd’s paralysis. The chapter emphasizes the crucial importance – and often the predominance at least in the early stages – of associated features that are often more suggestive of the diagnosis than the hemiplegias which are almost never isolated. The occurrence of true epileptic seizures in some cases may complicate the diagnostic problem. A particularly important aspect of the diagnostic problem of epilepsy vs. movement disorders is presented by children with both unequivocal movement disorders and epileptic seizures. Chapter 26 covers this issue extensively and reviews this recently investigated domain and the various, still imperfectly delineated syndromes of infantile convulsions followed by paroxysmal dyskinesias, sometimes associated with other movement disorders such as writer’s cramp and ataxia. The current genetic knowledge about these syndromes is also discussed. A special chapter (Chapter 28) deals with the genetics of disorders that feature both movement disorders and seizures. It includes discussion of the mitochondrial cytopathies and of the known or suspected ionic channel disorders (channelopathies) in humans and laboratory animals. Chapter 27 is more broadly concerned with the search for genes in various forms of epilepsy, mainly those that are transmitted in a Mendelian way. The chapter offers an exhaustive review of the topic, a list of the currently known genes or loci and a wealth of details about their possible mode of action when known. Controversial issues such as the location of the JME gene are extensively dealt with. The chapter ends with some general considerations on the distribution of epilepsy genes in the population and its possible explanations. Chapter 29 It has long been known that not all effects of antiepileptic drugs are necessarily beneficial and that both drug intoxication and an increase or modification of epileptic seizures may occur. The information, however, has been contained in many brief anecdotal reports and has been brought together here in a comprehensive manner in the first part of the chapter. Consideration of some relatively specific drug effects as a cause of seizure worsening or modification of seizure patterns constitutes the second portion. A discussion of the movement disorders precipitated by drugs constitutes the third section. The chapter continues with a discussion of movement disorders induced by drugs used for treating movement disorders, a paradoxical but well-known problem encompassing the tardive dyskinesias. Finally, seizures

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induced by drugs used for the treatment of movement disorders are discussed. This is a relatively neglected area and, in particular, there have been no attempts to discuss these issues comprehensively at national and international conferences. There are over 250 references in this review, which constitutes a complete and up-to-date summation of the information available. Another possible mechanism for the coexistence of epilepsy and neurological abnormalities, especially movement disorders, is suggested in Chapter 30 that reports lasting motor disturbances (ataxia, paresis, dystonia) in children with epilepsy, responsive to corticosteroids or ACTH treatment. The motor problems are thought to be a functional consequence of the epileptic activity itself rather than of lesions and milder forms of such disturbances might be relatively common. Chapter 31 In this era of intense pursuit of effectiveness of antiepileptics in nonepileptic disorders, it is important to present an overview of the different antiepileptic drugs that can also be used to treat movement disorders and of the rationale for this use. Both the effects of classical and ‘new’ antiepileptic drugs are presented, including those drugs which have a less well-defined use profile. The chapter highlights the fact that these drugs have multiple modes of action which are, as yet, not well understood. It is naïve to think that their role in movement disorders implies an epileptic etiology for some of these syndromes. The Editors Renzo Guerrini Jean Aicardi Frederick Andermann Mark Hallett

1

Epilepsies as channelopathies Giuliano Avanzini1 and Louis J. Ptàcek2 1

Department of Neurophysiology, Istituto Nazionale Neurologico C Besta, Milan, Italy Department of Neurology and Human Genetics, Howard Hughes Medical Institute, University of Utah, Salt Lake City, USA 2

Introduction In 1991, Ptàcek et al. identified the cause of hyperkalemic periodic paralysis as a mutation of the gene of the SCN4A Na channel. The following years saw the publication of a series of papers by the same and other researchers, which confirmed and completed the finding by demonstrating that other conditions belonging to the same group of muscular diseases (myotonic/periodic paralyses) could be attributed to mutations of the genes coding Na, Ca2 or Cl channel subunits (Ptàcek, 1998). Other ion channel gene mutations were subsequently identified as being involved in episodic ataxias (K and Ca2 channels), hemiplegic migraine (Ca2 channel), long-QT cardiac arrhythmias (K and Na channels), hyperekplexia (glycine receptor), and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (cholinergic receptor). All of these ‘channelopathies’ (Ptàcek, 1997), have the common characteristic of acute and transient presentation in subjects who otherwise seem to be perfectly normal, and this is also a common characteristic of idiopathic epilepsies due to alterations in neuronal excitability that cannot be attributed ‘to any underlying cause other than a possible hereditary predisposition’ (Commission, 1989). The aim of this chapter is to summarize some of the data suggesting that idiopathic epilepsies may be considered channelopathies. Epileptogenic alterations in neuronal excitability The excitability of neuronal cells depends on the movement of ions through specific cell membrane channels. The kinetics of transmembrane ion currents has been extensively investigated by means of various types of voltage clamp recordings, whereas the effect of ion currents on cell membrane potential can be detected Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Fig. 1.1

Schematic illustration of pump-induced transmembrane ion movements, ligand-activated channels (receptors) and voltage-dependent channels, drawn here on a cell membrane profile represented by a thick horizontal grey band indicating the lipid bilayer; the ions implicated in the activated currents are shown on the two sides of the membrane (Eextra and Iintracellular). On the right, the membrane is crossed by a microelectrode that can record the variations in membrane potential expressed in mVmillivolt (upper lines: current clamp) caused by the activation of the ion currents associated with the opening of the channels or active pump transport expressed in pApicoampere (lower lines: voltage clamp). (Modified from Avanzini et al., 1999.)

by means of current clamp recordings. Figure 1.1 schematically shows the profiles of the currents and their related variations in potentials generated by the activation of voltage-dependent or receptor-activated channels in comparison with baseline conditions maintained by means of ionic pump activity. The prevalence of depolarizing over hyperpolarizing effects leads to the phasic type of cell discharge (the dotted line in Fig. 1.2) that can be seen in some ‘intrinsically bursting’ (IB) cell subpopulations of the neocortex and area 3 of Ammon’s horn (CA3) of the hippocampus, which are particularly involved in the synchronization of cortical activity. Studies of various epilepsy models have shown that all of the neurons belonging to an epileptic neuronal aggregate consistently discharge in the form of particularly protracted ‘bursts’ that were christened by Matsumoto

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Fig. 1.2

Contribution of the transmembrane ion currents described in Fig.1.1 to the generation of simple (continuous line) or complex cell discharges (bursts or PDS: narrow dashed line). The horizontal lines below indicate the time of activation and inactivation of each current in relation to the temporal course of the discharge; the slow activation component of the Na and Ca2 currents is indicated by the dashed line: the hyperpolarization currents are depicted in black and the depolarizing currents in grey. A membrane resting potential of 70 mV is maintained by the continuous activity of the pump (dashed–dotted line). (From Avanzini et al., 1999.)

and Ajmone Marsan (1964), who were among the first to observe paroxysmal depolarization shifts (PDSS) in penicillin cortical foci. The presence of intense phasic discharges involving all of the neurons belonging to an epileptogenic area is therefore the significant cell event: every factor capable of transforming the discharging properties of cortical cells by inducing generalized and intense phasic activity should be considered potentially epileptogenic. GABAergic inhibitory transmission blockers (bicucullin, picrotoxin, penicillin), agonists or potentiators of the

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excitatory amino acids mediated transmission (kainate, ibothenate, NMDA, low Mg2), Na or Ca2 depolarizing current activators (veratridine or EGTA, BAPTA), and inhibitors of hyperpolarizing K currents (tetraethylammonium, intracellular Ca2, 4-aminopyridine) are all capable of inducing epilepsy and generalized phasic activity in cortical cells. It is therefore logical to expect that genetically determined modifications of the molecular structure of the channels that are capable of modifying their function in a similar way to the experimental manipulations described above may also be epileptogenic. The molecular structure of ion channels Ion channels are hetero-oligomeric membrane proteins typically consisting of two to six subunits that are specifically adapted to play the role of transmembrane ion flux regulators. The correspondence between the subunit composition and stoichiometry of ion channels is hampered by the difficulty of obtaining sufficient quantities of homogeneous material for biochemical purification because of the limited expression and considerable heterogeneity of the channels even in the same tissue. One important exception is the acetylcholine receptor (AchR), which can be obtained in very large quantities from the electric organ of the Torpedo marina and was the first receptor to be purified and characterized (Noda et al., 1983). AchR is the structural prototype of ligand-activated channels, and its pore region has a pentameric structure consisting of different subunits (Fig. 1.3). The subunits forming the voltage-dependent and nucleotide-cyclic-activated K channels (tetramers) and those making up the voltage-dependent heteropentamer Ca2 and heterodimer Na channels are also shown in Fig. 1.3. The disposition of the N and C terminals are represented in Fig. 1.3 from the extracellular side of the membrane in type 1 channels (receptors) and from the cytoplasmatic side of the membrane in type 2 channels (voltage-dependent). The N terminal region is particularly important in starting the process of subunit association that leads to the assembly of the channel. The assembly process is coadjuvated by the presence of accessory subunits and is significantly affected by a large number of different environmental influences. It leads to the formation of channels with different degrees of permeability to the various ions and different opening and closing kinetics, depending on the type of subunits assembled, their stoichiometric characteristics and the relative position of each subunit within the heterooligomeric complex. The identification of the molecular structure of the various subunits and their corresponding coding genes has revealed a surprising multiplicity of distinct sub-

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Epilepsies as channelopathies (a)

N

C ER lumen Membrane Cytoplasm

Neurotransmitter-gated ion channels (b)

N

C

Voltage-gated K+ channels Cyclic-nucleotide-gated channels

N

C

K+ channels Inward rectifier ATP-gated ion channels

N

C Voltage-gated Ca2+ channels Voltage-gated Na+ channels

Fig. 1.3

Schematic illustration of the structure of ligand-activated and voltage-dependent channels. For further explanations see text. (Modified from Green & Millar, 1995.)

units whose assembly can lead to a considerable number of channel subtypes with different properties (Green and Millar, 1995). One experimental artefice that has greatly contributed towards defining the structural and functional relationships of the channels is to express their constituent subunits in Xenopus oocytes by means of the injection of messenger RNA (mRNA) isolated from tissue or synthesized using cloned complementary DNA (cDNA). Xenopus oocytes are a number of millimetres in diameter and allow the precise measurement of ion currents by means of the voltage or patch clamp techniques developed by Neher and Sakmann (1976), which make it possible to analyse ion currents without breaking the cell membrane, even to the point of a single channel.

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Channelopathies and genetic epilepsies The power of the combined electrophysiological and biomolecular approach in identifying the pathogenetic relationships between gene mutations and alterations in neural excitability is demonstrated by a series of studies that led to the characterization of the shaker mutant of Drosophila melanogaster. This mutant was identified from a particular genotypical characteristic observed in some individuals which, when exposed to ether, manifested convulsive movements of the legs (Catsch, 1944; Kaplan & Trout, 1969). Electrophysiological recordings of the neuromuscular function of Drosophila shaker larvae (Jan & Jan, 1997) demonstrated an action potential repolarizing defect that appeared to be particularly prolonged because of a defect in the K IA current (Fig. 1.2). Once cloned and expressed in Xenopus oocytes, it was found that the shaker gene actually did code the constitutive protein of the type A K channel (Jan & Jan, 1992; and Ganetzky et al., 1995). Generalized non-convulsive epilepsies and Ca2+ channels

The possible implication of Ca2 channels, particularly those responsible for the IT low threshold Ca2 current, in the pathogenesis of generalized epilepsies with absence seizures was suggested in an experimental study carried out in the GAERS rat (genetic absence rat from Strasbourg), which was selectively cross-bred at the INSERM laboratory in Strasbourg. This breed spontaneously presents brief episodes of motor arrest with isolated facial myoclonies, associated with spike discharges of an average of 7–9 Hz, in a neurological and behavioural context of absolute normality. Apart from the greater internal frequency of spike-wave discharges, the GAERS rat generally represents a faithful model of human absence epilepsy and it has been possible to use it to demonstrate the pacemaker role of the rhythmic spike-wave discharges of the reticular nucleus of the thalamus (Rt). The Rt consists entirely of GABAergic cells that project to thalamic relay nuclei and receive collateral projections of both thalamo-cortical and cortico-thalamic fibres (Fig. 1.4). The Ca2 current is particularly developed in all of the thalamic nuclei (including the Rt), being inactive at resting potential and de-inactivated upon hyperpolarization (Jahnsen & Llinàs, 1984a, b; Mulle et al., 1986; Avanzini et al., 1989). At negative potentials of –60 MV or more, Rt neurons respond to every stimulus with a burst of action potentials sustained by the IT, followed by a profound hyperpolarization (due to the sequential activation of the Ca2-dependent K current) that returns the membrane potential to the voltage range in which IT is active. This generates a new burst once again followed by hyperpolarization, and so on (Avanzini et al., 1989). This alternation of bursts and hyperpolarization under-

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Fig. 1.4

Schematic illustration of the thalamo-cortical circuit responsible for the generation of spike-waves in GAERS rats. In light grey are shown the cortical cells and their firing patterns (second and third traces on the right) during spike-wave discharges (top trace on the right). TC (dark grey ): thalamo-cortical cell; Rt (black): cell of the reticular thalamic nucleus; ic: internal capsule. Rhythmic burst–hyperpolarizing sequences (bottom trace on the right) generated by Rt neurons induce in TC neurons rhythmic inhibitory postsynaptic potentials followed by a rebound burst (fourth trace on the right) that are reciprocally time related with Rt burst. (Modified from Avanzini et al., 1999.)

lies the rhythmogenic properties of Rt, which imposes its rhythm on the corticothalamic circuit responsible for spike-wave discharges. In GAERS rats, a lesion of the Rt abolishes the ipsilateral discharges (Avanzini et al., 1993). Furthermore, patch-clamp recordings of isolated GAERS Rt cells reveal a greater expression of IT, which probably represents the fundamental genetically determined defect in this animal model. Although the mutation responsible for GAERS epilepsy has not yet been characterized, there are some known mutations that can give rise to very similar electroclinical pictures. In the case of two of these (tottering, lethargic and stargazer), gene mutations have been found that, respectively, code for the 1A and 4, and 2 subunits of the calcium channel (Fletcher et al., 1996; Burgess et al.,

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1997; Letts et al., 1998). The functional effect of the consequent protein channel alteration on IT has not been characterized, but the search for genes codifying Ca2 channels in absence epilepsy appears to be a promising line of research. The recent result of Perez-Reyes et al. (1998), who have cloned the T-type channel, has opened up the way for the verification of the hypothesis in the short term. Nocturnal frontal epilepsy and the acetylcholine receptor

The idiopathic epilepsies include some benign infantile forms, the prototype of which is represented by benign partial epilepsy with centro-temporal spikes whose genetic cause is still unknown. Phillips et al. (1995) recently identified a large Australian family including 27 subjects affected by a form of exclusively nocturnal partial epilepsy with a linkage for locus 20q 13.2. Steinlein et al. (1995) subsequently discovered that a mutation of the 4 subunit of the nicotinic acetylcholine receptor may provide a molecular basis for this familial disease. Although the general value of this finding is still under investigation, it does suggest another possible epileptogenic mechanism associated with a genetic modification of acetylcholine receptors, whose role in this and other forms of human epilepsy merits further study. Benign familial neonatal convulsions and K+ channels

The definition benign familial neonatal convulsions (BFNC) refers to a form of hereditary idiopathic epilepsy in newborns with a dominant autosomal transmission. The seizures typically begin between the second and fourth day of life, and then gradually become less frequent until their spontaneous disappearance between the second and fifteenth week. The seizures are brief (lasting 1–3 minutes), primarily clonic with apneic episodes and perhaps an initial phase of tonic posture. The neurological picture is normal, as is the subsequent development of brain function. The EEG is normal or shows a picture of ‘theta pointu alternant’; 16% of the affected subjects experience a recurrence of seizures during the course of their lives. In 1989, Leppert et al. (1989) linkage mapped the gene responsible for BFNC on chromosome 20q, near to the markers D20S20 and D20S19, and this finding was subsequently confirmed by Malafosse et al. (1992) and Steinlein et al. (1992). However, Ryan et al. (1991) published a study concerning a family in which a linkage with the locus of chromosome 20 was excluded by the finding of another locus on chromosome 8q. Very recently, the group, which first mapped the gene on chromosome 20, published two separate papers (Singh et al., 1998; Charlier et al., 1998) describing the identification of mutations of genes KCNQ2 (chromosome 20) and KCNQ3 (chromosome 8) in different families. It is particularly interesting that both genes code for K channels belonging to the same KQT family as the

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already identified KCNQ1 gene (previously called KvLQTi), which is responsible for the cardiac arrhythmia due to ECG QT lengthening (Wang et al., 1996). When coexpressed with the ISK glycoprotein, KCNQ1 induces the appearance of a repolarizing K current with ‘delayed rectifier’ characteristics (Sanguinetti et al., 1996). The functional effect of the KCNQ2 mutation has recently been analysed in Xenopus oocytes by Bievert et al. (1998), the same group that had contributed to the localization study (Steinlein et al., 1992). KCNQ2 also appears to induce a delayed rectifier K current that was undetectable when the oocyte was injected with the mutant KCNQ2. The term ‘delayed rectifier’ was coined by Hodgkin et al. in 1949 to indicate the characteristics of the repolarizing K current (IK see Fig. 1.2) in the giant axon of the squid. It is intended to denote the fact that the increase in membrane conductance (rectification), due to the opening of the corresponding K channel, is delayed in comparison with that of the Na channel in relation to the beginning of the depolarizing pulse current used to evoke the action potential (Fig. 1.2). Contrary to what was originally thought, the pharmacological and kinetic characteristics of Ik seem to vary greatly from one cell type to another on the basis of different functional needs. Although a part of this variability can be attributed to factors modulating the function of the channel, e.g. phosphorylation, it has now been demonstrated that it expresses structural differences in the channels responsible for IK, which are also codified by different genes. Despite its substantial internal heterogeneity, the definition ‘delayed rectifier’ continues to be used for a type of K current. On the basis of its slow kinetics, the range of its activation characteristics and its pharmacological properties, this current can be easily distinguished from other types of K current, such as IA (rapid kinetics and a range of activation between 65 and 40 mV), IKCCA (Ca2 dependent), IAR (activation in hyperpolarization), IH (activation in hyperpolarization and every permeability to Na and K), IK(ATP) (voltage-independent, and blocked by ATP), IM (blocked by acetylcholine and muscarinic), and IK(NA) (activated by a high concentration of intracellular Na). The function of IK was initially correlated with action potential repolarization, but it actually collaborates with many other K currents in controlling membrane excitability. Of particular interest in the case of epileptogenesis is the limited duration of persistent depolarizing events (such as those sustaining PDS), which is due to the hyperpolarization of the membrane as a result of the K outflow. This effect is probably due to the combined influence of IK, IA, IK(ca) and IA(NA). Because it is active at about the resting potential, IK is particularly effective in distancing the threshold of the membrane potential for the generation of the high-frequency action potentials that characterize the neurons belonging to epileptic neuron aggregates. It is not yet known whether the KCNQ3 mutation determines a BFNC

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phenotype similar to that caused by the KCNQ2 mutation), nor as to why the two mutations are preferentially if not exclusively expressed in newborns and what possible genetic relationship there may be with another form of epilepsy that manifests itself with similar characteristics at around the sixth month of life (Vigevano et al., 1992) but would seem to be associated with another locus on chromosome 19q (Guipponi et al., 1997). Generalized epilepsy with febrile seizures and Na+ channels

It is known that Na channel gene mutations cause paroxysmal excitability changes in skeletal muscle and heart (see above). Wallace et al. (1998) have recently reported a mutation of voltage-gated Na channel 1 subunit gene (SCN1B) to be associated with a recently described familial epilepsy called generalized epilepsy with febrile seizures plus (GEFS) (Scheffer & Berkovic, 1997). GEFS patients present with febrile seizures that sometimes extend beyond the sixth year and may be associated with afebrile tonic–clonic, myoclonic, absence or atonic seizures, or myoclonic–astatic epilepsy. In a large Tasmanian family including 378 individuals from six generations, 26 subjects had GEFS syndrome, three had other forms of epilepsy, four had unclassified seizures and nine had unconfirmed seizures and were considered to be unaffected. Genetic study led to the identification of a mutation of the SCN1B gene which encodes the Na channel 1 subunit (Wallace et al., 1998). The functional consequences of the mutation were tested by coexpressing the human Na channel h1 with the rat  subunit RBII in Xenopus laevis oocytes. Whereas the coexpression of wild h1 with RBII hastens the time course of inactivation and accelerates recovery from inactivation, the coexpression of mutant h1 and RBII slightly increases the inactivation time course without having any effect on recovery. It can therefore, be expected that there will be an increase in the persistent fraction of the Na current (INAP). These results are particularly interesting in view of the recognized role of INAP in sustaining plateau potentials of neocortical pyramidal neurons (Stafstrom et al., 1985; Fleidervish & Gutnick, 1996), which have been shown to sustain the typical firing of intrinsically bursting neurons (Franceschetti et al., 1995; Mantegazza et al., 1998). Furthermore, pharmacological agents enhancing INAP in neocortical pyramidal neurons have been found to promote burst firing in otherwise nonbursting regular spiking cells (Mantegazza et al., 1998). On the other hand, it has been found that established antiepileptic drugs such as phenytoin (Chao & Alzheimer, 1995; Segal & Douglas, 1997), valproate (Taverna et al., 1998) and topiramate (Taverna et al., 1999) significantly reduce INAP in dissociated neocortical pyramidal neurons. All of these considerations make the SCN1B gene mutation reported by Wallace et al. (1998) very interesting for the pathogenesis of genetically determined epilepsies.

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Conclusions The currently avaiIable data support the hypothesis (Ptacek et al., 1991) that at least some genetic epilepsies can be considered channelopathies, and open up the way towards an approach based on the study of the genes implicated in neuronal excitability that are potentially responsible for idiopathic epilepsies. The advances in our knowledge of the mechanisms underlying epilepsy have made it possible to identify the role of membrane channels and receptors in the pathology of neuronal excitability. Alterations that lead to a prevalence of depolarizing (Na and Ca2) over hyperpolarizing (K and Ca2) currents, can facilitate the intense and generalized bursting discharges that characterize the neurons belonging to an epileptic neuronal aggregate. The experimental manipulations capable of modifying the inactivation kinetics of the Na current, the modulation of Ca2 currents and the characteristics of K currents are of particular interest. The combination of electrophysiological and biomolecular techniques has greatly improved our understanding of the genetic determinants of cell excitability. The application of such an integrated approach to some human epileptic pathologies has led to the establishment of the concept of channelopathy whose usefulness in the study of genetic epilepsies is suggested by the demonstration that some forms (in particular, benign neonatal convulsions) are dependent upon a genetically determined alteration in proteins/channels.

R E F E R E N C ES Avanzini, G., de Curtis, M., Panzica, F. & Spreafico, R. (1989). Intrinsic properties of nucleus reticularis thalami neurones of the rat studies in vitro. Journal of Physiology, 416, 111–22. Avanzini, G., Vergnes, M., Spreafico, R. & Marescaux, C. (1993). Calcium-dependent regulation of genetically determined spike and waves by the reticular thalamic nucleus of rats. Epilepsia, 34, 1–7. Avanzini, G., de Curtis, M., Panzica, F. (1999). Basi neurobiologiche dell’epilettogenesi. In L’Epilessia Oggi, 4th edn, ed. R. Canger, pp. 19–38. Milano: Masson. Avanzini, G., de Curtis, M., Pape, H.C. & Spreafico, R. (1999). Intrinsic properties of reticular thalamic neurons relevant to genetically determined spike-wave generation. In Jasper’s Basic Mechanisms of the Epilepsies, third edn. Advances in Neurology, Vol. 79, ed. A. DelgadoEscueta, W. A. Wilson, R. W. Olsen & R.J. Porter, pp. 297–309. Philadelphia: Lippincott Williams & Wilson. Bievert, C., Schroeder, B.C., Kubisch, C. et al. (1998). A potassium channel mutation in neonatal human epilepsy. Science, 279, 403–6. Burgess, D.L., Jones, J.M., Meisler, M.H. & Noebels, J.L. (1997). Mutation of the Ca2 channel  subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (Ih) mouse. Cell, 88, 385–92.

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G. Avanzini and L.J. Ptàcek Catsch, A. (1944). Eine erbliche Störung des Bewegungsmechanismus bei Drosophila melanogaster. Zeitschrift für induktive Abstammung und Vererbungslehre, 82, 64–6. Chao, T.I. & Alzheimer, C. (1995). Effect of phenytoin on the persistent Na current of mammalian CNS neurones. Neuroreport, 6, 1778–80. Charlier, C., Singh, N.A., Ryan, S.G. et al. (1998). A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nature Genetics, 18, 53–5. Commission on Classification and Terminology of the International League against Epilepsy (1989). Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia, 30, 389–99. Fleidervish, J.A. & Gutnick, M.J. (1996). Kinetics of slow inactivation of persistent sodium current in layer V. neurons of mouse neocortical slices. Journal of Neurophysiology, 76, 2125–30. Fletcher, C.F., Lutz, C.M., O’Sullivan, T.N. et al. (1996). Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell, 87, 607–17. Franceschetti, S., Guatteo, E., Panzica, F., Sancini, G., Wanke, E. & Avanzini, G. (1995). Ionic mechanisms underlying burst firing in pyramidal neurons: intracellular study in rat sensorimotor cortex. Brain Research, 69, 6127–39. Ganetzky, B., Warmke, J.W., Robertson, G. & Pallank, L. (1995). New potassium channel gene families in flies and mammals: from mutants to molecules. In Ion Channels and Genetic Diseases, ed. D.C. Dawson & R.A. Frizzell, pp.29–39. New York: Rockefeller University Press. Green, W. & Millar, N. (1995). Ion channel assembly. Trends in Neuroscience, 18, 280–7. Guipponi, M., Rivier, F., Vigevano, F. et al. (1997). Linkage mapping of benign familial infantile convulsions (BFIC) to chromosome 19q. Human Molecular Genetics, 6, 473–7. Hodgkin, A.L., Huxley, A.F. & Katz, B. (1949). Ionic current underlying activity in the giant axon of the squid. Arch. Science Physiology, 3, 129–50. Jahnsen, H. & Llinàs, R. (1984a). Electrophysiological properties of guinea-pig thalamic neurones. An in vitro study. Journal of Physiology, 349, 205–26. Jahnsen, H. & Llinàs, R. (1984b). Ionic basis for the electroresponsiveness and oscillatory properties of guinea-pig thalamic neurones in vitro. Journal of Physiology, 349, 227–47. Jan, L.Y. & Jan, Y.N. (1992). Structural elements involved in specific K channel functions. Annual Review of Physiology, 54, 537–55. Jan, L.Y. & Jan, Y.N. (1997). Cloned potassium channels from eukaryotes and prokaryotes. Annual Review of Neuroscience, 20, 91–123. Kaplan, W.D. & Trout, W.E. (1969). The behavior of four neurological mutants of Drosophila. Genetics, 61, 399–409. Leppert, M., Anderson, V.F., Quattlebaum, T. et al. (1989). Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature, 337, 647–8. Letts, V.A., Felix, R., Biddlecome, G.H. et al. (1998). The mouse stargazer gene encodes a neuronal Ca2-channel r subunit. Nature Genetics, 19; 340–7. Malafosse, A., Leboyer, M., Dulac, O. et al. (1992). Confirmation of linkage of benign familial neonatal convulsions to D20S19 and D20S20. Human Genetics, 89, 54–8. Mantegazza, M., Franceschetti, S. and Avanzini, G. (1998). Anemone toxin (ATXII) induced increase in persistent sodium current: effects on the firing properties of rat neocortical pyramidal neurones. Journal of Physiology, 507, 105–16.

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Epilepsies as channelopathies Matsumoto, H. & Ajmone Marsan, C. (1964). Cortical cellular phenomena in experimental epilepsy. Interictal manifestations. Experimental Neurology, 9, 286–304. Mulle, C., Madariaga, A. & Deschenes, M. (1986). Morphology and electrophysiological properties of nRt neurons in the cat: in vivo study of thalamic pacemaker. Journal of Neuroscience, 6, 2134–45. Neher, E. & Sakmann, B. (1976). Single-channel current recorded from the membrane of denervated frog muscle fibres. Nature, 260, 779–802. Noda, M., Takahaschi, H., Tanabe, T. et al. (1983). Structural homology of torpedo californica acetylcholine receptor subunits. Nature, 302, 528–32. Perez-Reyes, E., Cribbs, L.L., Daud, A. et al. (1998). Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature, 391, 896–900. Phillips, H.A., Scheffer, I.E., Berkovic, S.F. et al. (1995). Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2. Nature Genetics, 10, 117–18. Ptàcek, L.J. (1997). Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. Neuromuscular Disorders, 7, 250–5. Ptàcek, L.J. (1998). The familial periodic paralyses and nondystrophic myotonias. American Journal of Medicine, 105, 58–70. Ptàcek, L.J., George, A.L., Griggs, R.C. et al. (1991). Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell, 67, 1021–7. Ryan, S.G., Wiznitzer, M., Hollman, C., Torres, M.C., Szekeresova, M. & Schneider, S. (1991). Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity. Annals of Neurology, 29, 469–73. Sanguinetti M.C., Currant, M.E., Zou, A. et al. (1996). Coassembly of KVLQT1 and mink (IsK) proteins to form cardiac IKS potassium channel. Nature, 384, 80–3. Scheffer, E. & Berkovic, S.F. (1997). Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogeneous clinical phenotypes. Brain, 120, 479–90. Segal, M.M. & Douglas, A.F. (1997). Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin. Journal of Neurophysiology, 77, 3021–34. Singh, N.A., Charlier, C., Stauffer, D. et al. (1998). A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nature Genetics, 18, 25–9. Stafstrom, C.E., Schwindt, P.C., Chubb, M.C. & Crill, W.E. (1985). Properties of persistent sodium conductance and conductance of layer 5 neurones from cat sensorimotor cortex in vitro. Journal of Neurophysiology, 53, 153–70. Steinlein, O., Fischer, C., Keil, R., Smigrodzki, R. & Vogel, R. (1992). D20519 linked to lowvoltage EEG, benign neonatal convulsions and Fanconi anaemia, maps to a region of enhanced recombination and is localized between CpG islands. Human Molecular Genetics, 1, 325–9. Steinlein, O., Schuster, V., Fischer, C. & Haussler, M. (1995). Benign familial neonatal convulsions: confirmation of genetic heterogeneity and further evidence for a second locus on chromosome 8q. Human Genetics, 95, 25–9. Taverna, S., Mantegazza, M., Franceschetti, S. & Avanzini, G. (1998). Valproate selectively reduces the persistent fraction of Na current in neocortical neurons. Epilepsy Research, 32, 304–8. Taverna, S., Sancini, G., Mantegazza, M., Franceschetti, S. & Avanzini, G. (1999). Inhibition of

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G. Avanzini and L.J. Ptàcek transient and persistent Na current fractions by the new anticonvulsant topiramate. Journal of Pharmacological Experimental Therapy, 288, 960–8. Vigevano, F., Fusco, L., Di Capua, M., Ricci, S., Sebastianelli, R. & Lucchini, P. (1992). Benign infantile familial convulsions. European Journal of Pediatrics, 151, 608–12. Wallace, R.H., Wang, D.W., Singh, R. et al. (1998). Febrile seizures and generalized epilepsy in the Na-channel 1 subunit gene SCN1B. Nature Genetics, 19, 366–70. Wang, Q., Curran, M.E., Splawski, I. et al. (1996). Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genetics, 12, 17–23.

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Epilepsy and movement disorders in the GABAA receptor 3 subunit knockout mouse: model of Angelman syndrome Richard W. Olsen1 and Timothy M. DeLorey2 1 2

Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, USA Molecular Research Institute, Mountain View, CA, USA

GABAA receptor structure and function: multiple subunit genes, and implications for epilepsy and movement disorders?

-Aminobutyric acid type A (GABAA) receptors (GABAR) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system (Olsen & DeLorey, 1999). The GABAR belong to the superfamily of ligand-gated ion channel receptors, i.e. they are ion channel proteins whose opening is controlled by the binding of the neurotransmitter (DeLorey & Olsen, 1992). These GABAR are a family of heteropentamers formed from a family of at least 19 related subunits in mammals, named (1–6), (1–4), (1–3), , , , and (1–3) (Tyndale et al., 1995; Davies et al., 1997; Hedblom & Kirkness, 1997). Splicing variants exist for some subunits, primarily related to phosphorylation substrates in the intracellular loop, e.g. the 2 subunit longer version (2L) contains an 8 amino acid insert in the cytoplasmic loop that contains a consensus substrate site for phosphorylation by protein kinase C that is missing in 2S (Burt & Kamatchi, 1991; McKernan & Whiting, 1996). Important CNS drug targets are present on GABAR, notably sites for the benzodiazepines, barbiturates, neurosteroids, other general anesthetics, and picrotoxin-like convulsants (Macdonald & Olsen, 1994). The individual subunits show variable regional and temporal expression. A dozen or more heteropentameric isoforms of the GABAR occur naturally with reasonable abundance; these exhibit various pharmacological properties and presumably biological properties as well (Lüddens et al., 1995; McKernan & Whiting, 1996; Barnard et al., 1998). Some subunit combinations are relatively abundant in adult brain, e.g. 122 (IUPHAR nomenclature A1a2, Barnard et al., 1998) while others are more important in Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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neurodevelopment, or limited in expression to a few cell types (Laurie et al., 1992; Kim et al., 1996). The subunit genes are clustered on different chromosomes, indicating gene duplication as well as cluster duplication, e.g. 1/2/2/6 and on human chromosome 5, 5/3/3 on chromosome 15, 2/1/1/4 on chromosome 4, 3/ /4 (also known as or ) on the X chromosome, 1 and 2 on chromosome 6, and  on chromosome 1 (Tyndale et al., 1995; Olsen & Homanics, 2000). While there is some coordinate regulation of expression, for the most part, expression of these genes are all separately regulated. These GABAR subtypes vary in sensitivity to GABA and drug modulators (Macdonald & Olsen, 1994), subcellular targeting, i.e. synaptic vs. nonsynaptic; cell body vs. dendrite vs. nerve terminal localization (Nusser et al., 1998); and in other aspects of cell biology and regulation of function both short and long term, possibly involving protein phosphorylation mechanisms (Moss et al., 1996). Clustering of receptors at subsynaptic membranes on cell bodies or dendrites appears to involve specific interaction of certain subunits such as 2 with cytoskeleton linking proteins, like gephyrin (Essrich et al., 1998) or GABARAP (Wang et al., 1999) or  with microtubule-associated protein 1B (Hanley et al., 1999). Thus, the function of GABA depends very much on which GABAR are present in a given location or circuit, and the age examined. Various behaviors and pathophysiological conditions thus depend on specific GABAR isoforms of defined subunit composition. In turn, the function of GABAR depends on the specific subunit composition. The  subunits determine the benzodiazepine pharmacology, the  subunits affect the GABA sensitivity and phosphorylation, and the // / subunits determine the sensitivity to benzodiazepines and other drugs, as well as subcellular location. Besides its role as the major inhibitory neurotransmitter, GABA has a developmental role, stimulating proliferation, migration, and other differentiation events, including synaptogenesis and survival (Belhage et al., 1998); some of these effects appear to result from the excitatory/depolarizing effects of GABAR chloride channels, especially early in development (Ben-Ari et al., 1997). Additionally, impaired GABA function is suspected to be a major cause of epileptogenesis (Olsen & Avoli, 1997), with GABAR the major candidate mechanism (Olsen et al., 1999). Deficiency of GABA, produced by gene targeting of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) produces cleft palate (Asada et al., 1997) and epilepsy (Kash et al., 1997), as well as decreased developmental plasticity adaptation capability (Hensch et al., 1998). With respect to early expression, among the GABAR subunits, the 2, 3, 5, 3, and 2 are the primary embryonically expressed subunits. The 2 appears later around birth, and the 1 and  are postnatal subunits. The genes for the GABAR subunits 5/3/3 are clustered on chromosome 15 and are suggested to be important early in life and show a more limited expression in adult (Laurie et al., 1992;

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Persohn et al., 1992; Poulter et al., 1992; Frostholm et al., 1992). In particular, the 3 and 5 GABAR subunits are implicated in phenotypic characteristics of the pcp deletion mutation in mouse chromosome 7, characterized by cleft palate and early neonatal lethality, and neurological signs in the survivors, including ataxia and tremors (Nakatsu et al., 1993). The cleft palate was shown to be due to the deficiency of the 3 subunit gene (Culiat et al., 1995). Due to this and the possible relationship to the human genetic disorders Angelman syndrome (AS) and Prader–Willi syndrome resulting from a defect in the syntenic region of chromosome 15q, it was of interest to make a gene-targeted mouse for the promising potential AS candidate gene gabrb3. Mouse knockouts of the GABAR 3 subunit gene gabrb3 are described in this chapter. Knockouts also have been produced for other GABAR subunits. Disruption of the 2 subunit gene (gabrg2) resulted in early neonatal lethality for the homozygotes, and altered benzodiazepine pharmacology for the heterozygotes (Günther et al., 1995). The 2-deficient mice showed a loss of synaptically localized GABAR subunits as well as the anchoring protein gephyrin in neonatal brain, suggesting a crucial role for the 2 subunit and a possible contribution to early death (Essrich et al., 1998). While it could not be determined whether 2 knockout mice would develop epilepsy, intracerebroventricular injection of 2 subunit antisense oligonucleotides into normal rats resulted in a knockdown of 2 subunit expression in hippocampus and a phenotype of status epilepticus (Karle et al., 1998). Angelman syndrome: the possible role of GABAR beta 3 Angelman syndrome (AS) is a genetic neurodevelopmental disorder resulting from a deletion/mutation in maternal chromosome 15q11–13. AS is characterized by severe mental retardation, lack of speech, epilepsy, hyperactivity, motor incoordination, sleep disturbances, and craniofacial dysmorphism, once referred to as ‘happy puppet syndrome’ (Williams et al., 1995). While physical development progresses relatively normally, mental and motor development do not, arresting at about 1½–2-year-old level. The incidence for this disorder is as high as 1:10000 births, hence the epilepsies of AS represent about 1% of all epilepsies (Petersen et al., 1995). Seizures are observed in over 90% of AS individuals. AS patients exhibit atypical absence, myoclonic, atonic, tonic and tonic–clonic seizures (Boyd et al., 1988; Guerrini et al., 1996; Minassian et al., 1998). Characteristic EEG features of Angelman syndrome individuals include diffuse bifrontally dominant highamplitude 1 to 3 Hz notched or triphasic or polyphasic slow waves, or slow and sharp waves, made worse on eye closure and sleep (Minassian et al., 1998). Although seizures improve with age, they are still present in adulthood, especially during sleep (Sandanam et al., 1997; Guerrini et al., 1996; Minassian et al., 1998).

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AS is caused by a genetic defect in maternal chromosome 15q11–13. The failure of mutations in paternal chromosome 15 to produce AS suggests that the paternal genes are silenced and thus mutations in the maternal genes, the only ones expressed, lead to the phenotype, in this case, a disease. Such parent-of-originspecific epigenetic phenomena are termed ‘imprinting’. Imprinting is relatively rare and the mechanism is not known. There may be some relationship to DNA methylation and/or chromatin structure. Also, there may be some clues to imprinting in the better understood process of X-inactivation, in which one allele of the two Xchromosomes in females is silent. Recent studies indicate that imprinting may be time and place specific rather than universal, i.e. the imprinted gene is silenced only in certain cells and at certain ages (Nicholls et al., 1998; Lalande et al., 1999). The majority of AS cases are caused by a large deletion (4 Mb) in maternal 15q involving multiple genes. These include the UBE3A gene, which encodes a ubiquitin ligase involved in intracellular protein degradation/processing, and a cluster of GABAA receptor subunit genes, GABRB3, GABRA5 and GABRG3, which encode the proteins for the GABAA receptor subunits 3, 5 and 3, respectively (Greger et al., 1995). The AS phenotype can also be caused by uniparental paternal disomy for the 15q11–q13 region, or by mutations in this region that alter the paternal/maternal-specific expression, with paternal silencing on both alleles (imprinting mutations). A minority (20–25%) of Angelman syndrome cases lack this large deletion. Several, but by no means all, of these have been reported to possess a mutation in the UBE3A gene (Kishino et al., 1997; Matsuura et al., 1997). How this gene might produce the phenotype of Angelman syndrome is unclear and still to be elucidated. Consistent with its role in AS, the UBE3A gene appears to be imprinted, i.e. shows reduced expression from the paternal allele, in specific areas of mouse and human brain (Cattanach et al., 1997; Rougelle et al., 1997; Vu & Hoffman, 1997; Albrecht et al., 1997). However, patients with mutations of this gene, leading to a loss of function, have a milder phenotype than deletion cases, with fewer abnormalities in the electroencephalogram (EEG) and few if any seizures (Minassian et al., 1998). Thus, while it appears that a mutation in the UBE3A gene can cause a mild form of AS, it is likely that one or more genes in the typically deleted AS region contribute to the severe epilepsy and full array of clinical manifestations observed in deletion cases. A knockout mouse for UBE3A has been produced, and the heterozygotes have some symptoms similar to AS, such as defective learning, ataxia, and seizure susceptibility, which are more severe with the gene disrupted in the maternal as opposed to the paternal allele, consistent with imprinting (Jiang et al., 1998). The cluster of three GABAR genes located within the deleted AS chromosomal region are excellent candidates for a role in the AS phenotype on functional grounds, and evidence suggests that at least GABRB3 is involved in AS (Minassian et al., 1998; DeLorey et al., 1998, 1999). The 3 and 5 subunits are abundantly

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expressed in the developing mammalian brain with a slightly more restricted pattern of expression in adult brain, especially the 5 subunit (Laurie et al., 1992). Additional evidence linking GABA to AS includes the few reports of the neuropathology and neurochemistry of Angelman syndrome. Most noteworthy neuropathological findings in a single case include cerebellar atrophy with loss of some Purkinje and granule cells, and extensive Bergmann gliosis (Jay et al., 1991). A mild reduction of dendritic arbourization and dendritic spines of pyramidal neurons in the visual cortex was also observed. The same group also reports a marked reduction in GABA content in the cerebellar cortex and elevated glutamate content in frontal and occipital cortices. The reduced GABA content may be due to the loss of Purkinje cells and inhibitory GABAergic interneurons. A reduction in inhibitory cerebellar influences could result in cortical myoclonus (Marsden, 1982). In a separate study, a reduction of 22–28% in binding of the benzodiazepine [123I]iomazenil in the frontal and temporal cortex of a 27-year-old female AS patient was found using single photon emission computed tomography (SPECT: Odano et al., 1996). The GABAA receptor 3 subunit knockout mouse Recently, we generated a mutant mouse line with a targeted disruption of the GABAA receptor 3 subunit gene (gabrb3) (Homanics et al., 1997). Homologous recombination in embryonic stem cells was employed to disrupt the gabrb3 gene, which was subsequently passed through the germ line to generate mice without a functional gabrb3 gene. Although the mortality of these mice is high at birth, survivors were available for evaluation. These knockout mice were found to share several behavioral and physiological abnormalities with Angelman syndrome, namely, cognitive defects, sleep disturbance, movement disorders, and epilepsy (DeLorey et al., 1998, 1999). Movement disorders in GABAR 3 knockouts (summarized in Table 2.1) Mice with the gabrb3 gene disrupted, thus GABAR 3 subunit -/-, are hyperactive, often moving in a circle at the perimeter of the cage, or in a tighter circle in the centre of the area. However, they have ataxia by at least three standard assays: these mice cannot walk on a wire grid without their feet falling through the gaps. They fall off platforms, stationary rods, and their feet slip off a balance beam when attempting to navigate it. They cannot learn to stay on a rotating rod as well as control mice, despite many learning episodes. These mice do not know how to swim nor learn quickly. The animals also curl up into a ball when lifted by the tail, considered a sign of neurological impairment. Beta 3 knockout mice do not show essential tremor, but they do show some twitching of whiskers and head. This may

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Table 2.1. Movement disorders in GABAR 3 knockouts

Curling up in a ball when lifted by the tail Ataxia (by at least three of six standard measures) Fall off platform, stationary rod, balance beam Poor performance on rotarod compared to controls despite many learning episodes Difficulty in walking on a grid (feet fall through) Cannot swim Myoclonic jerks: head, shoulders Sensorimotor impairment/hypersensitivity Tight circling activity (as if chasing its own tail; ‘Whirling dervish’)

be part of an arrested behaviour that resembles an absence attack (see below). Most striking are myoclonic jerks of head and shoulders which become more frequent and violent with age from 3 to 9 months of age, often followed by convulsive seizures; the arrested behaviour and myoclonic jerks are accompanied by EEG abnormalities (see below). The animals also show a hyper-reflexia and hypersensitive response to many sensory stimuli, while ignoring other inputs, although they are not impaired in electrically elicited pain sensation nor locomotor capacity (Homanics et al., 1997; DeLorey et al., 1998). They show reduced behavioural sensitivity to anesthetic agents, with reduced sleep time following the drugs etomidate or midazolam, and reduced effects of volatile anesthetics on reduction of painful tail clamp immobilization (Quinlan et al., 1998). Comparing these mice to clinical AS, AS patients have widely spaced and clumsy gait, with ‘puppet-like’ posturing of extremities, and some aspects of ataxia. For example, when asked to locomote up, or, especially, down, a 4 cm step, the AS patient stumbles; or, a similar result occurs when distracted by being mildly struck by a thrown object such as a ball or stick (B. Neville, personal communication). They have difficulty in swimming and riding a bicycle. AS patients have cortical myoclonus as a major feature, among other seizure disorders (Guerrini et al., 1996). Epilepsy in 3 knockouts (summarized in Table 2.2) Neurons from these mice exhibit a functional deficit of GABAA receptors (Homanics et al., 1997; DeLorey et al., 1997; Krasowski et al., 1998; Huntsman et al., 1999). GABAA receptor density was remarkably reduced in these knockout mice as expected from the high incidence of 3-containing neurons in normal brain (Homanics et al., 1997).

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Table 2.2. Summary of epilepsy in GABAR 3 subunit knockout mouse

Arrested behaviour in middle of hyperactivity; abnormal EEG Interictal high amplitude slow waves, wave/spikes Large spikes in EEG, at first with no convulsions, evolving into: i(i) precursor to clonic seizure (ii) myoclonic jerk simultaneous with spike Increasing occurrence of myoclonic jerks with age, from 3–9 months. Increasing frequency of abnormal EEG patterns including wave/spike and spike/wave (2–4 Hz) with age Convulsive seizures with face, shoulders and forelimb involvement, sometimes proceeding to arched back (episthotonus) and tail, sometimes to tonic clonic seizures, falling down, hind limb extension and clonus Pharmacology: carbamazepine, fosphenytoin, baclofen, tiagabine make worse; ethosuximide makes better; valproate, clonazepam no effect Electrophysiology (in vitro cellular and slice): reduced synaptic inhibition in neonatal dorsal root ganglia; cultured embryonic hippocampal neurons; adult hippocampal slices; adult thalamus

Behavioural observations, coupled with EEG recordings in gabrb3 deficient mice, indicate that mice lacking the GABAA receptor 3 subunit are subject to an evolving epileptogenic condition that culminates in spontaneous seizures (DeLorey et al., 1998). Similarly, Matsumoto et al. (1992) described an age-dependent evolution of seizure types in AS. Several features of the epilepsy of the homozygotes are shared with Angelman syndrome. Both AS deletion patients and gabrb3 genedeficient mice exhibit marked abnormal EEG background, with slowing and interictal spikes. Multiple seizure types have been described in deletion AS patients and in gabrb3-deficient mice. Mice lacking the GABAR 3 subunit had clonic, myoclonic, and infrequent running/bouncing seizures. Frequent background EEG abnormalities were often associated with arrested behaviour, with activity occurring before and after. Such behaviour resembles an absence seizure, although the EEG did not show the high frequency spike/wave normally associated with absence seizures. Spike and wave EEG were observed, however, during periods of clonic seizures. The running/bouncing seizures were usually preceded by generalized clonic seizures. Seizures varied in severity, the milder seizure consists of twitching of muscles of face, whiskers, and ears. More severe seizures included head and bilateral forelimb jerks, arching of the tail, and falls. The gabrb3-deficient mice exhibit behavioural episodes of clonic seizure burst that are accompanied by high amplitude symmetric spike-wave discharges. The nature of the seizures in the mouse

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change with age, especially the development of frequent myoclonic jerks. Like the knockout mice, Angelman syndrome patients exhibit generalized high amplitude slow waves and spikes, myoclonic, multiple seizure types, especially atypical absence, and changes in seizures with age (Matsumoto et al., 1992; Boyd et al., 1988; Laan et al., 1996; Minassian et al., 1998). Of the antiepileptic drugs (AEDs) tested on the gabrb3-deficient mice, ethosuximide, a drug commonly prescribed to control absence, was effective at normalizing the EEG background and reducing ictal spike occurrence. Ethosuximide was more efficacious in the gabrb3 deficient mice than valproate and clonazepam, the most commonly prescribed AEDs for AS in North America (DeLorey et al., 1998). Laan et al. (1996) suggest the effectiveness of ethosuximide in treating seizures associated with AS. Our clinical experience with valproate (n10) indicates that it is not completely effective in controlling seizures or normalizing abnormal electrocortical activity in AS patients (Minassian et al., 1998). Carbamazepine was found to worsen the overall EEG and seizures in gabrb3 gene-deficient mice. Similarly, carbamazepine has been reported to have adverse effects on seizures in AS patients (Viani et al., 1995; Laan et al., 1996; Minassian et al., 1998). Baclofen, a GABAB receptor agonist, and THIP, a GABAA receptor agonist, also exacerbate the EEG abnormalities in these mice (DeLorey et al., 1998; Handforth et al., 2000). These findings suggest an involvement of an absence-like pathophysiology, in view of observations by Snead (1995) that GABAA and GABAB receptor agonists make absence-like seizures worse. The heterozygous mice also display seizures although less frequently than the homozygous mice, as well as intermediate defects in the other phenotypic characteristics (Homanics et al., 1997; DeLorey et al., 1998). Note that these 3 knockout mice have a severe phenotype with impaired learning and memory in every test employed (DeLorey et al., 1998), as well as hypersensitivity to sensory input and certain painful stimuli (Ugarte et al., 1998), hyposensitivity to anesthetic drugs (Quinlan et al., 1998), and a severe disturbance in their rest/activity cycle (DeLorey et al., 1998). Conclusions The complex pathological phenotype of the GABAR 3 subunit knockout mouse shows that the lack of a GABAR subunit can produce epilepsy and movement disorders. Lack of this particular subunit appears to contribute to Angelman syndrome, a type of human disorder that includes epilepsy and motor incoordination, plus mental retardation, hyperactivity, and sleep disturbance. Reduced inhibitory neurotransmission might be expected to give such a phenotype (Olsen et al., 1999; Kim & Olsen, 2000). Details of the effect will depend on which aspect of GABA

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function is altered. This is particularly so with GABAR, where each isoform, and indeed each subunit, has a unique regional and temporal expression (Olsen & Homanics, 2000). Detailed analysis of the phenotype of the gabrb3 knockout mouse is aimed at understanding the anatomical and physiological correlates of the epilepsy and movement disorders. The GABAR 3 subunit is widely expressed in the adult nervous system, although not as abundant as the 2 subunit (Persohn et al., 1992; Poulter et al., 1992; Frostholm et al., 1992). It is abundant in the hippocampal formation, sensory nerve ganglia, and spinal cord, moderately expressed in cortex and amygdala, and shows low levels in cerebellum, striatum, and hypothalamus. It is absent in thalamic relay nuclei, but present in the reticular nucleus of thalamus. In the gabrb3 knockout mouse, the absence of 3 subunit in these areas and the known functions of these regions is consistent with the described phenotype. Probably more important is the impairment of neurodevelopmental functions of GABAR (described above), since the 3 subunit is more abundantly expressed prenatally in most regions and the only  subunit present in some areas during embryogenesis (Laurie et al., 1992; Kim et al., 1996). Further study on the regional expression in the normal prenatal and neonatal brain is needed to understand the functional role of 3 in development. Then, more analysis of impaired physiology in the 3 knockout animals will provide insight into epileptogenesis, motor incoordination, mental retardation, and sleep disturbances. A similar approach with other candidate genes for human epilepsy and movement disorders, including other GABAR subunits, bodes well for rapid progress in understanding these major clinical problems. Acknowledgements We thank Drs A.V. Delgado-Escueta, A. Handforth, G. Homanics and B. Minassian for help with the material described here. Supported by NIH grants HD06576 to T.D. and NS 28772 to R.W.O.

R E F E R E N C ES

Albrecht, U., Sutcliffe, J.S., Cattanach, B.M. et al. (1997). Imprinted expression of the murine Angelman syndrome gene, UBE3A, in hippocampal and Purkinje neurons. Nature Genetics, 17, 75–8. Asada, H., Kawamura, Y., Maruyama, K. et al. (1997). Cleft palate and decreased brain GABA in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proceedings of the National Academy of Sciences, USA, 94, 6496–9.

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R.W. Olsen and T.M. DeLorey Barnard, E.A., Skolnick, P., Olsen et al. (1998). Sub-types of -aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. International Union of Pharmacology XV. Pharmacological Reviews, 50, 291–313. Belhage, B., Hansen, G.H., Elster, L. & Schousboe, A. (1998). Effects of -aminobutyric acid (GABA) on synaptogenesis and synaptic function. Perspectives in Developmental Neurobiology, 5, 235–46. Ben-Ari, Y., Khazipov, R., Leinekugel, X., Caillard, O. & Gaiarsa, J.L. (1997). GABAA, NMDA and AMPA receptors: a developmentally regulated ‘menage a trois’. Trends in the Neurosciences, 20, 523–9. Boyd, S.G., Harden, A. & Patton, M.A. (1988). The EEG in early diagnosis of the Angelman (Happy Puppet) syndrome. European Journal of Pediatrics, 147, 508–13. Burt, D.R. & Kamatchi, G.L. (1991). GABAA receptor subtypes: from pharmacology to molecular biology. FASEB Journal, 5, 2916–23. Cattanach, B.M., Barr, J.A., Beechey, C.V., Martin, J., Noebels, J. & Jones, J. (1997). A candidate model for Angelman syndrome in the mouse. Mammalian Genome, 8, 472–8. Culiat, C.T., Stubbs, L.J., Woychik, R.P., Russell, L.B., Johnson, D.K. & Rinchik, E.M. (1995). Deficiency of the 3 subunit of the GABAA receptor causes cleft palate in mice. Nature Genetics, 11, 344–6. Davies, P.A., Hanna, M.C., Hales, T.G. & Kirkness, E.F. (1997). Insensitivity to anaesthetic agents conferred by a class of GABAA receptor subunit. Nature, 385, 820–3. DeLorey, T.M. & Olsen, R.W. (1992). -Aminobutyric acidA receptor structure and function. Journal of Biological Chemistry, 267, 16747–50. DeLorey, T.M., Handforth, A., Kim, H. et al. (1997). Behavioral, molecular, and electrophysiogical changes in mice lacking the GABAA receptor 3 subunit gene. Abstracts of the Society for Neuroscience, 23, 812,#318.1. DeLorey, T.M., Handforth, A., Homanics, G.E. et al. (1998). Mice lacking the 3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. Journal of Neuroscience, 18, 8505–14. DeLorey, T.M., Handforth, A., Homanics, G.E., Minassian, B.A., Delgado-Escueta, A.V. & Olsen, R.W. (1999). The epilepsy of the GABAA receptor 3 subunit knockout mouse: comparison to the epilepsy of Angelman syndrome. In Genetics of Focal Epilepsies: Clinical Aspects and Molecular Biology, ed. S. Berkovic, P. Genton, C. Marescaux & F. Picard, pp. 267–74. London: John Libbey & Co. Essrich, C., Fritschy, J.M., Lorez, M., Benson, J. & Lüscher, B. (1998). Postsynaptic clustering of major GABAA receptor subtypes requires the 2 subunit and gephyrin. Nature Neuroscience, 1, 563–71. Frostholm, A., Zdilar, D., Luntz-Leybman, V., Janapati, V. & Rotter, A. (1992). Ontogeny of GABAA/benzodiazepine receptor subunit mRNAs in the murine inferior olive: transient appearance of 3 subunit mRNA and [3H]muscimol binding sites. Molecular Brain Research, 16, 246–54. Greger, V., Knoll, J.H.M., Woolf, E. et al. (1995). The -aminobutyric acid receptor 3 subunit gene (GABRG3) is tightly linked to the 5 subunit gene (GABRA5) on human chromosome 15q11–q13 and is transcribed in the same orientation. Genomics, 26, 258–64.

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Epilepsy and movement disorders Guerrini, R., DeLorey, T.M., Bonanni, P. et al. (1996). Cortical myoclonus of Angelman syndrome. Annals of Neurology, 40, 39–48. Günther, U., Benson, J., Benke, D. et al. (1995). Benzodiazepine-insensitive mice generated by targeted disruption of the 2 subunit gene of GABAA receptors. Proceedings of the National Academy of Sciences,USA, 92, 7749–53. Handforth, C.A., Asatourian, A., Sharma, G. et al. (2000). Ethosuximide improves the EEG in model of Angelman syndrome. Epilepsia, 41 (Suppl. 7), 6, #1.013. Hanley, J.G., Koulen, P., Bedford, F., Gordon-Weeks, P.R. & Moss, S.J. (1999). The protein MAP1B links GABAC receptors to the cytoskeleton at retinal synapses. Nature, 397, 66–9. Hedblom, E. & Kirkness, E.F. (1997). A novel class of GABAA receptor subunit in tissues of the reproductive system. Journal of Biological Chemistry, 272, 15346–50. Hensch, T.K., Fagiolini, M., Mataga, N., Stryker, M.P., Baekkeskov, S. & Kash, S.F. (1998). Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science, 282, 1504–8. Homanics, G.E., DeLorey, T.M., Firestone, L.L. et al. (1997). Mice devoid of -aminobutyrate type A receptor 3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proceedings of the National Academy of Sciences, USA, 94, 4143–8. Huntsman, M.M., Porcello, D.M., Homanics, G.E., DeLorey, T.M. & Huguenard, J.R. (1999). Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science, 283, 541–3. Jay, V., Becker, L.E., Chan, F.W. & Perry, T.L. (1991). Puppet-like syndrome of Angelman: a pathologic and neurochemical study. Neurology, 41, 416–22. Jiang, Y., Armstrong, D., Albrecht, U. et al. (1998). Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron, 21, 799–811. Karle, J., Woldbye, D.P.D., Elster, L. et al. (1998). Antisense oligonucleotide to GABAA receptor 2 subunit induces limbicstatus epilepticus. Journal of Neuroscience Research, 54, 863–9. Kash, S.F., Johnson, R.S., Tecott, L.H. et al. (1997). Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proceedings of the National Academy of Sciences, USA, 94, 14060–5. Kim, H. & Olsen, R.W. (2000). GABA-A receptors and disease. In Handbook of Experimental Pharmacology, vol. 150, Pharmacology of Inhibitory Amino Acid Neurotransmitters, ed. H. Möhler, Chap. 9, pp. 251–70. Heidelberg: Springer Verlag. Kim, H.Y., Olsen, R.W. & Tobin, A.J. (1996). GABA and GABAA receptors: development and regulation. In Receptor Dynamics in Neural Development, ed. C.A. Shaw, pp. 59–72. Boca Raton, FL:CRC Press. Kishino, T., Lalande, M. & Wagstaff, J. (1997). UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genetics, 15, 70–3. Krasowski, M.D., Rick, C.E., Harrison, N.L., Firestone, L.L. & Homanics, G.E. (1998). A deficit of functional GABAA receptors in neurons of 3 subunit knockout mice. Neuroscience Letters, 240, 81–4. Laan, L.A.E.M., Boer, A.T., Hennekam, R.C.M., Renier, W.O. & Brouwer, O.F. (1996). Angelman syndrome in adulthood. American Journal of Medical Genetics, 66, 356–60.

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R.W. Olsen and T.M. DeLorey Lalande, M., Minassian, B.A., DeLorey, T.M. & Olsen, R.W. (1999). Parental imprinting and Angelman syndrome. In Jasper’s Basic Mechanisms of the Epilepsies, Vol III, ed. A.V. DelgadoEscueta, W. Wilson, R.W. Olsen & R.J. Porter, pp. 421–9, New York: Lippincott-Williams & Wilkins. Laurie, E.J., Wisden, W. & Seeburg, P.H. (1992). The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. Journal of Neuroscience, 12, 4151–72. Lüddens, H., Korpi, E.R. & Seeburg, P.H. (1995). GABAA/benzodiazepine receptor heterogeneity: neurophysiological implications. Neuropharmacology, 34, 245–54. Macdonald, R.L. & Olsen, R.W. (1994). GABAA receptor channels. Annual Review of Neuroscience, 17, 569–602. McKernan, R.M. & Whiting, P.J. (1996). Which GABAA-receptor subtypes really occur in the brain? Trends in Neuroscience, 19, 139–43. Marsden, C.D. (1982). Studies on the normal and disordered human motor cortex. Electroencephalography and Clinical Neurophysiology, Supp 36, 430–4. Matsumoto, A., Kumagai, T., Miura, K., Miyazaki, S., Hayakawa, C. & Yamanaka, T. (1992). Epilepsy in Angelman syndrome associated with chromosome-15q deletion. Epilepsia, 33, 1083–90. Matsuura, T., Sutcliffe, J.S., Fang, P. et al. (1997). De novo truncation mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genetics, 15, 74–7. Minassian, B.A., DeLorey, T.M., Olsen, R.W. et al. (1998). Angelman syndrome: correlations between epilepsy phenotypes and genotypes. Annals of Neurology, 43, 485–93. Moss, S.J., McDonald, B., Gorrie, G.H., Krishek, B.K. & Smart, T.G. (1996). Regulation of GABAA receptors by multiple protein kinases. In GABA: Receptors, Transporters and Metabolism, ed. C. Tanaka & N.G. Bowery, pp. 173–84. Basel: Birkhauser Verlag. Nakatsu, Y., Tyndale, R.F., DeLorey, T.M. et al. (1993). A cluster of three GABAA receptor subunit genes is deleted in a neurological mutant of the mouse p locus. Nature, 364, 448–50. Nicholls, R.D., Saitoh, S. & Horsthemke, B. (1998). Imprinting in Prader–Willi and Angelman syndromes. Trends in Genetics, 14, 194–200. Nusser, Z., Sieghart, W. & Somogyi, P. (1998). Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. Journal of Neuroscience, 18, 1693–703. Odano, I., Anezaki, T., Ohkubo, M. et al. (1996). Decrease in benzodiazepine receptor binding in a patient with Angelman syndrome detected by iodine-123 iomazenil and single-photon emission tomography. European Journal of Nuclear Medicine, 23, 598–604. Olsen, R.W. & Avoli, M. (1997). GABA and epileptogenesis. Epilepsia, 38, 399–407. Olsen, R.W. & DeLorey, T.M. (1999). GABA and glycine. In Basic Neurochemistry, 6th edn, G.J. Siegel, B.W. Aganoff, R.W. Albers, S.K. Fisher & M.D. Uhler, pp. 335–46. New York:LippincottRaven. Olsen, R.W. & Homanics, G.E. (2000). Function of GABAA receptors: insights from mutant and knockout mice. In GABA in the Nervous System: The View at Fifty Years, ed. D.L. Martin & R.W. Olsen, pp. 81–96. Philadelphia: Lippincott, Williams & Wilkins.

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Epilepsy and movement disorders Olsen, R.W., DeLorey, T.M., Gordey, M. and Kang, M.H. (1999). Regulation of GABA receptor function and epilepsy. In Jasper’s Basic Mechanisms of the Epilepsies, vol III, ed. A.V. DelgadoEscueta, W. Wilson, R.W. Olsen & R.J. Porter, pp. 499–510. New York:Lippincott-Williams & Wilkins. Persohn, E., Malherbe, P. & Richards, J.G. (1992). Comparative molecular neuroanatomy of cloned GABAA receptors in the rat CNS. Journal of Comparative Neurology, 326, 193–216. Petersen, M.B., Brondum-Neilsen, K., Hansen, L.K. & Wulff, K. (1995). Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county. American Journal of Medical Genetics, 60, 261–2. Poulter, M.O., Barker, J.L., O’Carroll, A.M., Lolait, S.J. & Mahan, L.C. (1992). Differential and transient expression of GABAA receptor -subunit mRNAs in the developing rat CNS. Journal of Neuroscience, 12, 2888–900. Quinlan, J.J., Homanics, G.E. & Firestone, L.L. (1998). Anesthesia sensitivity in mice that lack the 3 subunit of the GABAA receptor. Anesthesiology, 88, 775–80. Rougelle, C., Glatt, H. & Lalande, M. (1997). The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nature Genetics, 17, 14–15. Sandanam, T., Beange, H., Robson, L., Woolnough, H., Buchholz, T. & Smith, A. (1997). Manifestations in institutionalised adults with Angelman syndrome due to deletion. American Journal of Medical Genetics, 70, 415–20. Snead, O.C. (1995). Basic mechanisms of generalized absence seizures. Annals of Neurology, 37, 146–57. Tyndale, R., Olsen, R.W. & Tobin, A.J. (1995). GABAA receptors, In Handbook of Receptors and Channels: Ligand and Voltage-Gated Ion Channels, ed. R.A. North, pp. 261–86. Boca Raton FL: CRC Press. Ugarte, S.D., Homanics, G.E., Quinlan, J.J., Firestone, L.L. & Hammond, D. (1998). Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the 3 subunit of the GABAA receptor. Abstracts of the Society for Neuroscience, 24, 641, #251.10. Viani, F., Romeo, A., Viri, M. et al. (1995). Seizure and EEG patterns in Angelman’s syndrome. Journal of Child Neurology, 10, 467–71. Vu, T.H. & Hoffman, A.R. (1997). Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nature Genetics, 17, 12–13. Wang, H., Bedford, F.K., Brandon, N.J., Moss, S.J. & Olsen, R.W. (1999). GABAA receptorassociated-protein links GABAA receptors and the cytoskeleton. Nature, 397, 69–72. Williams, C.A., Angelman, H., Clayton-Smith, J. et al. (1995). Angelman syndrome: Consensus for diagnostic criteria. American Journal of Medical Genetics, 56, 237–8.

3

Genetic reflex epilepsy from chicken to man: relations between genetic reflex epilepsy and movement disorders Robert Naquet1 and Cesira Batini2 1 2

Institut Alfred Fessard, Gif-sur-Yvette, France National Centre of Scientific Research, Université Pierre et Maria Curie, Paris, France

Introduction In 1909, Baglioni and Magnini observed that local strychninization of the motor cortex produced myoclonus in the dog. Later, Amantea (1921) demonstrated that such myoclonus was not only intensified by cutaneous stimulation of the area corresponding to the strychninized cortex, but also induced secondary generalized convulsions: he had discovered experimental reflex epilepsy. This work was extended by Clementi (1929), who described visual, acoustic, olfactory and gustative reflex epilepsy in the dog by locally increasing the excitability of individual sensory cortices while stimulating the corresponding sensory receptors (see Moruzzi, 1950). It was also extended by Terzian and Terzuolo (1951), who showed that reflex epilepsy is accompanied by an EEG afterdischarge. Although mentioned for the first time in the human by Gowers (1885) and called for a certain period of time ‘Brown–Sequard’s epilepsy’ (see Pagniez et al., 1933), it was not until the 1920s that acquired reflex epilepsy in humans was fully described to be the result of a local pathological increased excitability of the cortex (see Penfield & Jasper, 1954). In these focal epilepsies of animals and humans, the seizure is obtained by the coincidence of an hyperexcitable sensory cortex and the arrival to this cortex of an adequate input from the homologous sensory modality. In addition, in animals and humans having ‘no detectable’ lesion, transitory increased neuronal excitability leading to reflex epilepsy can be acquired subsequent to a metabolic or toxic disorder or under the influence of subliminal doses of known convulsant drugs. In some susceptible individuals of a particular species there is no need for cortical strychninization or injection of convulsant drugs to obtain reflex seizures. Such a case was probably first mentioned as being provoked in humans by an intermittent Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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light stimulation (ILS) by Apuleius ( 125), but it was only in 1939, that Morgan and Morgan observed that high frequency sound precipitated convulsions in albino rats. Thus, ‘genetic reflex epilepsy’ (GRE) was discovered. The present chapter will be devoted only to this form of epilepsy which manifests myoclonus or seizures and requires both a particular sensory stimulus called ‘epileptogenic’ and a predisposed subject. We classify the GRE motor seizures in two groups: (i) stimulus-locked (not outlasting the stimulus) myoclonus defined as a bilateral jerk and wild running called running fit (RF); (ii) seizures defined as self-sustained motor attacks (tonic, clonic or tonic–clonic). Seizures are preceded by a stimulus-locked symptom. The more common epileptogenic sensory modalities are the visual and acoustic, and the GRE is, respectively, designated as photogenic and audiogenic. Rodent GRE seizures are induced only by complex sound stimuli (CSS); chicken seizures are also induced by CSS but at higher intensities. Chicken, baboon and humans are particularly sensitive to ILS, but the effective frequency to induce seizures is around 15 Hz in humans and chicken and around 25 Hz in baboon. In humans, not only frequency, but also particular patterns and colours of light may be epileptogenic in predisposed subjects (Wilkins et al., 1975). This may be why seizures are frequently induced in children by television and videogames (Gastaut et al., 1960; KasteleijnNolst Trenité, 1994; Badinand-Hubert et al., 1998). While ILS induces myoclonia having the same frequency as the light flashes, sound induces RF in both rodents and chickens. In baboon and humans, myoclonus is also evoked by movements induced by sudden noise or contact: the afferent somatosensory component (SSS) of the movement is the effective stimulus (see Loiseau & Duché, 1989). Much less is known about predisposition. We know that it is genetically determined (chicken and rodents) or familialy transmitted (baboon and humans) and that it may be modulated by different factors like sex, age, maturation. Nevertheless, no specific gene has been described so far (however, see hyperekplexia). Whether the predisposition is a general neuronal defect or whether a particular network carrying the predisposition is sufficient to produce myoclonus and/or seizures, is not known. This is the general problem addressed to the studies of GRE. Animal models Several animal species are affected by GRE: chicken, mouse, rat, gerbil, rabbit, dog, baboon (See Löscher & Schmidt, 1988; Jobe et al., 1994; Naquet & Valin, 1998). We will briefly describe here only chickens, rodents and baboons, the three most studied animal models. Fayoumi chicken

In 1970, Crawford discovered epileptic chickens in a strain called Fayoumi to which he gave the name of Fepi (for Fayoumi epileptic). While the name and the

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mutation remained, the original strain was lost and a synthetic population of epileptic chickens was produced, carrying an autosomal recessive mutation responsible for the epilepsy. The Canadian school described the presence of continuous interictal EEG paroxysmal discharges (PDs), the ‘clinical’ symptomatology of the ILS-induced seizures, and their control by anticonvulsant drugs (see Crichlow & Crawford, 1974; Johnson & Davis, 1983). Recently, it was also demonstrated that the seizures can be induced in Fepi by CSS (see Fadhlallah et al., 1995). The two types of symptoms are distinguished: stimulus-locked consisting of neck myoclonus at the light frequency during ILS, and of RF during CSS; and selfsustained generalized convulsions, which are identical whatever the stimulus. Concerning the EEG, it was observed (Teillet et al., 1991) that PD were blocked (B) during motor seizures and replaced by low voltage, fast activity often followed by flattening and therefore called ‘desynchronization’ (D) or ‘desynchronization and flattening’. These EEG changes could be evoked even in paralysed animals. In these conditions, microelectrode studies revealed the primary involvement of brainstem structures on ILS-induced avian GRE (Guy et al., 1993). Finally, under metrazol, the Fepi had lower threshold for induction of EEG seizures than heterozygous and normal chicks (Guy et al., 1992). The animals were also recorded in ovo (Guy et al., 1995), and it was found that different symptoms appear at different stages of development. Thus, PDs start at embryonic day17 (E17), just when a few synapses become functional in normal chicken (Curtis et al., 1989); B and D start at E20, during explosive synaptogenesis in normal chicken (Corner et al., 1977); but motor seizures only appear after hatching. This avian model allows in ovo construction of brain chimeras by exchanging all or part of the neural epithelium between two embryos (Le Douarin, 1969). With this method (see Batini et al., 1996), the reflex epilepsy was transferred from a predisposed Fepi donor to a normal animal, thus demonstrating that the grafted tissues retain their intrinsic epileptogenic character. By constructing brain chimeras having partial grafts of the Fepi neural epithelium, it was possible to demonstrate (Fig. 3.1) that (i) the entire phenotype was transferred by exchanging the prosencephalic and mesencephalic embryonic vesicles; (ii) the resting PDs and their suppression under stimulation were transferred from an epileptic prosencephalon (Fig. 3.2(a)1); (iii) ILS-induced myoclonus and CSS-induced RF and convulsions were transferred with grafts of an epileptic mesencephalon only (Fig. 3.2(a)2); (iv) the prosencephalon by itself does not induce any stimulus-induced motor symptomatology, but facilitates the generation of convulsions. From these experiments we learn that individual epileptic symptoms of the Fepi phenotype are generated by individual predisposed structures or networks. The interictal PDs (indicating epileptic predisposition), which are not always present in other reflex epilepsies, are very prominent in the Fepi. Presumably each predisposed

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Type chimera

Stimulus RestEEG

IctalEEG

Seizures

(a)

(b)

Normal

Normal

Normal

Normal

(c)

GS GS GS

Fig. 3.1

Summary of the results obtained in the different types of Fepi chimeras. In the left column of the figure, schematic drawings of two day incubation normal chicken embryo (white) partly grafted with Fepi embryo (black). (a) Graft of a Fepi prosencephalon. (b) Graft of a Fepi mesencephalon. (c) Graft of a Fepi prosencephalon and mesencephalon. BDblockage of cPD and EEG desynchronization; cPDcontinuous paroxysmal discharge; CSScomplex sound stimulation; GSgeneralized seizures; ILSintermittent light stimulation; Mymyoclonia; RFrunning fit.

structure carries the same dysfunction but can generate a specific symptom when solicitated by an adequate stimulation. However, in both Fepi and the chimeras only the stimulus-locked symptoms can be generated separately, not the self-sustained convulsions which always follow myoclonus or RF. In other words, convulsions appear to be the result of a generalization from the stimulus-locked symptoms. Rodents

Typical generalized seizures induced by CSS are also described in predisposd mice, rats and rabbits (see Collins, 1972). However, most of the studies were performed in mice and rats and the several genetically predisposed strains differ principally for the severity of the seizure. Thus in DBA/2 mice, but not in rats, seizures can be fatal (Niaussat & Laget, 1963). The Sprague–Dawley or Wistar-derived rat strains were classified according to a severity scale for the audiogenic seizure expression (Garcia-Cairasco et al., 1993). In spite of these quantitative differences, all the strains and species have common CSS-induced motor symptomatology, consisting of RF followed by self-sustained generalized convulsions. The EEG does not show any PD, neither at rest, nor during seizures. The genetic mechanism for transmission has been described as autosomal

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(a)

(a)

(b)

Fig. 3.2

Roles of the prosencephalon and the mesencephalon in ILS-induced myoclonus of Fepi chimeras and Papio papio. (a1) Fepi pros-chimera characterized by continuous EEG PD at rest; ILS induces BD but no motor manifestation (EMGneck electromyogram). (Adapted from Fadlallah et al., 1995). (a2) Fepi mes-chimera characterized by normal EEG at rest; the ILS-induced neck myoclonia at the flash frequency does not outlast the stimulation. (b) ILS-induced myoclonus in a photosensitive Papio papio; the onset of the cortical PD (marked by dashed lines in the lower trace) precede the EMG discharges (upper trace.) (Adapted from Menini et al., 1994.)

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dominant in GEPR-9 but as autosomal recessive for DBA/2J mice, and in both cases it is suggested to be polygenic (Seyfried et al., 1980; Ribak et al., 1988). This model resembles the avian audiogenic GRE, the only difference being the resting EEG which is normal in rodents but paroxysmal in Fepi; and it is entirely homologous to the auditory GRE of the mesencephalic chimeras. The homology with the Fepi and the mesencephalic chimera also extends to the brainstem origin. In fact, in the GEPR, audiogenic seizures persist after decortication (Chocholova, 1962), but are suppressed by brainstem lesions, including lesions localized to the inferior colliculus (see Browning et al., 1985); in DBA/2 mice, audiogenic seizures induce c-fos expression in the brainstem auditory nuclei, namely in the inferior colliculus (Le Gal La Salle & Naquet, 1990). In the inferior colliculus of the GEPR there is also decreased GABA mediated inhibition (see Faingold et al., 1994), decreased sensitivity to benzodiazepines and a dysfunction of the NMDA receptors (Faingold & Naritoku, 1992). These localized neurotransmitter dysfunctions could be interpreted as initiating seizures. Additional generalized deficits in neuromodulators were also described (see Millan, 1988); they may participate in the seizure predisposition of the rodent GRE. Finally, GEPR seizures are controlled by antiepileptic drugs that also control generalized seizures in humans (Faingold & Naritoku, 1992; Chapman & Meldrum, 1987) so that rodent audiogenic GRE is considered a good model for testing drugs to be used for treatment of epilepsies in humans. This model appears to be homologous to the Fepi audiogenic GRE for the ictal symptoms and for the brainstem origin, the only difference being the interictal EEG, normal in rodents but paroxysmal in chickens. Papio papio

Killam et al. (1966, 1967) described a photomyoclonic syndrome in the baboon Papio Papio. Since 60% of the animals captured in Casamance, but only 10% captured in other areas of Senegal were affected, it was concluded that the photosensitivity is familialy transmitted (Balzamo et al., 1975; Naquet & Valin, 1998). At rest and during slow wave sleep, the EEG shows PDs in the fronto-rolandic areas (FR) (Fisher-Williams et al., 1968). The baboon shows two types of paroxysmal manifestations (PMs), one induced by ILS and the other by SSS. Although different, ILS and SSS-induced PMs may coexist in the same subject (Menini et al., 1994). Photogenic epilepsy

Under ILS, the first symptom is a PD at the light frequency in the FR which increase progressively in amplitude. In less susceptible animals this may be the only sign. In other animals or in the same animal, with prolonged ILS the FR spikes continue to

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increase in amplitude and finally induce eyelid myoclonia. There is then a progression of the myoclonia to the face, the neck, the limbs and to the entire body. At this point, the generalized myoclonia does not follow the ILS frequency but the FR spikes, which are now regularly interrupted by paroxysmal slow waves and progress to other cortical territories (Fig. 3.2(b)). All these manifestations cease with ILS. Only in a few very susceptible animals, two types of self-sustained seizures may follow: slow rhythmic myoclonia of the upper limbs accompanied by a bilateral rhythmic synchronous afterdischarge in the FR or by characteristic clinical and EEG Grand Mal seizure. Different experiments were performed using evoked potentials and extracellular recordings, local injections of GABA in different cortical regions, section of corpus callosum (see Naquet & Wada, 1992), retinal lesions, or focal visual stimulation (Fukuda et al., 1989). They demonstrate that the FR generates the photogenic epilepsy of the baboon. However, it was impossible to induce myoclonus of the eyelids by electrical stimulation of this territory, and ILS-induced myoclonus and PDs were suppressed by visual cortex ablation but not modified by cerebellar lesions (Brailowsky et al., 1978). This photogenic epilepsy may be modulated by many neurotransmitters (see Naquet & Meldrum, 1986), and is controlled by benzodiazepines, compounds facilitating GABAergic transmission and excitatory amino acid antagonists (Chapman & Meldrum, 1983). Finally, there is a deficit of GABA metabolites in the cerebrospinal fluid of the photosensitive baboon (Lloyd et al., 1986). Myoclonia induced by SSS

A different type of myoclonia induced by contact or by startle consists of a jerk of the neck, shoulder and trunk muscles, propagating to the proximal part of the limbs, but not (or rarely) progressing to the face and eyelids and never preceded or accompanied by PDs. They are followed by a normal evoked potential around the vertex. They never induce self-sustained PDs nor Grand Mal seizures. This type of myoclonia is facilitated by cerebellar ablations (Fig. 3.3(a)) (Brailowsky et al., 1978) and by administration of benzodiazepines (Valin et al., 1981). On the contrary, it is suppressed by physostigmine (Rektor et al., 1986). Human syndromes We will briefly describe below a number of syndromes found in humans,1 some of which are already classified among the GRE. Still others are genetic reflex 1

We will omit, however, the ILS-induced ‘Petit Mal absence’ (Hirsch et al., 1994) and some other syndromes less characteristically found in humans.

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(a)

(b)

Fig. 3.3

Self-sustained seizures induced by somatosensory stimulation. (a) Oscilloscopic records of movement-induced tonic reaction in a Papio papio after cerebellar vermis ablation. EEGfront–central record; ACCmechanogram obtained by an accelerometer fixed in the animal head; EMGtrapezius muscle record. Amplitude calibration50 mV, time bars50 ms. (Adapted from Brailowsky et al., 1978). (b): EEG, EKG and respiratory rhythm (PNO) during a “generalized” attack in a 26-day-old child with hyperekplexia. Arrow at the top right correspond to the tapping of the nose inducing a violent startle response followed by a massive tonic vibratory seizure accompanied by high amplitude muscular artefacts. (Adapted from Dalla Bernardina et al., 1989.) Note that in both (a) and (b) the EEG remains normal.

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movement disorders for which the epileptic nature is contested. They have, however, a partial homology with uncontested GRE animal models. Photogenic paroxysmal manifestations

Discovered in humans by Walter et al. (1948), different types of ILS-induced clinical and EEG symptoms were simultaneously described by Gastaut (1951) and Bickford et al. (1952). Eyelid myoclonia

This consists of jerks of the muscles around the eyes (Harding & Jeavons, 1994) synchronous with flashes progressing to the muscles of the neck nape and blocked by opening the eyes. The EEG shows ‘spikes’ synchronous with myoclonia in the anterior frontal region detectable at the beginning of the stimulation and increasing progressively in amplitude. They are blinking artefacts (Bickford et al., 1952), also called the photomyoclogic response (Klass & Fisher-Williams, 1976). Following Gastaut (1951) myoclonia depends on ‘hyperexcitability of the neurones in the mesencephalic region bringing on a local irradiation rapidly propagated to the motoneurones of the 3rd and 7th pair’. This ILS response is more frequent in adults than in children and only 3% of the subjects have other epileptic manifestations (Gastaut et al., 1958). It was considered related to psychiatric syndromes and ‘not significant for the diagnosis of seizure disorders’ (Newmark & Penry, 1979). Recently, Artieda and Obeso (1993) described eyelid myoclonia associated with FR paroxysmal-evoked potentials in old patients. We must emphasize the striking homology of this syndrome of man with the photogenic symptoms of the Fepi Mes-Chimera.2 Generalized myoclonia

ILS can also induce generalized jerks occuring with eyes opened or closed. With prolonged ILS, they may trigger Grand Mal seizures. In highly sensitive subjects, the first symptom may be toe jerks synchronous with flashes. Generally, each myoclonus is associated with a generalized PD, which may remain the only symptom. PDs react poorly to opening the eyes, can briefly outlast ILS or be followed by typical Grand Mal. Such patients may also exhibit an arrest of speech, fine myoclonia of the eyelids with eyes opened and eye deviation as in ‘Petit Mal absence’. This syndrome is more common in young than in old subjects and is associated with other epileptic symptoms in more than 80% of the cases (Gastaut et al., 1958). It is generated in the cortico-thalamic circuits (Avoli & Gloor, 1994). 2

It is interesting to note that birds do not have eyelids and thus cannot show palpebral myoclonus.

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In a few subjects, eyelid myoclonia with photomyoclogic responses precede generalized myoclonia with PDs and Grand Mal seizures. In this case, the thalamocortical and brainstem circuits are both involved, brainstem being the first generator. This syndrome is somewhat similar to the photogenic epilepsy of Fepi and baboon. Occipital seizures

Also induced by ILS (Naquet et al., 1960), they may or may not be preceded by generalized PDs. They can be unilateral, bilateral or with interside shifting, followed or not by generalization. The clinical symptomatology, transitory blindness and localized cephalalgia preceding generalization, depends on duration and extent of progression of the EEG seizures. These seizures, rarely described before TV and videogames were available, are frequently observed at present (Badinand-Hubert et al., 1998). Occipital seizures are unknown in animals, but they have similarities with the bilateral FR seizures of the baboon. Somatosensory paroxysmal manifestations Startle disease or hyperekplexia

Startle is a polysynaptic alerting reflex in response to an unexpected stimulus (Suhren et al., 1966). The disease (Andermann & Andermann, 1986) is characterized by an exaggerated startle reaction to sudden visual, auditory or proprioceptive stimuli ineffective in a normal subject and hampers normal activity (see Dalla Bernardina et al., 1989). This disease could be secondary to cortical lesions, but other cases have an autosomal dominant hereditary transmission. The mutation affects the 1 (GLRA1) subunit of the inhibitory glycine receptor localized to the 5q32 chromosomal region (Grenningloh et al., 1990). Recently, it was shown that the mutation affects the ligand binding function (Shiang et al., 1993) and blocks the Cl channels of the receptor (Saul et al., 1999). In a minor form, affecting young adults, excessive startle, enhanced by fever, fatigue or emotion, is the only symptom. In the major form, affecting neonatal and infants, the startle response is associated with transient generalized hypertonia when the subject is awakened or handled, frequent falls without loss of consciousness, hesitating gait and nocturnal jerks. Sudden attacks of generalized stiffness with violent shaking of the limbs, apnea, cyanosis, and, with prolonged fits, severe bradycardia and vomiting are described. They may disappear spontaneously within the first year of life, but the startle response persists until adulthood. Both forms have normal resting EEG. During attacks, muscular artefacts mask the EEG activity (Fig. 3.3(b)), but at the end the absence of PDs become evident. Slow activity, possibly ‘anoxo-ischemic’, appears during a few seconds (Dalla Bernardina et al., 1989). Anticonvulsant drugs are not very effective, but benzodiazepines reduce the attacks.

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Startle disease is generally considered ‘non-epileptic’. Nevertheless, for Hillion and Beaumanoir (1989) it is due to ‘hyperexcitability of brainstem centres by insufficient higher inhibitory mechanisms’. It resembles SSS-induced myoclonia in Papio papio and, although with a different stimulus, to the ILS-induced myoclonus in mes-chimeras and to the ILS-induced photomyologic response in humans. Myoclonus epilepsy in infancy

This is a rare syndrome appearing between 3 and 12 months, myoclonus being generally the only symptom during its short evolution (12 to 14 months) (Ricci et al., 1995; Guerrini et al., 1994). Initially, startle only triggers myoclonus, then simple sensory stimuli from different modalities may also be the trigger. Myoclonus involves the arms and head (the child does not fall), is accompanied by brief generalized PDs, and is generally controlled by valproate. Although long-term followup is unusual, no children have been reported to have late recurrence or another form of epilepsy. A family history of epilepsy is frequent and the epileptic nature of the syndrome is uncontested. Among several important questions raised by this syndrome, the following are worth mentioning. Is this an early form of startle epilepsy? Is this a special subgroup with an unusual age-dependent idiopathic generalized epilepsy having benign outcome due to maturation? Is it related to ‘non-epileptic’ syndromes in infants with myoclonus? Paroxysmal kinesigenic choreoathetosis (PKC)

Identified in 1967 by Kertesz, PKC is a rare disease with a remarkably homogeneous symptomatology. Seizures are precipitated during rest by a sudden movement; they are short (30 s–2 min), frequent (up to 100/day) and well controlled by anticonvulsant drugs. The attacks are announced by a strange sensation in the limb whose movement trigger the seizure. The limb and the hemibody rapidly adopt a dystonic posture, abnormal movements (flexion, extension, twisting) and, with longer seizures, writhing and choreic, athetotic or ballistic movements. Speech often becomes slurred, but consciousness is never impaired. Seizures may appear during childhood or adolescence, disappear at ages 20–40, and are more frequent in males. Fifty per cent of the cases are familial, with a genetic pattern suggesting a dominant autosomal inheritance. The frequency of epilepsy in the family is above average (Cler et al., 1990). Lance (1977) proposed that PKC has an ‘hereditary or sporadic biochemical lesion of extrapyramidal structures’ and that proprioceptive input to basal ganglia release an unknown neurotransmitter responsible for the attacks. The epileptic nature of PKC is admitted by some authors and denied by others. PKC is an example of where the distinction between ‘movement disorders’ and epileptic seizures is not clear.

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Conclusions The PMs (myoclonia, RF and seizures) induced by sensory stimuli studied in this work (neurodegenerative syndromes of humans have been voluntarily omitted), do not fit in a single group and are difficult to summarize. Nevertheless, they are tentatively described in Fig. 3.4 and classified according to the effective stimulus. The difficulties do not arise from the identification of the signs known as revealing an epilepsy predisposition. They depend on the fact that some of the PMs are driven by the arrival of specific afferences to the cortex, and the cortex alone; others by the arrival of the afferences to the brainstem nuclei and do not involve the cortex; finally, some others are the consequence of the afferences reaching both, brainstem and cortex, one or the other being involved first. The species, its place in phylogenesis and its specific sensory dominance (visual in bird and humans, auditory in rodents) must be taken into account to explain such results, but the type of the stimulus may also be a determinant factor of the different symptomatology. Thus, with auditory stimuli, PMs are only induced by brainstem circuits, whatever the species; with SSS, most of the PMs originate in the brainstem or basal ganglia circuits and do not involve the cortex (Papio papio and humans), although in other cases (humans) the brainstem origin may be transitorily associated with the cortico-thalamic circuits. With ILS, all the possibilities exist, so that humans can express the same kind of PMs found in Papio papio, or those found in the meschimeras and, in other instances, it can express its own specific PM. The comparative analysis of the genetic reflex syndromes entitles us to conclude that GRE may be of cortical origin only or of brainstem origin only throughout the species including humans. With the development of corticalization, the cortical circuits acquire an increased control of brainstem circuits. Very likely, one of the major difficulties comes from the unsolved problem still under discussion at present of the terminology. If, to be called ‘epileptic’, a myoclonus and/or a seizure need to be associated to a PD, many of the syndromes here described in animals and humans cannot be called GRE but ‘movement disorders’. In this case, the following will be epileptic: the ILS-induced generalized myoclonus and seizures and the occipital seizures in man; all the ILS-induced PM in the baboon; and the benign myoclonus epilepsy of the child. On the contrary, those syndromes having a familial history of epilepsy as well as those associated with real ‘epileptic’ PM, would not be ‘epileptic’ if no PMs are found during seizures. To accept such a position, the epileptologist should admit that PDs not associated with any clinical symptom cannot be considered ‘epileptic’. The recently described Landau–Kleffer syndrome (see Gordon, 1997) in which the continuous presence of PDs is not necessarily accompanied by clinical epileptic seizures has, however, been considered epileptic. Finally, going from experimental data to clinical observations, we learned that both syndromes with an ‘electrical’ expression only, as well

Resting EEG

Partial myocl

Generalized myocl

Focal seizures

Generalized seizures

Resting EEG

Running fits

Generalized seizures

Ictal EEG

Origin

Resting EEG

Myoclonia

Generalized seizures

Ictal EEG

Origin

(a)

Origin

Genetic reflex epilepsy from chicken to man

Ictal EEG

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Fepi, pros-mes chimera Pros- chimera Mes- chimera Papio papio Human eyelid myoclonia Generalized myoclonia Occipital seizures

(b)

Fepi, pros-mes chimera Pros- chimera Mes- chimera

(c)

Papio papio Human myocl epil in Infant Hyperekplexia PKC Fig. 3.4

Tables summarizing characteristic data of individual ILS- (a) CSS- (b) and SSS- (c) induced GRE from chicken to man. BDblockage of PDs and EEG desynchronization; BGbasal ganglia; Bsbrainstem; cPD continous PD; CSScomplex sound stimulation; Cxcortex; DEEG desynchronization; iPDisolated PDs; ILSintermittent light stimulation; PDParoxysmal discharge; SSS somatosensory stimulation.

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as syndromes with apparently ‘clinical’ expression only, can be retained to define epilepsy. In other words, we prefer to call ‘epileptic’ both syndromes with and without PMs. At the present time, when the emphasis is on diversifying syndromes to accommodate diversified symptoms, we propose to schematically classify all of them as GRE, hoping that the advancement in genetics knowledge will help us to understand the differences.

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R. Naquet and C. Batini Penfield, W. & Jasper, H.H. (1954). Epilepsy and the Functional Anatomy of the Human Brain, pp. 896. Boston: Little Brown. Rektor, I., Bryere, P., Silva-Barrat, C. & Menini, Ch (1986). Stimulus-sensitive myoclonus of the baboon Papio papio: pharmacological studies reveal interactions between benzodiazepines and the central cholinergic system. Experimental Neurology, 91, 13–22. Ribak, C.E., Roberts, R.C., Byun, M.Y. & Kim, H.L. (1988). Anatomical and behavioral analyses of the inheritance of audiogenic seizures in the progeny of genetically epilepsy-prone and Sprague–Dawley rats. Epilepsy Research, 2, 345–55. Ricci, S., Cusmai, R., Fusco, L. & Vigevano, F. (1995). Reflex myoclonic epilepsy in infancy: a new age-dependent idiopathic epileptic syndrome related to startle reaction. Epilepsia, 36, 342–8. Saul, B., Kuner, T., Sobetzko, D. et al. (1999). Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating. Journal of Neuroscience, 19(3), 869–77. Seyfried, T.N., Yu, R.K. & Glaser, G.H. (1980). Genetic analysis of audiogenic seizures susceptibility in C57BL/6J x DBA/2J recombinant inbred strains of mice. Genetics, 94, 701–18. Shiang, R., Ryan, S.G., Zhu, Y.Z., Han, A.F., O’Connell, P. & Wasmuth, J.J. (1993). Mutation in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, Hyperekplexia. Nature Genetics, 5, 351–8. Suhren, O., Bruyn, G.W. & Tuynman, J.A. (1966). Hyperexplexia. A hereditary startle syndrome. Journal of Neurological Science, 3, 577–605. Teillet, M.A., Naquet, R., Le Gal La Salle, G., Merat, P., Schuler, B. & Le Douarin, N.M. (1991). Transfer of genetic epilepsy by embryonic brain grafts in the chicken. Proceedings of the National Academy of Sciences, USA, 88, 6966–70. Terzian, H. & Terzuolo, C. (1951). Ricerche electrofisiologiche sull’epilessia fotica di Clementi. Archives of Fisiol. Fasc. 5, 301–20. Valin, A., Cepeda, C., Rey, E. & Naquet, R. (1981). Opposite effects of lorazepam on two kinds of myoclonus in the photosensitive Papio papio. EEG Clinical Neurophysiology, 52, 647–51. Walter, W.G., Walter, V., Gastaut, H. & Gastaut, Y. (1948). Une forme nouvelle de l’épilepsie: l’épilepsie photogénique. Reviews of Neurology, 80, 613–14. Wilkins, D.E., Andermann, F. & Ives, J. (1975). Stripes, complex cells and seizures. Brain, 98, 365–80.

4

Functional MRI of the motor cortex Raphaël Massarelli1, Angelo Gemignani2, Michela Tosetti3, Domenico Montanaro4, Raffaello Cannapicchi4, and in memoriam Claudio Munari 1

CNRS UMR 5542 Faculty Laënnec, University C. Bernard, Lyon, France Department of Physiology and Biochemistry, University of Pisa, Italy 3 MR Department, Stella Maris Scientific Institute, Calambrone, Pisa, Italy 4 Department of Neuroradiology, S. Chiara Hospital, Pisa, Italy 2

Festina lente1

The Decade of the Brain has witnessed important methodological innovations that have greatly facilitated the study and the knowledge of brain functions. Among the new tools which are nowadays at the disposition of researchers, neuroimaging techniques have attracted much interest not only among neuroscientists but also in the media since the assumption has been made public that these methodologies allow us to ‘see’ the brain at work. We will see in the following that this is partly natural exaggeration by the media. It is the feeling of the authors that a certain amount of caution should be taken into account in the case of a methodology (functional magnetic resonance imaging, fMRI) which, at present, is certainly most promising in revealing brain functions under various, and not restrictive, cerebral events such as those concerning sensory, motor and cognitive functions. This will be done in the following under the form of three questions which, we think, should be considered every time a patient (or a normal subject) is under study. A short introduction Neuroimaging techniques such as MRI belong to the progeny of physics which has brought a commendable intuition to become an extremely complex discipline. To 1

This Latin expression may be translated as: ‘rush slowly’. It indicates, in our minds, the necessity to exercise caution when using very complex methodology which may, however, if appropriately employed, be of enormous scientific and clinical interest.

Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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clearly understand the physical principles of MRI, the knowledgeable intervention of quantum mechanics is an obligatory step. As a prerequisite, it is thus advisable to approach this methodology from a multidisciplinary standpoint, with a multidisciplinary team, and to constantly remember that what one sees might potentially be a multidisciplinary methodological artefact. It is not within the scope of the present chapter to describe the theory of MRI. Excellent reviews have been written on the subject (see, for example, Aine, 1995). Suffice to say, and it is rather important to stress the point, that the imaging of the brain can be realized because we are able to see the movement of proton spins (the hydrogen of water) and the increases in blood flow that are the consequent effect of the activation of brain areas, as stated more than one century ago (Roy & Sherrington, 1890). In a seminal report, Belliveau et al. (1991), showed the functional activation of the visual occipital areas (appearing as hyperintense pixels) after stimulation with a flashing red light. The result was obtained after injection of a contrast agent. Later, the discovery of the BOLD effect (Ogawa et al., 1990), revealing that the degree of blood oxygenation can be used as a contrast agent, made useless the injection of any foreign product and rendered fMRI entirely not invasive. It must be borne in mind, that whatever is seen by fMRI is blood movements, an effect which is secondary to the functional activation of the cerebral tissue. A variety of applications, in the years following the report of Belliveau et al. (1991), have made fMRI the most promising of the neuroimaging techniques, owing to its excellent spatio-temporal resolution. Publications regarding fMRI are becoming very important and among the most relevant results obtained, we might mention as an example, the studies of Tootell et al. (1995) on the visual system showing similar complexity of interaction among occipital cerebral territories. This had been shown in monkeys, the variability of the human homunculus that was shown by Sanes et al. (1995) and the complexity of grasping and reaching arm movements by Dettmers et al. (1996). It is in the study of the ‘higher brain functions’, however, that the sophistication of fMRI has been most prominent and impressive. For example, the cognitive studies which reveal the function and interaction of brain areas during visual (Kosslyn et al., 1995) or motor imagery (Roth et al., 1996; see the review of Jeannerod & Decety, 1995) and those on the modulation of the functional connectivity in the dorsal stream induced by attentional mechanisms (Büchel & Friston, 1997). The latter approach opens a door to the study of complexity (Tononi et al., 1994) and consciousness (Tononi & Edelman, 1998). The clinical applications of fMRI have evolved at a relatively slow pace, mainly for two reasons. The first one is related to the lack of a common standardization of the software leading to the final postprocessing of the data. The second is inherent to the incomplete knowledge of the nature of the phenomenon that is at the basis

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of fMRI, the BOLD effect, that has induced a great caution in the interpretation of the data. The largest application of fMRI up to now has been the study of the pathophysiological aspects related to the sensory–motor domain. This has been due to the relative ease of sensory–motor tasks that are well standardized and controlled (finger tips opposition to the thumb, for example, parametric controlled force or sensory tasks with scratching or puffing…), and to the knowledge of human cortical neurophysiology that allows the diagnosis of neurological sensory–motor abnormalities. Clinical applications of fMRI relate to three specific aspects of such abnormalities: • anatomical identification of functional areas activated by a plastic remodelling of the primary localization following acquired or congenital lesions; • anatomical identification of the secondary areas that, following chronic, severe lesions of the primary areas, replace the latter; • correlation between abnormal electrical cortical activity and fMRI responses without any evident functional alteration. Abnormalities due to tumoural lesions or vascular malformations can be followed by fMRI to identify, with the greatest precision allowed by the methodology, functional areas close to the site of the lesions. This has been used as a prerequisite to neurosurgery and has given its proofs with respect to more complex methodologies such as PET, stereo-EEG and intraoperative ERPs (Mueller et al., 1996; Jack et al., 1994). Clinical applications of fMRI have further highlighted its methodological efficacy in neurological (tumours: Schulder et al., 1998, epilepsy: Duncan, 1997; Kuzniecky, 1997; Weiss et al., 1998) and clinical psychiatry (schizophrenia: Kindermann et al., 1997, obsessive compulsive disorders: Breiter & Rauch, 1996). The first report of a dynamic MRI study in epilepsy is by Fish et al. (1988) where the authors observed hyperintense signals in the frontal lobe of a patient with epilepsia partialis continua using two spin-echo pulse sequences proportional to regional blood flow. Increased perfusion in the temporo-parietal cortex was observed in a partial status epilepticus, using a contrast enhancement with a gadolinium containing contrast agent (Warach et al., 1994). Ictal changes were further observed as variations in regional cerebral blood flow (Jackson et al., 1993; Detre et al., 1995; Warach et al., 1996). Several studies have shown the usefulness of fMRI as presurgical functional mapping methodology, as it has been done in the case of the primary motor and sensory cortices (Hammeke et al., 1994; Jack et al., 1994; Puce et al., 1995). Aside fMRI, renewed interest in MRI has been sought with the application of diffusion-weighted and pure diffusion sequences. These measure the restrained

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diffusion of water in the cerebral tissue resulting in hypersignals, which can accurately give the anatomical localization of the epileptic zone (Righini et al., 1994; Helpern & Huang, 1995; Wang et al., 1996; Ebisu et al., 1996; Zhong et al., 1997; Wieshman et al., 1997). Some of these studies illustrate the first of the three questions that we wish to raise in the present report. Where are we looking at? In the framework of the clinical research programme of the INSERM U438 in Grenoble we have been interested to apply fMRI to epilepsy and as a representative example, we would like to cite the case of a young woman (22 yrs of age) suffering from intractable epilepsy, who had undergone presurgical diagnostic identification of the focus by stereoEEG exploration. The case was interesting from an fMRI point of view, as the patient presented a schizencephalic cleft in the temporal lobe, surrounded by polymicrogyria. In a trial to countercheck by fMRI the results obtained with SEEG, the patient was asked to oppose the right hand fingers to the thumb, rotate the ankle and move the foot digits, and to move the lips in proeminence and the tongue inside the mouth. The results (Massarelli et al., 1998) showed a correspondence between the position of SEEG electrodes which identified the sensory and the primary motor areas of the hand and of the right foot with fMRI activations. The finding suggests the possibility that fMRI may be used to identify anatomo-functional areas in pathological conditions, but does not entirely substitute SEEG to detect the epileptic foci. This approach led to an effort to assess the presurgical diagnostic value of fMRI on the functionality of the cortical areas surrounding tumours. This was done with the double purpose of revealing the plastic rearrangements due to the mass effect of a tumour and to purvey functional maps of evident utility during surgery. An example is shown in Fig. 4.1 (see colour plate section) where the movement of the digits of the right foot and of opposition of the fingers to the thumb of the right hand activated areas surrounding the neoplastic formation. The results show that the sensory–motor system did not appear to be largely influenced by the tumoural mass, even if some rearrangements were present in secondary motor areas. A more conservative attitude could suggest the possibility that the activations were an epiphenomenon of physiological or physical origin. It was thus decided to perform experiments in order to study the reproducibility of the primary motor area responsible for the right hand task. Normal subjects were asked to repeat the same task (finger opposition) several folds and in very much the same way. The activations (analysed as number of pixels) were measured in four slices (5 mm thick each) positioned in correspondence to the hand area according to the Talairach and Tournoux (1988) atlas. The

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Table 4.1. Number of pixels (meanstandard deviation) in primary motor cortex activated during right hand finger tapping

MI Subjects

Slice 1

Slice 2

Slice 3

Slice 4

1 n6

(121.611.6 (53.7%)

(112.04.5 (37.5%)

(18.46.2 (73.8%)

(110.16.2 (61.4%)

2 n6

(116.25.5 (88.7%)

(110.35.7 (55.3%)

(19.83.6 (18.2%)

(128.09.5 (33.9%)

3 n6

( 19.519.5 (100%)

(127.27.6 (28%)

(26.85.0 (18.6%)

(118.512.7 (68.6%)

4 n6

( 14.513.2 (91%)

(116.58.5 (137%)

(10

(117.25.7 (79%)

5 n6

(112.81.8 (14%)

(117.56.8 (38.8%)

(17.06.6 (38.8%)

(117.83.7 (47.4%)

6 n6

(13.08.0 (61.5%)

(118.55.8 (68.2%)

(13.212.7 (96.2%)

(116.27.7 (124%)

7 n5

(40.623.6 (58%)

(153.69.2 (17.2%)

(26.611.6 (43.6%)

nd

Notes: In parenthesis the SD is expressed as a percentage of the mean. nnumber of scans per subject (1–7); ndnot determined.

mean average of the pixel number in each slice was then calculated with its standard deviation. The results showed that the number of pixels was highly variable in three out of four slices (in subject 7 two out of three), ranging in some instances from 0 to more than 100 pixels. In all subjects, however, the number of pixels was reproducible in only one slice (Table 4.1), that showed a limited variability. Such a low variability was still segregated in the same slice when the analysis was repeated several times and several days thereafter (not shown). The first interpretation of these data by anyone working with modern neuroimaging techniques is the possibility of an artefact concerning, for example, the excitation of proton spins, the signal to noise ratio or a purely statistical phenomenon implying that there is always a mean with a ‘reasonable’ standard deviation when studying whatever population. If this is true, why repeatedly the same slice? Even if the physical phenomena are at the basis of the technique and their interference cannot be excluded, let us assume a physiological explanation as a reasonable temptation, additionally that the results indicate that the functional cortical response to a relatively complex movement of the digits is reproducibly found in the same area

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of the cortical ribbon and non reproducibly in three other locations. In other terms, we are confronted with a centre of gravity for the movement which may require the intervention of peripheral locations. Such intervention may be constantly changing because of changing perceptions, i.e. the phenomena dynamically integrated in the primary motor ribbon are constantly different. Conversely, the results imply that the positioning of slices to measure the thumb motor area, for example, on the basis of the Talairach and Tournoux atlas may be misleading. It is possible while using one scan, to fall on an area which does not correspond to the area of the thumb and which is activated because of a particular perceptive and purely transitory status. Regardless of the physical or physiological basis of the phenomenon, caution has to be taken when interpreting functional activations in the absence of a rigorous reproduction of the task. The answer to the question is that we are looking at variable functional regions corresponding to a dynamic mosaic which is selectively and strictly established for each individual homunculus. Why are we looking at? An example of a possible answer was given by the work of Jackson et al. (1993) on the cerebral activations measured in a 4-year-old boy during ictal discharges due to a temporal lobe epilepsy. In three areas of the left temporal lobe, hyperintense signals were measured, with signal increases as high as 20–25% above interictal background. The authors measured the hyperintensities with a BOLD sequence and it is widely accepted that activations measured by the BOLD contrast show signal increases, on the average, 2–5% higher than the signal at rest. Where does the roughly 20% difference come from? Experiments performed at the INSERM U 438 (Delon-Martin et al., 1999) have shown the presence of functional responses to a motor task, with ranges between 20 and 40% of signal increase and in some subjects, recorded up to 60%. The results were obtained by subtracting the BOLD signal at rest from the one obtained during the task. It was later found that this percentage increase corresponded to an increased blood flow in pial veins draining the cortical areas involved in the execution of the movement. Unfortunately, these veinous responses, due to the unspecific drainage of blood, may come from various areas which may or may not be activated at the same time and in an undistinguishable manner. As a consequence, they may give artefactual higher signals if the accuracy of the response is sought for. It is thus advisable to subtract the activations obtained by a functional MR Angiography, even when using an echo planar sequence. By means of a phase contrast sequence, it is, however possible to measure the

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increase in blood flow velocity in an orthogonal section of a vein. Such measurement was made in the Trolard vein of normal subjects during the execution of the hand motor task and found to vary from 20 to 72% (Delon-Martin et al., 1999). An increased blood flow was actually measured even when the subjects were asked to simulate the motor task without actually executing it. Considering that these pial veins drain the blood from several territories, the measurement of blood flow made in these veins lacks topographical specificity. These experiments, however, show the possibility of quantifying blood flow from a territory roughly corresponding to the primary sensory–motor cortex during execution and simulation of a motor task. This means that the internal rehearsing of a motor task (without the execution of the movement) is sufficient to specifically increase the local blood flow much like its execution. Thus the answer to the question is: ‘because blood flow increases’, and this leads to the next question. What are we looking at? This is a difficult question if one does not refute, as a matter of principle, questions that may have a philosophical connotation. At the risk of appearing compliant with Monsieur De La Palisse, it is common ground to say that the brain, as all the other organs, never stops working, even temporarily. A ‘resting activity’ is illusory (Biswal et al., 1995, 1997). Even if it is possible to plan experimental paradigms which limit the study to the activation of a restricted and specific area, this can only be done provided that other areas are not connected for its function. The functioning of the brain appears to be the effect of an interaction (connectivity) among different areas (Büchel & Friston, 1997). The study of connectivity illustrates once more that the brain is a non-linear dynamic system sensitive to initial conditions (Lopes da Silva et al., 1994; Glans, 1997). Following our findings of the increase of blood flow after motor simulation, further experiments showed that the primary motor cortex, and not only the veins draining it, may be activated when subjects simulate a motor hand task, i.e. its mimesis.2 2

It should be useful to open a parenthesis on the meaning of ‘simulation’. The term has been semantically accepted and largely used throughout the literature. However, the greek word mimesis might be closer to the significance of the task when taken in the aristotelian definition (Aristoteles, Poetics, 1448b, 20). In our experience there are two ways by which subjects describe how they simulate: they either see their fingers moving in opposition to the thumb or they feel them. Some are capable to shift from one to the other but, in general, it is possible to separate individuals into two categories. In the former case the task is close to an imagery task, in the latter it is more the mimesis of the action and it corresponds to what is experienced by athletes when mentally rehearsing a physical effort.

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The participation of the MI cortex in the mimesis of a motor task might imply the involvement of the primary motor area as one of the mechanisms involved in the passage from intention to action. We reasoned that, if this was the case, the mimesis of the movement done immediately before its execution should affect the actual movement. This appeared to be the case. Even if an important interindividual variability was present, two findings showed that mimesis had an effect upon the execution of the movement. The first was that statistically more pixels were recruited in the contralateral and in the ipsilateral primary motor cortex. The second finding was that more areas with a reduced signal were detected in the ipsilateral hemisphere when the movement was preceded by mimesis than in its absence (Fig. 4.2: see colour plate section). In our postprocessing treatment, the analysis of the data defines as significant the pixels that are highly correlated with the experimental protocol. They will appear as hyperintense signals. Hypointense signals, instead, represent signals that are in inverse correlation to the paradigm. Similar experiments performed on motor tasks with positron emission tomography (using 15O water) have shown the presence of hyposignals that were interpreted to indicate the reduction of regional cerebral blood flow. This is in accordance with the hypothesis of a transcallosal inhibition of the ipsilateral hemisphere (Ferbert et al., 1992). Perspectives The vast spectrum of physiological and clinical applications of fMRI makes this methodology one of the most promising in the study of cortical abnormalities, providing the possibility to apply fast sequences. fMRI will then be suitable to most clinical institutions to study not only the timing of cortical response but also the temporal hierarchical development and the modulation produced by areas progressively or simultaneously involved in the overall cortical response. From a clinical standpoint, this will add a further important element, the precise establishment of the site of interference at which a lesion or a pharmacological agent may act, in the range of events characteristic of a given cortical response. Acknowledgements Several colleagues have participated to the studies performed at the INSERM U438 in Grenoble, notably: M. Raybaudi, C. Delon-Martin and C. Segebarth (INSERM U 438), J. Décety and M. Jeannerod (at the time INSERM U 94, Lyon), A. Benabid (INSERM U 318, Grenoble), JF LeBas (Unité IRM, CHU Grenoble), P. Kahane (Unité sur l’Épilepsie, CHU, Grenoble).

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Neuromagnetic methods and transcranial magnetic stimulation for testing sensorimotor cortex excitability Paolo Maria Rossini1, Alfredo Berardelli2 and Roberto Cantello3 1

Department of Neurology, CRCCS AFaR Ospedale Fatebenefratelli, Rome, Italy Departimento Scienze Neurologiche, Università La Sapienza, Rome, Italy 3 Clinica Neurologica, Università del Piemonte Orientale, Novara, Italy 2

Magnetoencephalography (MEG): physiological background Magnetoencephalography (MEG) is a non-invasive technique able to spatially identify the synchronous firing neurons in restricted cortical areas, either for spontaneous cerebral activity or in response to an external stimulus. MEG is unaffected by scalp and skull, and preferentially reflects the tangential component of dipoles in the depth of gyri and sulci. The neuromagnetic technique consists of measurement of the magnetic field over the scalp, as generated by the bioelectrical currents in the brain. In order to achieve the sensitivity needed to measure these very weak magnetic fields (about 1015 as compared to the earth magnetic field), the use of new superconducting magnetometers (superconducting quantum interferences devices or SQUID) and of devoted shielding is mandatory. Under the symmetry conditions, well approximated in the case of the head, it can be shown that the component of the magnetic field perpendicular to the skull is mostly sensitive to the tangential component of the primary current source, and negligibly to the field generated by the volume currents and to the distortions, smearing effects and filtering of frequency components, mainly in the faster rhythms caused by the intervening tissues (Romani & Rossini, 1988; Okada et al., 1999). This represents an advantage in respect to the purely electric measurement of neural activity, especially for the postsynaptic component at the level of the cortical mantle. The magnetic field is simultaneously measured over many scalp sites, with a rapid sampling in the time domain, and from these data the isofield contour maps are calculated and studied. Whenever a dipolar structure is evident, the best equivalent dipolar source can be localized by Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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a least-square fit (equivalent current dipole – (ECD)) explaining the field distribution. MEG allows the spatial evolution of an ECD, or of several ECDs, which are able to explain 90% or more of the magnetic field pattern on the scalp with a time resolution of one millisecond or less. Because of its physical properties, MEG allows a precise 3D-localization of the firing neuronal pool. The integration with data coming from magnetic resonance imaging allows the localization of the ECD in the brain (Fig. 5.1: see colour plate section). Neuromagnetic mapping of sensorimotor cortex in humans has been recently performed after stimulation of peripheral nerves. Direct stimulation of mixed or sensory nerves of upper and lower limbs evoked clearly distinguishable somatosensory evoked fields (SEFs). The main early components of these fields have a latency of 20–30 ms for the hand and 40–60 ms for the foot, with an approximate depth of the related ECDs ranging from 1.5 to 5 cm (Hari, 1990; Rossini et al., 1989). Separate stimulation of digital sensory nerves in individual fingers permits one to distinguish the relative ECD. The ECD responsible for the SEFs to thumb stimulation is 1–2 cm more lateral than that of the little finger. Using this method, the topography, extension and interhemispheric spatial differences of the ‘sensory hand’ have been recently measured in healthy humans (Rossini et al., 1994a; Wikstrom et al., 1997). Absolute values have been found quite stable within the same subject when repeatedly tested, but they are highly variable from subject to subject, while their interhemispheric differences vary little (Tecchio et al., 1998). Experimental and clinical conditions exclusively or predominantly affecting one hemisphere can therefore disrupt such interhemispheric symmetry. Transcranial magnetic stimulation (TMS): physiological background TMS is generated by the discharge of specially designed capacitors which flows through a copper coil and produces a transient magnetic field of strong intensity (Barker et al., 1985). This magnetic field passes through the skull without appreciable attenuation. It induces weak currents, which lead to negligible activation of nociceptive terminals, but cause the excitation of neural elements, with a maximal depth of a few centimetres. In many instances, the more focal ‘butterfly’ or ‘figureof-eight’ coil has replaced the original, large round coil. The direction of the current flowing within the coil is crucial for the preferential activation of different neuronal aggregates. In the primary motor cortex, corticospinal activation occurs within the grey matter, i.e. it affects very rostral elements of the corticospinal neurone or acts trans-synaptically via cortico-cortical interneurons. Electrical cortical stimuli elicit different volleys along the corticospinal fibres. The first wave is the D (direct) wave, while the subsequent waves are I (indirect) waves, because they originate from direct or indirect (trans-synaptic) activation of the corticospinal neurone. TMS

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preferentially elicits I-waves. It can produce D-waves at high stimulus intensities or if the coil is tilted, oriented or shaped in a particular way. The descending excitatory inputs reach the spinal alpha-motoneurone, generating a series of excitatory postsynaptic potentials that summate to fire the neurones in accordance with the Henneman size principle (Henneman et al., 1965). The resulting volleys travel along the peripheral nerves to reach the target muscles. The final response, recorded as a surface compound action potential, is the motor evoked potential (MEP). MEPs can also be recorded after stimulation of the ventral roots via the same coil positioned at strategical sites over the cervical or lumbar enlargement. The latency difference between cortical and root MEPs represents the central motor conduction time along the pyramidal fibres (CCT). The threshold for eliciting MEPs in a given target muscle (Rossini et al., 1994b) and the MEP size are of special interest for excitability measurements. The threshold, which is lower if the target muscle is preactivated, depends on the ability of the corticospinal neurone to fire high frequency trains of action potentials. This is why antiepileptic drugs acting on the voltagedepending ion channels can increase the threshold (Ziemann et al., 1996a). Many physiological and pathological variables produce significant threshold changes. The MEP size, best expressed as a percentage of the maximum M wave, increases with increasing stimulus intensities and activation of the target muscle. It also changes in response to a variety of conditioning stimuli (e.g. somatosensory, cerebellar and transcallosal). Of course, both the threshold and the MEP size depend also on the excitability of the spinal alpha-motoneurone. Thus, a study of H- or F-waves must implement any evaluation of such indices. The cortical silent period is a negative effect of TMS. It consists of an interruption of the EMG background on which the MEP impinges when the target muscle is active. It immediately follows the MEP. The late portion of the cortical silent period is thought to reflect inhibitory mechanisms intrinsic to the primary motor cortex (Cantello et al., 1992). This implies a potential interest in the evaluation of the excitatory balance of the cortex. Also, different neuroactive drugs are capable of changing the silent period, suggesting further potential applications in the pharmacological field. However, there are uncertainties about the basic physiology of this variable that limit its actual investigational value. Cracco and Cracco (1997) recently reviewed many of the aspects of TMS mentioned above. Paired-TMS: corticocortical inhibition and excitation In paired-pulse TMS, two stimuli separated by a brief, programmable interval, are delivered through the same (usually focal) coil. The first (conditioning) stimulus is subthreshold for evoking MEPs in the relaxed target muscle. Originally, its suggested intensity was 0.8relaxed threshold (Kujirai et al., 1993). In many subsequent studies, an intensity of 0.9threshold in the active muscle was adopted, to

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Fig. 5.2

A typical corticocortical inhibition and facilitation curve obtained by paired TMS. The inhibitory phase occurs at short ISIs (1–5 ms), whilst the facilitatory phase occurs at later ISIs (8–16 ms). ISIinterstimulus interval. Bars represent SD.

minimize the chance of producing descending volleys and alpha-motoneuronal activation. The latter would distort any analysis of purely cortical excitability. A suprathreshold (usually 1.2 x relaxed threshold) test stimulus follows, at intervals from 0 to 15–30 ms. For each interstimulus intervals (ISIs), 8 to 16 conditioned and control MEPs are recorded in a random order and subject to differential averaging. At short ISIs (1–5 ms), the conditioned MEP is inhibited, whilst at longer ISIs (8–20 ms) it is facilitated. If the size of the conditioned MEP as a percentage of the control MEP is plotted against the ISIs, a characteristic intracortical inhibition and facilitation curve can be drawn (Fig. 5.2). The mechanisms underlying these changes are thought to be located in the primary motor cortex, since the spinal alpha-motoneurone excitability is not significantly altered by the conditioning stimulus. Moreover, no effect is seen when the test stimulus, instead of being magnetic, is an anodal electric shock. Anodal electric stimuli are likely to activate corticospinal axons within the white matter (Rossini et al., 1985). Thus, the lack of effects is compatible with a cortical genesis of the inhibitory and excitatory phenomena. Poststimulus time histograms of the firing of a single motor unit in a hand muscle disclosed that both the conditioning and the test TMS shocks influence the I wave-related discharges. Thus, inhibition and excitation should be ascribed to trans-synaptic phenomena, i.e. to a cortico-cortical circuitry. Ziemann et al. (1996b) suggested that inhibition and facilitation have distinct mechanisms: subthreshold magnetic stimuli activate separate populations of inhibitory and excitatory interneurones within the cortex that interact at the corticospinal neurone. Gamma-amino-butyric acid (GABA) would be the most involved neurotransmit-

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ter, as suggested by the different effects on intracortical inhibition and facilitation exerted by GABAergic vs. non-GABAergic antiepileptic drugs in normal subject (Ziemann et al., 1996a). Hanajima et al. (1998), through studies of the descending volleys, further concluded in favour of a crucial pathophysiological role of GABAergic transmission. Corticocortical inhibition and excitation are likely to play an important role in motor control, as shown by their changes related to different motor tasks (Liepert et al., 1998), to somatosensory afferences (Cantello et al., 1997a) and to handedness (Civardi et al., 1998). Indeed, they were found altered in movement disorders such as Parkinson’s disease (Ridding et al., 1995a) and focal dystonia (Ridding et al., 1995b). MEG and epilepsy In comparison with the classic EEG techniques, MEG might be of higher value in localizing epileptogenic foci. Magnetic fields pass through the scalp structures without attenuation or distortion. Unlike the EEG, the source of MEG activity is mostly or exclusively tangential, and this may lead to an easier application of the inverse dipole methods of localization. The spatial characteristics and activity of actual MEG spike generators can be modelled reliably by a single dipole characterized via an iterative minimization methodology. If the paroxysms are generated within serially activated neuronal pools of circuitry, they can be discriminated as individual ECDs thanks to the time resolution of the MEG technique (Ebersole, 1997). Approximately, such dipole corresponds to the centre of the actual spike source and has a similar orientation. Currently, the calculated dipoles are projected onto an individual MRI-based anatomic reconstruction of the brain. MEG and MRI signals are recorded in a coordinate way, as this procedure is often termed magnetic source imaging (MSI) (Ebersole, 1997). Earlier MEG studies had the limitation of covering a relatively small region of the head at a time, which caused the need for repeat recordings and replacement of the sensor at different scalp sites. Nevertheless, the studies succeeded in providing topographic information on epileptogenic spike foci and by spatially identifying the related ECDs generator sources. Recently, MEG sensors with a much larger number of channels (typically 37 to 74, but 128 channels are now available) were developed, which imply wholehead recordings. This way, many investigators showed a very high topographic correlation between the MEG spike source and the location of tumours, or the presence of hippocampal atrophy, or the site of PET/SPECT functional abnormalities (Stefan et al., 1992). Others suggested that the MEG localizing value might be higher for foci of the cerebral convexity, since mesial temporal lobe foci can be identified through imaging techniques or by EEG recordings via sphenoidal electrodes (Smith et al., 1995). In patients with extratemporal epilepsy, MEG sources

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showed good concordance with the localization of ictal onset or irritative zones by means of depth electrodes (Eliashiv et al., 1995). MEG was also able to supply useful localising information in patients with no detectable abnormality on MRI or CT imaging (Ebersole, 1997). On the whole, many think that MEG/MSI studies could succeed in reducing the actual need for invasive recording, in screening an epileptic patient for corrective neurosurgery. Simultaneous recording of MEG and EEG signals appears to have important applications. Ebersole et al. (1993) stressed that at least one-third of the sources of epileptic EEG activity correspond to magnetic fields that change over time. This implies that instantaneous modelling of a single dipole is not sufficient to describe the evolving (in time and space) nature of the epileptic discharge. Rather, the stability of the MEG dipole should be evaluated, and the various components examined. The earliest active source has the greatest clinical value to depict the actual origin site of the discharge. Many authors think that the combination of MEG and EEG data will offer the ideal amount of information to assess the location of epileptogenic areas and achieve the goal of reducing invasive recordings (Ebersole, 1997). This is because MEG is maximally sensitive to a tangential, and EEG to a radial direction, of the propagated signal. Future technical advances promise to supply the most effectiveness in the combination of the two methods. TMS and epilepsy Studies of patients with epilepsy have been based on the typical single-pulse TMS, on repetitive TMS and on paired TMS as well (Ziemann et al., 1998; Cantello et al., 1998a). TMS would appear an ideal tool for studying human epilepsies in a noninvasive fashion, since it can give information on the intrinsic excitability status of the cerebral cortex, particularly the primary motor cortex, and alterations of cortical excitability are a classic background phenomenon of epileptogenesis. The TMS threshold has been studied by several authors, the most consistent conclusion being that threshold is increased by those antiepileptic drugs that act directly on the ion membrane channels (phenytoin, carbamazepine, etc.). The large use of these drugs in any given epileptic population renders this finding non-specific. Threshold changes due to some specific epileptic syndromes have been described in idiopathic generalized epilepsy (Reutens & Berkovic, 1992), where a cortical hyperexcitability was found, that fits the pathophysiology of the corresponding animal models. However, these studies did not pay extensive attention to possible disease- or drug-related changes in the excitability of the spinal station of the corticospinal system, and could not be replicated in at least one subsequent work (Gianelli et al., 1994). Studies of the central silent period in epileptic patients are surprisingly few. The most systematic one is probably that of Cincotta et al. (1998),

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Fig. 5.3

Corticocortical inhibition and facilitation curves obtained by paired TMS. In a subgroup of seven patients suffering from cryptogenic partial epilepsy, the curve shows severe lack of inhibition and excess facilitation. Changes are bilateral. Bars represent SEM. Black lines patients. Dotted linescontrols.

who found a silent period prolongation contralateral to epileptic foci located in the primary motor cortex. This phenomenon would represent some sort of compensatory enhancement of the cortical inhibitory activity in response to the presence of the epileptogenic area. Interestingly, many antiepileptic drugs can alter the duration of the central silent period (Ziemann et al., 1998; Cantello et al., 1998a). Further studies are needed to clarify some intriguing findings, such as the apparently opposite effect of two very similar benzodiazepines (diazepam and lorazepam). Paired TMS promises a closer link to the clinical situation of the patient, because it can describe in greater detail the balance between inhibitory and excitatory interneuronal activities within the primary motor cortex. Antiepileptic drugs

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do affect these activities in a way depending on their mechanism of action (Ziemann et al., 1996a). Defective inhibition/excess excitation was found in patients with juvenile myoclonus epilepsy (Caramia et al., 1996). Studies of patient populations are in progress. Patients with focal epilepsy show an interhemispheric asymmetry of the motor cortex inhibitory properties, as signalled by the different SP progression patterns to increasing TCS intensity between the ‘epileptic’ and ‘non-epileptic hemispheres’. The SP following TCS of the ‘epileptic’ side lacks the physiological increase in duration with stimulus intensity, while SP duration linearly increases when the ‘nonepileptic’ hemisphere is tested with higher stimulus intensity. These findings, in association with a symmetrical behaviour of the motor threshold and MEP size, might reflect a selective functional deficiency of the motor cortex inhibitory responses which could reflect the hyperexcitability of the epileptic brain (Cicinelli et al., 2000). In partial epilepsies, there are subgroups of patients showing bilateral changes in the cortical excitatory balance, rather than alterations ipsilateral to the epileptogenic area (Fig. 5.3) (Cantello et al., 1998b). Changes do not appear to depend on the type of drug administered. Rather, a correlation with a more severe clinical course and more frequent interictal epileptic EEG discharges of the generalized type (featuring a poorer prognosis) emerged (Cantello et al., 1998b). Special TMS studies provided a pathophysiological insight in progressive myoclonic epilepsy showing an excessive excitability of the primary motor cortex, in response to afferent stimuli with respect to normals (Mariorenzi et al., 1991; Reutens et al., 1993; Cantello et al., 1997b). Also, new features of epilepsia partialis continua (Cockerell et al., 1996) and focal myoclonus (Cantello et al., 1997b) were described, highlighting that, in some cases, jerks thought to be of an epileptic nature originate from subcortical rather than cortical structures. Special TMS techniques were also used to highlight a transient decrease of the corticospinal excitability time locked to the ‘wave’ element of typical 3 Hz spike-and-wave discharges (Gianelli et al., 1994). Because of its interference with the normal functioning of specific cortical areas, fast (1 Hz) r-TMS may be of use in the determination of the hemispheric dominance for language. To date, this procedure cannot yet replace the Wada test, but may usefully supplement functional MRI imaging (Binder et al., 1996) for this aim (Ziemann et al., 1998; Cantello et al., 1998a). Slow (1 Hz) repetitive TMS can depress MI excitability, in a way similar to the long-term depression phenomenon (Chen et al., 1997). This might have potential therapeutic effects in the epileptic conditions associated with primary motor cortex overactivity (e.g. cortical myoclonus). Many have studied TMS as a means for activating the epileptic focus. The initial enthusiasm has been moderated by subsequent controversial results. Thus, TMS does not appear as an appropriate tool for reducing the need for invasive

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investigations in patients being prepared for epilepsy surgery. Safety is a major issue when studying epileptic patients with TMS (Tassinari et al., 1990). In particular, there are strict international guidelines for the use of repetitive TMS (Wassermann, 1996). Transcranial magnetic stimulation in movement disorders TMS techniques have provided useful information on the pathophysiology of movement disorders. In Parkinson’s disease, where the corticomotoneurone conduction is normal, paired-shock studies investigating the cortical SP and suppression of the size of the test MEP have disclosed changes in cortical excitability. The cortical silent period is shorter in Parkinson’s disease patients than in normal subjects and can be prolonged after pharmacological and surgical treatment (Cantello et al., 1991; Priori et al., 1994a). Paired-shock studies using differing techniques have demonstrated changes in the activity of various sets of cortical interneurones (Ridding et al., 1995a; Berardelli et al., 1996). Abnormalities in the silent period and in the suppression of the test response, disclosed by the paired-shock technique, can be normalized by anti-Parkinsonian therapy. These effects have been attributed to dopamine-induced changes in cortical inhibitory mechanisms. The MEP facilitation normally seen in response to repetitive TMS delivered in trains is absent in Parkinsonian patients, possibly owing to increased inhibition of cortical motor areas in Parkinson’s disease. Repetitive TMS has also identified changes in the excitability of cortical motor areas in dystonia. The size of responses evoked by TMS increases more steeply with increasing stimulus intensity or with increasing levels of background contraction in dystonic patients than in normal subjects (Mavroudakis et al., 1995; Ikoma et al., 1996). A mild shortening of the silent period is a common finding and some reports also describe changes in corticocortical inhibition similar to those in Parkinson’s disease (Ridding et al., 1995a; Rona et al., 1997). In patients with Huntington’s disease, TMS studies sometimes report an abnormal cortical silent period (Priori et al., 1994b), whereas the pairedshock technique has so far failed to disclose definite changes. Patients with essential tremor have normal corticomotoneuronal conduction and normal cortical motor area excitability (Romeo et al., 1998). MEG and stroke Because of the higher incidence of stroke in the territory of the middle cerebral artery affecting subcortical and cortical sensorimotor fibres and relays, somatosensory evoked fields (SEFs) have been recorded following separate electrical stimulation of the median nerve at wrist, the thumb and the little fingers of the two hands.

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Intensities are usually set at about twice the subjective threshold of perception for fingers and just above the motor threshold for the nerve at the wrist. Responses were recorded on the hemiscalp contralateral to the stimulated side over the parietal region. Only the initial part of SEFs, which contains the most stable, repeatable waves and are also independent from the subject’s attention (N20m, P30m), are usually analysed. Equivalent current dipole (ECD) characteristics (spatial coordinates and strength) are calculated at 1 ms intervals in the 15–50 ms poststimulus epoch, using a moving dipole model, Lavenberg–Marquard least-square fit, inside an homogeneously conducting sphere. The ‘hand extension’ can also be measured as the linear distance in millimetres between the centres of the ECD activated by stimulation of the fifth and the first fingers of the contralateral hand. The MEG–MRI common reference system is defined on the basis of three anatomical landmarks (vit. E capsules) for MRI, microcurrents circulating in small coils for MEG, fixed on nasion, left and right preauricolar points (Fig. 5.1, colour plate). Nineteen patients suffering from a unique, unilateral stroke lesion have been enrolled in a pilot study (Rossini et al., 1998b). Twelve out of 19 patients with reliable SEFs from the affected hemisphere (AH), showed an excessive interhemispheric asymmetry of signal strength at least for one stimulated district. A total of 15 ECD pairs from homologous districts exceeded the normative range. Strength abnormalities affected more the P30m component. When latency delays were accompanied by ECD spatial displacements, these always affected the N20 component generator sources. The MEG/MRI integration showed all ECDs localized outside the areas of anatomical lesion. Interestingly, even displaced hand areas maintained the classical ‘homunculus’ somatotopy seen in the healthy hemispheres (the thumb being more lateral, the little finger more medial and the median nerve lying in-between). Abnormalities include a significant enlargement of the hand extension in the AH, with a medial shift of the little finger, and the tendency of both fingers’ representations to shift anteriorly. It is worth underlining that abnormal parameters were also encountered in the unaffected hemisphere (UH), but spatial displacements of ECDs did not mirror each other in the two hemispheres. Larger cortical representation of the sensorimotor area correlated with poor clinical recovery, including partial sensory and motor performances. Significant inverse correlation linked sensorimotor hand scores and latency delays in AH, motor scores and abnormalities in ECD spatial properties. Analysis of wave shape interhemispheric correlation showed an extremely high value in normal subjects and in patients without ECD displacements, showing symmetric organizations in the two hemispheres. On the contrary, the correlation coefficient dropped to very low levels whenever ECD displacements were present. This suggests the possibility of newly established neural networks which justify a change of response morphology on the AH with possible latency prolongation.

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Our findings suggest that new brain areas, which are not usually reached by a dense connection with hand and finger sensory receptors, may act as primary somatosensory hand centres and allow progressive clinical recovery from a vascular insult (Rossini et al., 1994a, 1998a, b; Tecchio et al., 1998).

TMS and stroke Patients affected by monohemispheric cerebrovascular lesions were studied in the ‘acute stage’ and/or in clinical stabilised conditions. Standard procedures of TMS were carried out 24–72 hours after the stroke, 1 week and up to 6 months later. Motor evoked potentials (MEPs) were bilaterally recorded in relaxed awake subjects, from deltoid and abductor digiti minimi (ADM) muscles. The excitability threshold for MEPs elicitation was defined (Rossini et al., 1994a) in at least one muscle. Thereafter, the TCS intensity was increased by 10% of the stimulator output to obtain a greater probability of response. F-waves and compound motor action potentials (c-MAPs) from ADM muscles were obtained during ulnar nerve supramaximal stimulation at the wrist on each side, to calculate the central conduction time (CCT) along the corticospinal fibres mediating MEPs (Rossini et al., 1985, 1987). The following parameters have been measured at three recording sessions: Excitability threshold with muscles at rest; MEPs latency and amplitude measured peak-to-peak during relaxation and during contraction; CCT obtained via the Fwave method and interhemispheric asymmetry for the above mentioned parameters. Data obtained from the unaffected hemisphere (UH) in each recording session did not differ from those obtained in normal subjects, whereas the responses from the affected hemisphere (AH) changed significantly during follow-up. The excitability threshold was significantly higher in the AH, compared with the UH and with normal subjects (P0.001). Latencies of MEPs were significantly prolonged and showed a lower than normal amplitude, especially during contraction. CCT was prolonged (P0.002). Interhemispheric differences between AH and UH were significant for all the parameters studied. These parameters showed a progressive improvement in one week and especially six months after the cerebrovascular lesion, when there were no significant interhemispheric differences between affected and unaffected hemispheres, excluding the excitability threshold. In patients in ‘clinically stabilized’ conditions (60 days – first recording T1, and 120 days, second recording T2 – after the stroke), a map of the cortical motor output of the hand was constructed, scanning 11 positions on each hemiscalp, to cover the precentral area. TMS was delivered via a focal 8-shaped coil.

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Besides all the above parameters, the following were also calculated: the extension of motor cortical output area as represented by the number of scalp sites from which TMS triggered MEPs in the target muscle, the onset latency of MEPs triggered from the ‘hot spot’, the onset latencies of MEPs from the scalp sites adjacent to the ‘hot spot’ for the calculation of the ‘hot spot vs. surround’ latency difference, and the duration of the silent period (SP) (Cicinelli et al., 1997a; Traversa et al., 1997, Rossini et al., 1998b). The excitability thresholds in the AH were significantly higher and the MEP amplitude smaller despite stronger TCS being employed also in this group. The area of cortical output to the target muscle was also significantly and asymmetrically restricted, compared with normals and with the patients’ UH. The percentage of altered parameters was significantly higher in T1 and in subcortical lesions, probably due to a large number of densely packed fibres affected by a subcortical lesion and to a less efficient short-term ‘plastic’ reorganization. In T2, the ‘subcortical’ patients presented an amelioration of the neurophysiological parameters reaching the same level of the ‘cortical’ group. Anomalous ‘hot spot’ sites were observed more frequently in the cortical group. Recovery in cortical patients with anomalous ‘hot spot’ sites might rely on the activation of brain areas outside the usual boundaries of the primary motor cortex. This finding may represent a neurophysiological marker of plastic rearrangements of cortical motor output. The ‘hot spot’ vs. surround latency differences in T1 showed an inversion of the normal pattern (which shows the minimal latency from the ‘hot spot’ and latency values about 1 ms longer from the surround); such an abnormality recovered in T2. A significant enlargement of the hand motor cortical output area from AH was found in T2, compared with T1 in 67% of cases. This was usually coupled with clinical improvement as shown by the clinical score (Barthel index and Canadian neurological scale). It is worth mentioning that those patients demonstrating an enlargement of the hand area also showed a correlated improvement of the hand score. The site of lesion (cortical or subcortical) did not influence the final clinical outcome. CCT was found to be prolonged from the AH even when a clinically relevant amelioration was present. The mechanism for such a prolongation is probably multifactorial, namely the loss of fast-propagating corticospinal neurones, the slowing of neuronal propagation at the lesional site, the contribution of direct cortico-motoneuronal connection from non-primary motor areas (not present in normal MEPs), the loss of tonic facilitatory sensory feedback from the hand, and the involvement of newly established cortico-cortical connections (not present in normal MEPs). An increased output from the UH was found in a subacute stroke patient (Cicinelli et al., 1997a). This significantly decreased in the following recording session, associated with an increased AH output. Interhemispheric differences vary

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significantly less than absolute values across subjects (Cicinelli et al., 1997b). They represent a powerful clinical indicator, as recently demonstrated in stroke patients (Traversa et al., 1997). Interhemispheric balancing of contracted MEPs amplitude may represent a ‘marker’ of clinical recovery (Cicinelli et al., 1997a). It is possible that the ‘transhemispheric diaschisis’ leads to hyperexcitability of the hemisphere contralateral (UH) to a neocortical infarction, due to the prolonged lack of inhibitory modulation of transcallosal fibres from the AH. The progressive reduction of UH hyperexcitability might be interpreted as a progressive recovery of transcallosal inhibition by the AH. Another possible and not mutually exclusive explanation is based on the increased use of the unaffected hand/arm following a unilateral stroke. This might per se increase the muscle responsiveness to the stimulation and would recede with improved use of the affected arm in the frame of an use-dependent adaptation (Traversa et al., 1998). Conclusions One of the most astonishing properties of the mammalian brain is its capacity of adaptation for change, commonly referred to as neural plasticity. Pioneering studies have repeatedly shown how the brain possesses the capacity to reorganize itself after peripheral deprivation by allowing neighbouring cortical regions to expand into territories normally occupied by input from the deprived sense organs (Brasil Neto et al., 1993). More recently, a bulk of experimental evidence has been collected in support of the hypothesis that neuronal aggregates adjacent to a lesion in the sensorimotor brain areas can progressively take over the function of the damaged neurones (Weder et al., 1994; Chollet et al., 1991). Such a reorganization, if occurring in the affected hemisphere of a patient with a monohemispheric lesion, should significantly modify the interhemispheric symmetry of somatotopic organization of the sensorimotor cortices and largely subtend clinical recovery of motor performances and sensorimotor integration. Animal experiments have shown that some plastic rearrangements of the CNS functions secondary to peripheral nerve/roots or cerebral lesions not only occur in childhood, but are also present in adulthood (Merzenich et al., 1983). MEG and TMS techniques demonstrate well the short-term reorganization of the topography of sensorimotor cortical areas in the healthy following sensory deprivation from the periphery (Rossini et al., 1996a, b, Rossini et al., 1994c). Finally, long-term reorganization of these areas was demonstrated in blind adults learning the Braille method (Sterr et al., 1998; Cohen et al., 1997; Pascual Leone et al., 1993) and in amputees suffering from ‘phantom limb syndrome’ (Flor et al., 1995). Other models of topographic modifications in hemispheric somatotopy are related to

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motor learning: in adults, they include musicians and the effects of repeated motor imagery (Elbert et al., 1995; Rossi et al., 1998a). Therefore, it is relatively well established that short- and long-term reorganization of cortical input–output flow during learning and following a lesion and rehabilitation procedures is active in adults, and neuromagnetic (MEG and TMS) techniques are able to provide important tools on the amount and mechanisms of such reorganizations (Fig. 5.4: see colour plate section). Finally, the combined use of MEG and TMS seems quite promising in the field of epileptology. It provides a valuable tool for assessing cortical excitability and for localizing the epileptic aggregates in space and time.

Acknowledgement The authors acknowledge the highly professional and valuable help of Dr Flavia Pauri in assessing the present manuscript.

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Motor dysfunction resulting from epileptic activity involving the sensorimotor cortex Renzo Guerrini1, Lucio Parmeggiani2, Alan Shewmon3, Guido Rubboli4 and Carlo Alberto Tassinari4 1

Neurosciences Unit, Institute of Child Health, The Wolfson Centre, London, UK Institute of Child Neurology and Psychiatry, University of Pisa, Italy 3 Department of Pediatric Neurology, UCLA Medical Center, Los Angeles, CA, USA 4 Department of Neurology, Bellaria Hospital, University of Bologna, Italy 2

Introduction Epileptic activity involving the sensorimotor cortex can be associated with a wide spectrum of motor manifestations, such as clonic or tonic phenomena, paresis (Penfield & Jasper, 1954; Fisher, 1978; Globus et al., 1982; Tinuper et al., 1987; Lee & Lerner, 1990; Primavera et al., 1993; So, 1995), epileptic negative myoclonus (Tassinari, 1981; Guerrini et al., 1993; Tassinari et al., 1995; Noachtar et al., 1997), apraxia (Neville & Boyd, 1995; Maquet et al., 1995), ataxia (Bennett et al., 1982; Dalla Bernardina et al., 1989), and motor neglect (Galletti et al., 1992; Guerrini et al., 1993). Neurophysiological investigations and, more recently, functional imaging studies have provided a growing amount of data that have proved extremely useful for diagnostic purposes and for pathophysiological speculations. However, the understanding of the mechanisms underlying the different clinical events associated with paroxysmal activity in the sensorimotor cortex is still incomplete. Excitatory or disinhibitory neuronal mechanisms as well as hypersynchronous inhibitory phenomena may play a role (Engel, 1995), as suggested by the finding that ‘interictal’ spike-and-wave discharges (SW) involving a specific cortical area can disrupt its physiological functions (Shewmon & Erwin, 1988a,b,c; 1989). In the present chapter, we will focus on those types of motor dysfunction resulting from epileptic activity in the sensorimotor cortex, characterized clinically by an altered execution of a motor task or by the inability to perform it, such as epileptic negative myoclonus (ENM), partial atonic seizures (PAS), and syndromes resulting from frequent paroxysmal activity in the sensorimotor cortex. Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Epileptic negative myoclonus Definition

Epileptic negative myoclonus (ENM) is defined as a brief, jerky, involuntary movement due to transient muscular atonia during maintenance of posture, time locked to EEG paroxysmal activity (usually a SW discharge) in the contralateral hemisphere, and without evidence of an antecedent myoclonic jerk in the antagonist muscle (Tassinari et al., 1968, 1995; Tassinari, 1981; Wang et al., 1984; Cirignotta & Lugaresi, 1991; Guerrini et al., 1993). Background

The first description of brief, rhythmic lapses of postural tone, involving fingers, arms or legs, and face was reported in patients with hepatic encephalopathy (Adams & Foley, 1949). Polygraphic studies demonstrated that those movements, called asterixis, were due to intermittent pauses of the interferential electromyographic (EMG) activity, lasting 200–500 ms (Adams & Foley, 1953). Some years later, Lance and Adams (1963), studying patients with posthypoxic myoclonus, found that myoclonic jerks were followed by muscular ‘silent periods’. They also demonstrated that some jerky movements produced by EMG silent periods could occur without evidence of a preceding myoclonic jerk. A similar phenomenon, i.e. EMG silent period not preceded by a myoclonic burst, was described by Pagni et al. (1964) following direct electrical stimulation near the capsulo-thalamic boundary. Shahani and Young (1976) introduced the term ‘negative myoclonus’ to identify involuntary movements associated with EMG silent periods (Young & Shahani, 1986). In the 1980s and 1990s, several reports described patients with epilepsy who presented brief postural lapses in different body segments. Polygraphic recordings demonstrated that jerky movements consisted of a brief suppression of the EMG activity, time locked to a spike or a SW complex on contralateral central areas (Tassinari, 1981; Cirignotta & Lugaresi, 1991; Oguni et al., 1992; Guerrini et al., 1993). The term ENM was coined to label this motor disorder (Tassinari et al., 1990; Guerrini et al., 1993). Clinical features

ENM is a relatively uncommon motor disorder; however its incidence is probably underestimated. Indeed, its occurrence may be missed, if it is not carefully looked for, by asking the patient to maintain a tonic contraction. In this condition, definition of the limit between ictal and interictal EEG abnormalities may prove to be arbitrary, as SW discharges, which are not associated with clinical manifestation

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when the patient is at rest, can produce an atonic phenomenon if he or she is asked to maintain a posture. ENM can occur in the clinical context of various aetiologies. It has been described in typical and atypical benign partial epilepsies of infancy (Aicardi & Chevrie, 1982; Lerman, 1986; Caraballo et al., 1989; Dalla Bernardina et al., 1990; Kanazawa & Kawai, 1990; Oguni et al., 1992, 1998; Guerrini et al., 1993; Tassinari et al., 1995), affecting children who have normal development and normal brain imaging. ENM can be concomitant with seizure onset or appear even years later (Kanazawa & Kawai, 1990; Guerrini et al., 1993; Tassinari et al., 1995; Oguni et al., 1998). Moreover, at least in some patients, ENM may be a transitory disorder, rendering the estimation of its real incidence even more difficult to establish. Its clinical manifestations can be as mild as a motor ‘instability’ (Tassinari et al., 1995), but more frequently consist of dropping of objects from the hands, head nodding (Oguni et al., 1992) staggering or falls (Aicardi & Chevrie, 1982; Lerman, 1986; Caraballo et al., 1989). Sometimes ENM may be accompanied by motor neglect (Guerrini et al., 1993), whereby affected patients appear to cease using the body segment(s) involved, in the absence of any sign of reduced strength. ENM can be induced by antiepileptic drugs, particularly carbamazepine (Lerman, 1986; Caraballo et al., 1989; Guerrini et al., 1998a; Nanba & Maegaki, 1999). In these cases, epilepsy and ENM have usually a good prognosis with remission by the age of 10 years (Aicardi & Chevrie, 1982; Kanazawa & Kawai, 1990; Oguni et al., 1992, 1998; Guerrini et al., 1993). Recent studies report a significant response of ENM to ethosuximide treatment (Oguni et al., 1998; Capovilla et al., 1999). EEG shows focal SW discharges with maximum amplitude in centro-parietotemporal regions (Kanazawa & Kawai, 1990; Oguni et al., 1992, 1998). In some children the discharges become diffuse and continuous during sleep, reproducing an EEG pattern similar to ‘electrical status epilepticus during slow sleep’ (Patry et al., 1971; Tassinari et al., 1992). Symptomatic epileptic conditions associated with ENM include mitochondrial diseases (Guerrini et al., 1993; Shibasaki et al., 1994), Lafora disease (Tassinari et al., 1995), vascular malformations (Tassinari et al., 1995), birth anoxia (Rubboli et al., 1995), cortical dysplasia (Guerrini et al., 1993; Gambardella et al., 1997; Noachtar et al., 1997). In symptomatic cases age at onset of epilepsy ranged from 2 to 14 years and onset of ENM was concomitant or delayed up to several years. Evolution of both epilepsy and ENM is related to etiology. Symptomatic ENM can be associated with different seizure types ranging from simple or complex partial to generalized tonic–clonic seizures. Finally, in some patients, despite a clinical picture of symptomatic epilepsy, no etiology can be demonstrated.

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Neurophysiological and functional neuroimaging

In conventional polygraphic recordings, ENM is characterized by brief pauses of ongoing EMG activity, usually lasting 100–400 ms, time-locked to a contralateral spike or SW, showing peak amplitude in the centro-parietal (Kanazawa & Kawai, 1990; Oguni et al., 1992, 1998; Tassinari et al., 1995; Noachtar et al., 1997), central (Cirignotta & Lugaresi, 1991; Guerrini et al., 1993; Gambardella et al., 1997), fronto-central (Rubboli et al., 1995; Baumgartner et al., 1996), or vertex electrodes (Tassinari et al., 1996; Capovilla et al., 1999). Unilateral SW discharges are usually associated with postural lapses of the contralateral arm, while bilateral SW discharges may produce dropping of both arms (Tassinari et al., 1968; Oguni et al., 1992); vertex spikes usually cause a brief muscular inhibition in one or both lower limbs (Guerrini et al., 1993; Tassinari et al., 1996; Capovilla et al., 1999). In children with atypical rolandic epilepsy and ENM, generalized 2–3 Hz SW discharges can be associated with head and arm dropping and unresponsiveness, a picture resembling atonic absences (Oguni et al., 1992). ENM duration is correlated with spike amplitude (Oguni et al., 1992; Rubboli et al., 1995; Tassinari et al., 1995), spike area (product of spike duration by spike amplitude) (Noachtar et al., 1997) or slow wave duration and amplitude (Guerrini et al., 1998a). Latency between ENM onset and time-locked SW, measured from spike onset (Guerrini et al., 1993; Baumgartner et al., 1996) or from spike peak (Rubboli et al., 1995; Tassinari et al., 1995; Oguni et al., 1998) (Fig. 6.1: see colour plate section) or from slow wave onset (Fig. 6.2) ranges between 15 ms and 50 ms, as measured on raw EEG or after silent period-locked averaging or spike averaging. Cirignotta and Lugaresi (1991) studied spinal motor neuron excitability during ENM by means of the H-reflex from the medial popliteal nerve in one boy with normal MRI. They found that stimulation delivered 150 ms after cortical spikes related to ENM was not followed by a detectable H-reflex. The authors concluded that the excitatory potential related to the spike was not expressed clinically, while the cortical inhibitory potential related to the slow wave was propagated to spinal motoneuron pools, leading to ENM and H-reflex inhibition. However, Tassinari et al. (1995), studying a patient with symptomatic epilepsy, did not find modification in latency, amplitude, and frequency of F-waves elicited 30 to 120 ms after ENM onset. In the same patient, transcranial magnetic stimulation failed to produce motor-evoked potentials if performed during ENM. These findings support the hypothesis that a cortical inhibitory mechanism underlies ENM. Rubboli and coworkers (1995) found that spikes related to ENM have a significantly longer duration than non-ENM-related spikes and manifest a peculiar double-peaked morphology. The second peak mapped to the frontal area, followed the spike peak by around 40 ms, and preceded the onset of the EMG silent period

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Fig. 6.2

Silent-locked averaging in a 7-year-old boy with rolandic epilepsy and ENM. Slow-wave onset preceded the onset of silent period by around 13 ms. Two traces, each generated by averaging 30 EEG epochs, are overlapped to ensure reliability. LDleft deltoid.

by about 30 ms. Onset of the slow wave was about 25 ms after the onset of the EMG silent period. The authors hypothesized that this frontal inhibitory component resulted from spreading of paroxysmal activity from the central to the homolateral frontal area which is ultimately responsible for ENM generation. Baumgartner et al. (1996) reported similar findings by performing SPECT and MRI co-registration during ENM that demonstrated marked hyperperfusion in the middle frontal and supramarginal gyrus corresponding to premotor areas. Tassinari et al. (1995) and Noachtar et al. (1997) observed ENM associated with spikes in the postcentral region; ENM duration was significantly correlated with spike amplitude (Tassinari et al., 1995) or spike area (Noachtar et al., 1997). Moreover, in Noachtar et al.’s patient, the postcentral cortex was hyperexcitable, as shown by giant somatosensory evoked potentials (SEPs). The authors concluded that the hyperexcitable dysplastic postcentral cortex exerted a direct or indirect inhibitory effect on the output from the primary motor cortex. Shibasaki and coworkers (1994) reached similar conclusions by studying three patients with progressive myoclonus epilepsy and cortical reflex negative myoclonus. In these

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patients, electrical stimulation of the median nerve during sustained wrist extension produced frequent short postural lapses of the ipsilateral hand. Enhanced early components of SEPs were closely related to negative myoclonus. A significant correlation between SEPs amplitude and negative myoclonus duration was demonstrated in one patient. Excitability of the primary somatosensory cortex, studied by paired median nerve stimuli, was decreased during the poststimulus period that corresponded to the duration of induced negative myoclonus in each individual case. These data seem to indicate that cortical reflex negative myoclonus may result from cortical inhibition (Shibasaki et al., 1994). Support to this interpretation comes from recent subdural electrode studies in patients who were evaluated for epilepsy surgery (Ikeda et al., 2000). Studying the excitability of primary sensorimotor cortex by means of direct cortical stimulation, the authors found that electrodes overlying the sensorimotor cortex could be stimulated producing either a positive or negative motor response, while stimulation of electrodes overlying the so-called negative motor areas (Lüders et al., 1995) was ineffective. Summary and conclusion

ENM is an ictal motor disorder that can occur in an etiologically wide spectrum of epileptic conditions. The clinical impact of ENM can range from an almost unnoticed disturbance to disabling motor impairment. Neurophysiologic and neuroimaging studies point to cortical origin for ENM, possibly through an inhibitory mechanism involving the sensorimotor and the frontal cortices. Focal SW discharges in the sensorimotor cortex could produce a temporary dysfunction, clinically evident as ENM, similar to the topographically specific function-disrupting effects on visual perceptual and reaction-time tasks exerted by posterior quadrant SW discharges (Shewmon & Erwin 1988a,b,c; 1989). Partial atonic seizures Definition

Partial atonic seizures (PAS) are clinically characterized by ictal paresis or paralysis of one body segment. Ictal EEG shows a focal discharge, usually involving the fronto-central areas (So, 1995). Background

According to Gastaut and Broughton (1972), Higer first described PAS in 1889, as epileptic hemiplegia. Single patient reports by Jackson (1890) and Holmes (1927), suggested transient paresis of a limb without preceding convulsive activity, as a possible seizure manifestation. Penfield and Jasper (1954) described a patient in whom

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‘a sudden paralysis may occur without warning or it may be preceded by some sensory phenomena in the same part’; they defined this manifestation as inhibitory epilepsy. Gastaut and Broughton (1972) identified two types of PAS: unilateral atonic seizures as involving one hemibody and somatic inhibitory seizures having focal distribution. Clinical features

A total of 50 patients with PAS have been described. Associated anatomic abnormalities include ischemic cerebrovascular diseases (Fisher, 1978; Globus et al., 1982; Lee & Lerner, 1990; Primavera et al., 1993), tumours (Penfield & Jasper, 1954; Kofman & Tasker, 1967; Fisher, 1978; Abou Khalil et al., 1995; Matsumoto et al., 2000), focal cortical dysplasia (Abou Khalil et al., 1995; Lance, 1995), mesiotemporal sclerosis (Oestreich et al., 1995), vascular malformations (Noachtar & Luders, 1999). In some patients no etiology was found (Beaussart & Beaussart-Boulenge, 1969; Waltregny et al., 1969; Hanson & Chodos, 1978; Niedermeyer et al., 1979; Tinuper et al., 1987; Dierckx et al., 1988; Shirasaka et al., 1990; Abou Khilil et al., 1995; Thomas et al., 1998; Dale & Cross, 1999). Tumours and dysplastic lesions mostly involved the parietal lobe (Kofman & Tasker, 1967; Abou Khalil et al., 1995; Lance, 1995; Matsumoto et al., 2000), but other patients presented with frontal lobe abnormalities on MRI (Noachtar & Luders, 1999). Partial atonic seizures are characterized by sudden paralysis or paresis of a limb, a hemibody or rarely all limbs, which can be preceded or accompanied by numbness involving the same or a different body part. Associated manifestations include deviation of the eyes or head towards the side of the paralysed limb (Waltregny et al., 1969; Hanson & Chodos, 1978; Globus et al., 1982; Thomas et al., 1998), clonic jerks in a different body part (Penfield & Jasper, 1954; Abou Khalil et al., 1995, So, 1995), or dysphasia/aphasia (Fisher, 1978; Globus et al., 1982; Primavera et al., 1993). A clinical syndrome indistinguishable from unilateral asomatognosia or Anton–Babinski syndrome has been described in one patient (Thomas et al., 1998). It can be difficult to differentiate ictal from postictal paresis (Hanson & Chodos 1978). In three patients, aged from newborn to 12 years, a partial motor seizure preceded the onset of PAS involving the same limb, favouring diagnosis of Todd’s paresis. However, ictal EEG activity was present in the contralateral hemisphere in two children with unilateral ictal paresis in whom, in addition, acute administration of antiepileptic drugs (AEDs) cleared the symptoms. Duration of PAS ranged from a few seconds to several hours. Some patients (both children and adults) have been reported presenting with very long seizures (30 minutes), which can be considered non-convulsive epileptic status. In four of these patients a hemiparesis or a monoparesis lasted several days, eventually to disappear

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upon AED administration (Smith et al., 1997; Dale & Cross, 1999). Ictal EEG was recorded in 30 patients, usually showing SW or slow wave discharges (16/30 – 53%) or rhythmic ictal activity (14/30 – 47%) in frontal or centroparietal areas (19/30 – 63%), the temporal lobe (6/30 – 20%) or distributed over a wide scalp region (5/30 – 17%) contralateral to the paralysed limb(s). Seizure discharges involved the mesial frontal or the primary sensorimotor cortices in the only two patients who had ictal subdural recording (Noachtar & Luders, 1999; Matsumoto et al., 2000). Neurophysiological characterization

PAS may have a long duration, sometimes presenting as status epilepticus. Data from electrical stimulation of human cerebral cortex reveal the existence of frontal regions whose activation produces inhibition of voluntary movement, lasting as long as the stimulus is active (Lüders et al., 1995). These regions, defined as ‘negative motor areas’, correspond to the inferior frontal gyrus anterior to the primary face motor area (primary negative motor area – Lüders et al., 1992) and to the mesial portion of the superior frontal gyrus, immediately anterior to the face motor area of the supplementary sensorimotor cortex (supplementary negative motor area – Lim et al., 1994). As demonstrated in animal models (Matelli et al., 1991; Rizzolatti et al., 1990), these areas seem to be involved in the organization and integration of voluntary movement. Epileptic activity involving these areas can lead to apraxia and motor inhibition manifested as PAS (Lüders et al., 1995). An alternative explanation is that epileptic discharges in the primary sensorimotor cortex can produce negative motor phenomena via direct inhibition of the spinal motoneuron pool as observed both in human pathology (Matsumoto et al., 2000) and in experimental animal models (Elger et al., 1981). It is difficult to speculate whether PAS and ENM share, at least partially, common pathogenic mechanisms, although some recent data support the idea that primary sensorimotor cortex may participate in the genesis of both phenomena (Ikeda et al., 2000; Matsumoto et al., 2000). Differential diagnosis

In older patients PAS are usually mistaken for transient ischemic attacks (TIA) (Thomas et al., 1998), whereas in children and adolescents differential diagnosis is with migraine with prolonged aura (Headache Classification Committee of the International Headache Society, 1988), or rarely with alternating hemiplegia (Shirasaka et al., 1990). As reported by Fisher (1978) some clinical features are highly indicative of PAS: i development of focal paralysis seconds to minutes before a motor seizure begins in the same limb;

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ii occurrence of a motor deficit, indistinguishable from postictal paresis, occasionally observed in the same body part; iii contemporary presence of a motor seizure and an ictal paresis in different body segments; iv presence of a somatosensory ‘aura’ that can be followed by a motor seizure or by a PAS in the same body segment. However, ictal EEG recording remains of paramount importance to establish a correct diagnosis. PAS associated with ictal EEG discharges should allow, without major difficulties, the differential diagnosis with TIA, migraine with prolonged aura and alternating hemiplegia, which are never accompanied by ictal discharges. Motor impairment due to frequent paroxysmal discharges involving the sensorimotor cortex Bennett and coworkers (1982) reported three children, aged 3, 7 and 13 years with different etiologic conditions who experienced transient gait and limb ataxia. Two of these patients had epilepsy, treated with AEDs in therapeutic range. The third patient had no epilepsy and did not receive treatment. During the episodes of transient ataxia all patients underwent EEG recordings that showed frequent bursts of SW activity. Adjustment of AED regimen produced dramatic clinical and EEG improvement. Neville and Boyd (1995) reported two children who developed a gait disorder that cleared on corticosteroid treatment. Both children had normal development and normal MRI. One of them had complex partial seizures from age 5 and gradually developed a persistent dystonic posturing of the right hemibody, broad based walking and deterioration of speech. His EEG showed frequent left frontotemporal SW discharges clearly increased during sleep. The other child’s gait disorder consisted of transient choreoathetoid movements of both lower limbs on attempt to walk. EEG recordings showed frequent SW discharges at the vertex, which were increased by tactile stimulation of the feet or by walking. EEG abnormalities and clinical symptoms cleared with steroid treatment in both children. This report provides a clear example of transient motor dysfunction associated with frequent EEG abnormalities probably involving the sensorimotor cortex. Similarly, in a series of patients with perisylvian polymicrogyria, hemiparesis worsened with increasing EEG abnormalities or seizure frequency (Guerrini et al., 1996). Moreover, some of them, who did not show neurological deficit, developed transient hemiparesis in periods of seizure worsening. Epilepsy with CSWS results from the association of various seizure types, partial or generalized, occurring during sleep, and atypical/atonic absences while awake.

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Patients are almost equally divided between those with a cryptogenic and those with a symptomatic epilepsy (Jayakar & Seshia, 1991). Among symptomatic patients, polymicrogyria is a common association (Guerrini et al., 1998b). The characteristic EEG pattern consists of continuous diffuse spike-waves during slowwave sleep. Duration varies from months to years. Despite the usually benign evolution of seizures, prognosis is guarded because of the appearance of neuropsychological disorders (Patry et al., 1971; Tassinari et al., 1992). The vast majority of children with CSWS experience global cognitive impairment and behavioural problems (hyperkinesia or, rarely, psychotic behaviour); some have motor impairment (Rousselle & Revol, 1995). Occurrence of an aphasic disorder raises the issue of the nosologic boundaries with Landau–Kleffner syndrome (LKS) and supports the hypothesis that LKS is a clinical variant of an electroclinical condition characterized by an encephalopathy associated with ‘electrical status epilepticus during sleep’ (Tassinari et al., 2000; Tassinari & Michelucci, 2000). Reviewing the literature, we identified 16 children or adolescents with motor dysfunction during cryptogenic or symptomatic CSWS syndrome. Motor dysfunction appeared 1 to 3 years after seizure onset, usually concomitant with the finding of CSWS and consisted of hemiparesis (Dalla Bernardina et al., 1989; Veggiotti et al., 1999), ataxia (Dalla Bernardina et al., 1989; Badinand-Hubert et al., 1995), apraxia (Blennow & Ors, 1995; Bulteau et al., 1995; Metz-Lutz et al., 1995; Maquet et al., 1995) or transitory motor neglect (Galletti et al., 1992; Maquet et al., 1995). In four patients an aphasic disorder was associated. In one patient with right motor neglect, continuous EEG abnormalities during sleep were located in the left central area (Galletti et al., 1992). A PET scan with fluorodeoxyglucose was performed in one patient with left hemineglect and apraxia during continuous EEG monitoring. Hypermetabolism was found in the right parietal and temporal cortex with wider distribution during sleep (Maquet et al., 1995). Three patients with hypoxic–ischemic encephalopathy and hemiparesis showed a worsening of motor deficit during the hours following night-time sleep (Veggiotti et al., 1999). During sleep they had continuous abnormalities confined to one hemisphere. Benzodiazepine treatment was partially effective in two patients. Hydrocortisone was administered with good results in three children, but relapse of motor dysfunction was observed in two upon tapering of the steroid (Bulteau et al., 1995; MetzLutz et al., 1995). It is therefore possible that children with CSWS exhibit discrete subsyndromes according to the most prominent cortical deficit. Outcome and drug sensitivity of motor signs do not differ from those of the other manifestations of CSWS. Conceptually the selective or prominent language impairment of Landau–Kleffner

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syndrome would be closely related, differing mainly by the location of neurones predominantly affected by the epileptic dysfunction. (See also the case report session).

Conclusions This chapter outlines the clinico-electrophysiological features of motor dysfunction, such as ENM, PAS, and motor impairments related to the occurrence of paroxysmal epileptic activity in the sensorimotor cortex. These phenomena can pose challenging diagnostic problems, and emphasize the role of appropriate neurophysiological investigations, particularly polygraphic recordings with simultaneous EEG–EMG monitoring, to establish the correct diagnosis. Pathophysiology of this motor dysfunction is only partially understood, although several hypotheses support a central role of cortical structures. Although in most cases these disorders appear to originate from SW-related interference with or without inactivation of systems involved in motor programme and execution, a possible role of cortical active inhibitory mechanisms cannot be excluded in some cases. The pathways mediating epilepsy-related motor dysfunction are still unknown. C A S E R E P O R TS SW-related gait disorder responsive to steroids. Case report 1 This is a 10-year-old boy with moderate mental retardation, partial epilepsy and left hemiparesis due to perinatal hemorrhagic encephalopathy. He was born by a prolonged vaginal delivery at term. Apgar score was 8 at 1 minute and 9 at 5 minutes. On day 3 he developed clonic seizures involving the left hemibody. A CT scan showed intraventricular hemorrhage. Phenobarbital treatment was started. During the following days, no seizures were observed, but the child developed left hemiparesis and posthemorrhagic hydrocephalus. He was treated with a ventriculo-peritoneal shunt on day 40, but was then re-operated several times, because of shunting inefficacy. Finally he developed meningoencephalitis at 12 months due to shunt infection. Motor development was delayed, with sitting at 13 months and independent walking by 3 years. The child spoke simple phrases at 3 years of age and complete sentences at 6 years. He was diagnosed with mild autistic behaviour. Complex partial seizures characterized by eye and head deviation to the left, eventually associated with left arm extension and right arm flexion in a fencing posture, began at 3 years and 5 months of age. They occurred daily and most often presented during sleep. EEG showed isolated spikes on a slow background activity on the right posterior region and rare

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R. Guerrini et al. contralateral independent spikes. Moderate activation of EEG abnormalities occurred during sleep. Magnetic resonance imaging (MRI) showed mildly enlarged ventricles and bilateral posterior gliotic lesions. Carbamazepine, Vigabatrin, Phenobarbital, and Clobazam proved to be only partially effective. From age 4 years 6 months onwards, his parents reported an intermittent gait disorder with worsening of left hemiparesis associated with mild motor dysfunction of the right leg. The child walked on a broad base and was prone to falling. EEG recordings showed remarkable increase in SW activity in bilateral (right more than left) parieto-occipital electrodes during wakefulness and sleep. Frequent right posterior, fast, low-voltage discharges were captured during sleep, representing brief subclinical seizures (Fig. 6.3 left). Gradually, the child’s walking difficulties became continuous, at times making ambulation impossible. At age 6 years and 5 months, hydrocortisone treatment was started, reaching a plateau dose of 20 mg/kg/day, which was maintained for 2 months. The child’s walking improved. His gait was more stable and right-sided motor dysfunction disappeared. A reduction in seizure frequency was also observed. SW activity was markedly reduced and right-cerebral seizure discharges during sleep were not observed (Fig. 6.3 right). Over the following 6 months steroids were tapered. Seizures gradually regained presteroid frequency. Interictal EEG abnormalities increased, becoming subcontinuous during sleep. In the following 3 years his clinical situation remained stable. No further gait disorders were reported. Case report 2 This 6-year-old boy had moderate mental retardation and partial epilepsy. His was born at term by Caesarean section. Motor development was slightly delayed, reaching unaided ambulation by 2 years of age, but expressive language was absent and comprehension limited to simple sentences. Two febrile seizures were reported at age 5 and 17 months and an afebrile seizure at 9 months. All episodes presented upon awakening and were characterized by staring, hypotonia and vomiting. Interictal EEG showed slowing in the right parieto-occipital region. No treatment was initiated until 3 years of age, when a sleep EEG recording showed continuous, bilateral, parieto-occipital SW discharges. MRI showed a vascular dysplastic lesion involving the posterior part of the right frontal lobe. The child was then treated with clobazam, ethosuximide, and valproic acid without reduction of EEG abnormalities. His parents reported gradual gait deterioration beginning age 4 years 6 months, with broad-based walking and frequent falling. He became unable to run or to climb stairs. An awake EEG showed frequent bilateral parietal SW, which became diffuse and continuous during sleep (Fig. 6.4 left). Hydrocortisone treatment (15 mg/kg/day) was maintained for 3 months. Repeated EEG showed a gradual reduction of SW discharges, which became fragmented and restricted to posterior quadrants during sleep (Fig. 6.4 right). The boy’s gait gradually improved and after 3 months of treatment he started running and climbing stairs again. The steroids were then tapered over 2 months. His parents once more noted a mild gait disturbance, and sleep EEG was characterized by the reappearance of CSWS. Subsequent cycles of steroid treatment produced transient benefits, followed by relapses.

Fig. 6.3

EEG recording during sleep in patient 1. Left: before hydrocortisone treatment, subcontinuous SWs are recorded bilaterally from anterior electrodes. Frequent rhythmic discharges are present in right parieto-occipital leads. Right: on hydrocortisone treatment, SWs are clearly reduced and right parieto-occipital ictal discharges have ceased. L. Delt.left deltoid; R. Delt.right deltoid.

Fig. 6.4

EEG recording during sleep in patient 2. Left: frequent SW discharges involving bilateral, parieto-occipital electrodes before hydrocortisone therapy. Right: EEG abnormalities are clearly reduced on hydrocortisone. L. Delt.left deltoid; R. Delt.right deltoid.

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Nocturnal frontal lobe epilepsy Paolo Tinuper1, Elio Lugaresi1, Federico Vigevano2 and Samuel F. Berkovic3 1

Institute of Clinical Neurology, University of Bologna, Italy Section of Neurophysiology, Bambino Gesù Children’s Hospital, Rome, Italy 3 Department of Neurology, Austin and Repatriation Medical Centre, University of Melbourne, Victoria, Australia 2

Introduction Epilepsy is a chronic condition characterized by recurring seizures. In most epileptic syndromes spontaneous seizures are random, i.e they occur independently from the patient’s state of arousal. However, the role of the sleep state, and particularly different stages of sleep, in facilitating ictal or interictal discharges, has been the object of several studies and recent reviews (Shouse et al., 1997a,b). The synchronized EEG activity and preserved muscular tone characterizing the early stage of sleep facilitate the propagation of interictal discharges and seizure onset, whereas inhibited muscular tone and desynchronized EEG activity prevent seizure onset during Rem sleep. Moreover, thalamocortical drive evoking physiological sleep transients (K-complexes and spindles activity) and burst-pause firing in cortical neurons during NRem sleep may facilitate the spread of bisynchronous discharges in generalized epilepsies. The most common epileptic situations related to sleep include some forms of idiopathic generalized epilepsies such as epilepsy with grand mal (GTC) on awakening and juvenile myoclonic epilepsy (JME) in which myoclonic jerks or generalized convulsion appear typically after awakening and are provoked by sleep deprivation. Sleep is a strong seizure trigger in benign epilepsy of childhood with centrotemporal spikes (BECT) a form of idiopathic (with age-related onset) localization-related epilepsies, in which partial motor seizures occur in sleep in 70–80% of cases and interictal spikes appear only during sleep in about 30% of patients. Other very rare conditions in which sleep plays a fundamental role in the pathogenetic epileptic process are the Landau–Kleffer syndrome (LKS) and the situation Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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named continuous spikes and waves during sleep (CSWS). In these conditions, the almost continous paroxysmal EEG activity causes inappropriate contacts in functional brain areas interacting with age-dependent synaptogenesis and, consequently produces acquired speech disturbance in LKS and cognitive and behavioural disturbances in CSWS. Although localization-related seizures in lesional or cryptogenetic epilepsy usually have a random occurrence, attacks may acquire a regular circadian rhythm during life in some patients and tend to appear preferentially during sleep. Videopolysomnographic monitoring techniques have yielded much insight into seizures occurring during sleep. This chapter describes a relatively new epileptic syndrome with seizures occurring almost exclusively during sleep, i.e. nocturnal frontal lobe epilepsy. Historical review of nocturnal frontal lobe epilepsy In 1977 Pedley and Guilleminault first reported some cases of episodic nocturnal wandering (ENW). The bizarre and complex motor pattern of these episodes, reminiscent of orbital frontal seizures previously described by Tharp (1972), and the positive response to antiepileptic drugs suggested an epileptic origin despite inconclusive EEG recordings. This was the hypothesis (Maselli et al., 1988; Oswald, 1989), but later the epileptic nature of the ENW was conclusively demonstrated (Plazzi et al., 1995). Under the term hypnogenic or nocturnal paroxysmal dystonia (NPD), Lugaresi (1981–1986) described some cases in which polygraphic recordings under audiovisual control demonstrated NRem sleep-related dystonic dyskinetic attacks clearly characterized by stereotyped features. The clinical pattern suggested a paroxysmal motor disorder of extrapyramidal origin, but the efficacy of antiepileptic drugs and the short duration of attacks were reminiscent of sleep-related epileptic seizures. Clear-cut ictal and interictal EEG discharges were subsequently demonstrated in three cases (Tinuper et al., 1990). A blind comparison of NPD attacks with and without epileptic discharges later demonstrated that the seizures were clinically identical (Meierkord et al., 1993). The epileptic origin of NPD with short-lasting attacks was thus definitely confirmed. Meanwhile, it had also been confirmed that epileptic seizures of orbitofrontal origin are often characterized by complex bimanual bipedal motor activities and rocking movements (Williamson et al., 1985; Wada, 1988). In 1986 Peled and Lavie described some cases in which recurrent paroxysmal awakenings arising from NRem sleep and associated with daytime sleepiness responded to antiepileptic treatment, again suggesting an epileptic origin. Some years later video-EEG recordings in similar cases disclosed that these

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attacks were accompanied by abnormal stereotyped motor patterns and in some cases by ictal and interictal EEG discharges. Paroxysmal arousals (PA) (Montagna et al., 1990) was the term proposed to classify these attacks. PA, NPD and ENW may arise in the same subject, sometimes recurring in quasiperiodic sequences (Montagna, 1992; Sforza et al., 1993). This type of attack is thus part of a spectrum of an epileptic syndrome related to the deep-seated frontal foci. This epileptic syndrome was labelled under the term nocturnal frontal lobe epilepsy by Scheffer et al. (1994, 1995), who also demonstrated that the disorder can be inherited in an autosomal dominant fashion. Clinical aspects of nocturnal frontal lobe seizures The clinical features and semiological aspects of NFLE have been recently reviewed by the Bologna school (Tinuper et al., 1997; Tinuper & Baruzzi, 1999; Provini et al., 1999). A common characteristic is the onset of the episodes from NonRem sleep, mainly during stages 1 and 2. In a series of 100 patients we recorded seizures arising from Rem sleep only in three cases. About one-third of the patients had occasional seizures (identical to the nocturnal ones) during the daytime, but these were very sporadic and occurred for a limited period of the illness. Prolonged polysomnographic recordings coupled with close circuit audio-video monitoring distinguished seizures with different intensity and duration leading the authors to recognize, at least in some patients, a continuity of a spectrum from very short episodes to full-blown seizures, and prolonged seizures sometimes mimicking a sleepwalking attack. NFLE seizures are characterized by a sudden arousal from sleep with a body movement that can start in the limbs, head or trunk, followed by complex, often violent behaviour, sometimes with cycling or kicking, or rocking or repetitive body movements prevalent at the trunk and legs, mimicking sexual or defensive behaviour. The patients may vocalize, scream or swear during the attack. Fear is the expression frequently observed in their faces. ‘Pure’ myoclonic or clonic jerks are rarely observed whereas limbs tend frequently to assume a dystonic or tonic posture, always asymmetric in the four limbs. Secondary generalization with generalized tonic–clonic seizures is very rare. Normally, there is no postictal confusional state and patients go back to sleep. Seizures are identical in each individual patient and may conserve their stereotypy for years. In some patients, the seizures may be more reminiscent of an involvement of the orbito-basal structures from the ictal discharge (i.e. with bipedal or bimanual ictal activity or with complex semipurposeful or violent behaviour). In other patients, with seizures characterized mostly by an asymmetric tonic–dyskinetic posture involving trunk, head and limbs, an involvement of the supplementary motor area is most convincing. In

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general, however, NFLE seizures may incorporate all the features described in frontal lobe seizures (Tharp, 1972; Geier et al., 1977; Wada & Purve, 1984; Williamson et al., 1985; Delgado-Escueta et al., 1987; Waterman et al., 1987; Ajmone Marsan, 1988; Morris et al., 1988; Wada, 1988; Bancaud & Talairach, 1992; Bleasel & Morris, 1996; So, 1998). On the other hand, apart from the ictal semiology of the attacks, it may be difficult to identify a clearcut interictal focus in NFLE patients on the basis of surface EEG recording, and even ictal recording may fail to detect focalized discharges. In the Bologna series, only half of the patients showed epileptic focal abnormalities in wake and sleep EEGs, sometimes detected only by sphenoidal or zygomatic leads and in the same proportion ictal EEG failed to disclose clear epileptic discharges. Moreover, neuroradiological investigations normally fail to locate the epileptogenic tissue and disclosed structural abnormalities only in 14% of our cases. Characteristically, ictal autonomic changes are remarkable in NFLE seizures, with tachycardia, tachypnea and irregular breathing. Another type of seizure recorded in our patients are very short (about 2 to 20 seconds) attacks characterized by a brief, sudden arousal from sleep. The patients would open their eyes, suddenly sitting up in bed with a frightened expression, sometimes accompanied by a short yell. Limbs may assume short-maintained dystonic or tonic asymmetric posturing. These short attacks were previously named ‘paroxysmal arousals’ (Montagna et al., 1990). Rare seizures were characterized by prolonged attacks (2 to 3 minutes) during which the patients had semipurposeful ambulatory behaviour mimicking a sleepwalking attack. During the seizures the patients would jump, scream, trying to leave the sleep room, with an agitated frightened expression. Motor activity sometimes revealed a dystonic component. During these seizures, the EEG displayed continuous epileptiform activity, predominant on the frontal regions. Due to their similarities with somnambulic attacks these seizures were named epileptic nocturnal wanderings (Plazzi et al., 1995). Reviewing all the video-polygraphic data, we found patients who present only one type of attack but the majority showed, often on the same night, attacks of different duration. However, the onset of the seizures was strictly stereotyped in the same patient, and only the duration and the subsequent manifestation differentiated the seizures. It may be assumed therefore, that in these patients the duration and cortical extension of the ictal discharge provoked different clinical patterns. It has been noted, however, that patients presenting with paroxysmal arousals alone have a better prognosis, seizures during the daytime and secondarily generalized seizures never occur and treatment is not mandatory if seizures, disrupting sleep, do not provoke daytime somnolence.

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Patients with NFLE seizures report a very high frequency of seizures (more than four a week in 60% of cases and often several times (up to 20) on the same night). Video-polygraphy records very frequent episodes not reported by patients or witnesses. Moreover, in 25% of patients, seizures or fragments of seizures tend to recur with a quasiperiodic interval during prolonged sleep portions (Sforza et al., 1993). Periodicity varies from 20 to 120 seconds but in the majority of cases is around 20–40 seconds. During non-Rem sleep K-complexes, muscle tone, heart rate, breathing and blood pressure oscillate every 20–40 seconds probably following a thalamic pacemaker (Lugaresi, 1972). This suggests that K-complexes activate epileptic foci within the frontal mesial structures (Tinuper et al., 1990; Sforza et al., 1993). I L LU ST R AT I V E C A S E R E P O R T A 27-year-old right-handed man, without any personal or familial antecedents (apart from a second cousin with a grand mal seizure during sleep at age 20) began to present diurnal seizures, at age 24, characterized by brief episodes of vertigo accompanied by a feeling of instability. These seizures occurred many times per day and disappeared at age 26, when seizures during sleep appeared. They consisted of a sudden arousal accompanied by the same sensation of vertigo followed by an abrupt abduction of the four limbs in a tonic posture sometimes followed by myoclonic jerks. Seizures lasted less than a minute but occurred three or four times per night. They were considered generalized tonic–clonic seizures and treated unsuccessfully with phenobarbital, valproic acid, carbamazepine, gammavinyl-gaba and clobazam in various associations. Several interictal EEG tracings during wake have been reported to be normal. Nuclear magnetic resonance of the brain disclosed an arachnoid cyst in the cistern of the cerebellar vermis. Neurological examination was normal. During prolonged video-polygraphic monitoring of a diurnal nap several seizures were recorded during non-Rem sleep. They consisted (Fig. 7.1) of a sudden arousal with opening of the eyes and forward flexion of the head; the patient grasped the arms of the chair with repetitive pelvic movements and visual grimaces. Thereafter, he raised his right arm stiffened over his head while his left arm was flaying; his legs were abduced with the left leg flexed in a dystonic posture. This tonic–dystonic asymmetric posture with superimposed mild vibration, without jerks was maintained for about 15 seconds. The seizures lasted 30 to 40 seconds. During the seizures, the patient was unable to reply but did not lose consciousness. No postictal deficit was detected. On EEG (Fig. 7.2), background activity flattened 1.5 seconds before the first ictal movement. A fast, low amplitude activity was detected over frontal and vertex regions, but immediately masked by muscle artefacts. Breathing irregularities and tachycardia accompanied the episodes. Postictal slowing was absent. During slow non-Rem sleep, the patient presented very frequent minor episodes characterized only by a sudden arousal with eye opening and a brief, rapid abduction of his arms, more evident on the right (Fig. 7.3). These minor attacks corresponded, on EEG, to a

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Fig. 7.1

Consecutive pictures taken from the video recording of the seizure. See text for description.

Fig. 7.2

Polygraphic recording of the seizure: note the K-complex preceding the ictal onset (arrow) and the fast EEG rhythm coinciding with the contraction of the deltoid muscles.

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Fig. 7.3

Consecutive pictures taken from the video recording of one seizure limited to a sudden arousal with eye opening and minor motor activity. K-complex followed by a brief fast rhythm over the anterior regions (Fig. 7.3). Polygraphically and clinically these episodes were stereotyped and had a quasiperiodic occurrence (every 40 seconds) during some sleep portion (Fig. 7.4). They represent the initial part of the complete seizure described above. These minor episodes have not been noted by the family. On the basis of VideoEEG recording the diagnosis of nocturnal frontal lobe epilepsy was made and therapy with oxacarbazepine started with an improvement of the clinical picture.

Nocturnal frontal lobe epilepsy in children Nocturnal frontal lobe seizures often arise in childhood, with a third of published cases occurring before puberty. Some reports in the literature are devoted to childhood series with onset even in the first years of life (Vigevano & Fusco, 1993). The semiology of the seizures is similar to that described in adults. There is always a postural type tonic contraction which forces the child into uncustomary positions, occasionally followed by repetitive movements of the limbs and trunk. Sometimes the children present only brief tonic contractions while awake or asleep, subjectively described as ‘shivers’ or ‘undefinable feelings’ running through the whole body or parts of it. In these cases, the epileptic nature of the phenomena is not

Fig. 7.4

Polygraphic recordings of three minor seizures show the stereotypy of the EEG and the motor pattern. Note the recurrence of seizures every 40 seconds.

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always readily understood. ‘Minimal’ episodes are sometimes mistaken for psychological manifestations and the child is then treated for psychiatric problems. Diagnosis is easier when the seizures include more evident motor manifestations. Onset is often dramatic: the child may have seizures, while awake or asleep, that are initially isolated but then increasingly more frequent, to the point of recurring every 2 to 3 days. In some cases, the seizure frequency at onset may suggest acute central nervous system damage. In cases with seizures exclusively during sleep, the ictal phenomena are sometimes erroneously interpreted as parasomnia, such as pavor nocturnus or sleepwalking. The incidence of parasomnia in the families of some patients is particularly high and it cannot be excluded that the relatives actually had frontal seizures. The seizures occur prevalently during sleep with a very high frequency, while seizures during arousal are sporadic. Cases resistant to treatment sometimes present seizure exacerbation while awake, with repetitive seizures for some hours after waking. Ictal EEG in children demonstrates more frequently than in adults a clearly recognizable pathologic pattern, characterized for the most part by rapid activity on the alpha or beta band, diffuse or more evident on one side, with increasing amplitude and synchronous ending on the two hemispheres (Vigevano & Fusco, 1993). Brief subclinical discharges of rapid diffuse activity are often recorded during sleep phases I and II. Interictal EEG is generally normal, or shows rapid spikes in the vertex region or frontal regions. Pediatric series include cases with recovery before puberty. Resistance to treatment is observed in 50% of cases. Some patients are seizure-free for months and sometimes years. The most effective drug is carbamazepine. Progressive psychic impairment, with behavioural disturbance, language regression and occasionally psychotic behaviour, can be observed in drug-resistant cases with frequent seizures. Genetics of NFLE The syndrome of NFLE may be associated with structural lesions within the frontal lobe but frequently no abnormality is found on high resolution magnetic resonance imaging. While many non-lesional cases have no known etiology, some cases have a family history of seizures (Lugaresi et al., 1986; Vigevano & Fusco, 1993). Detailed study of some familial cases showed that the affected family members also had a seizure pattern of NFLE and that the trait was inherited in an autosomal dominant fashion with a penetrance of 70% (Scheffer et al., 1994, 1995). There is a marked variation in severity amongst family members. This makes the familial nature easy to overlook as relatives of the proband may be only mildly affected.

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Following the initial recognition of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in Australian, English and French Canadian families in 1994 (Scheffer et al., 1994, 1995), numerous other families were identified in Europe (particularly in Italy) and elsewhere around the world (Oldani et al., 1996, 1998; Magnusson et al., 1996; Thomas et al., 1998; Khatami et al., 1998; Provini et al., 1999; Hirose et al., 1999; Saenz et al., 1999; Stenlein et al., 2000; and unpublished observations). A very large family with over 20 affected individuals was identified in South Australia and molecular genetic studies established linkage to chromosome 20q13.2–q13.3 in 1995 (Phillips et al., 1995). The genetic defect was subsequently isolated to the a4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) by a positional candidate approach in the same year (Steinlein et al., 1995). A missense mutation of a highly conserved amino acid residue in the M2 domain (Ser248Phe; amino acid numbering referring to the Torpedo a subunit) was found. The mutation was shown to be present in all affected family members, but was not found in 333 independent control individuals (Steinlein et al., 1997). Subsequently, the same mutation was observed in families of Spanish and Norwegian origin (Saenz et al., 1999; Steinlein et al., 2000). In 1997, a different mutation (named 776ins3) in the same gene was identified in an unrelated Norwegian family. An insertion mutation, rather than a point mutation was found. Again, the mutation was placed in the channel-forming M2 domain, adding an additional leucine to the extracellular end of the domain (Steinlein et al., 1997). A third mutation in this gene (Ser252Leu) was recently described in a Japanese family with ADNFLE (Hirose et al., 1999). For the mutations, Ser248Phe and 776ins3, the properties of the normal receptor composed of a4 and b2 subunits and the mutant receptors where a4 subunits carried one of the mutations were compared by means of cDNA manipulation and expression in Xenopus oocytes. Both mutations were shown to have major functional effects in this expression system but, surprisingly, the effects of the two mutations were somewhat different in terms of receptor affinity for acetylcholine and desensitization kinetics. However, both mutations probably impair calcium entry into cells and render the receptor less efficient (Weiland et al., 1996; Bertrand et al., 1998). Study of a large number of ADNFLE families now suggests that abnormalities in CHRNA4 on chromosome 20 are an uncommon cause of this syndrome (Hayman et al., 1997; Phillips et al., 1998). There is evidence of a second locus on chromosome 15q, where there is a cluster of three other nicotinic receptor subunits, but mutations have not yet been identified. Examination of apparently sporadic nonlesional cases of NFLE has not, to date, revealed evidence of nicotinic receptor gene mutations.

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Ajmone Marsan, C. (1988). Seizures originating from the orbital cortex of the frontal lobe. Epilepsia, 29, 208. Bancaud, J. & Talairach, J. (1992). Clinical semiology of frontal lobe seizures. In Frontal Lobe Seizures and Epilepsies, ed. P. Chauvel, A.V. Delgado-Escueta, E. Halgren & J. Bancaud, Advances in Neurology, vol. 57. pp. 3–58. New York: Raven Press. Bertrand, S., Weiland, S., Berkovic, S.F., Steinlein, O.K. & Bertrand, D. (1998). Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy. British Journal of Pharmacology, 125, 751–60. Bleasel, A.F. & Morris, H.H. (1996). Supplementary sensorimotor area epilepsy in adults. In Supplementary Sensorimotor Area, ed. H.O. Luders, pp. 271–84. Advances in Neurology, vol 70, Philadelphia: Lippincott-Raven. Delgado-Escueta, A.V., Swartz, B.E., Maldonado, H.M., Walsh, G.O., Rand, R.W. & Halgren, E. (1987). Complex partial seizures of frontal lobe origin. In Presurgical Evaluation of Epileptics, ed. H.G. Wieser & C.E. Engel, pp.268–99. New York: Springer-Verlag. Geier, S., Bancaud, J., Talairach, J., Bonis, A., Szikla, G. & Enjelvin, M. (1977). The seizures of frontal lobe epilepsy. Neurology, 27, pp. 951–8. Hayman, M., Scheffer, I.E., Chinvarun, Y., Berlangieri, S.U. & Berkovic, S.F. (1997). Autosomal dominant nocturnal frontal lobe epilepsy: demonstration of focal frontal onset and intrafamilial variation. Neurology, 49, 969–75. Hirose, S., Iwati, H., Akiyoshi, H. et al. (1999). A novel point mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology, 53, 1749–53. Khatami, R., Neumann, M., Schulz, H. & Kolmel, H.W. (1998). A family with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. Journal of Neurology, 245, 809–10. Lugaresi, E. & Cirignotta, F. (1981). Hypnogenic paroxysmal dystonia; epileptic seizures or a new syndrome? Sleep, 4, pp. 129–38. Lugaresi, E., Coccagna, G., Mantovani, M. & Lebtrun, R. (1972). Some periodic phenomena arising during drowsiness and sleep in man. Electroencephalography and Clinical Neurophysiology, 32, 701–5. Lugaresi, E., Cirignotta, F. & Montagna, P. (1986). Nocturnal paroxysmal dystonia. Journal of Neurology, Neurosurgery and Psychiatry, 49, 375–80. Magnusson, A., Nakken, K.O. & Brubakk, E. (1996). Autosomal dominant frontal epilepsy. Lancet, 347, 1191–2. Maselli, R.A., Rosemberg, R.S. & Spire, J.P. (1988). Episodic nocturnal wanderings in non-epileptic young patients. Sleep, 11, pp. 156–61. Meierkord, H., Fish, D.R., Smith, S.J., Scott, C.A., Shorvon, S.D. & Marsden, C.D. (1993). Is nocturnal paroxysmal dystonia a form of frontal lobe epilepsy? Movement Disorders, 8, 38–42. Montagna, P., Sforza, E., Tinuper, P., Cirignotta, F. & Lugaresi, E. (1990). Paroxysmal arousal during sleep. Neurology, 40, pp. 1063–6.

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P. Tinuper et al. nicotinic acetylcholine receptor a4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nature Genetics, 11, 201–3. Steinlein, O.K., Magnusson, A., Stoodt, J. et al. (1997). An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Human Molecular Genetics, 6, pp. 943–8. Steinlein, O.K., Stoodt, J., Mulley, J., Berchovic, S.F., Sheffer, I.E. & Brodtkorb, E. (2000). Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy. Epilepsia, 41, 529–35 Tharp, B.R. (1972). Orbital frontal seizures. A unique electroencephalographic and clinical syndrome. Epilepsia, 13, 627–42. Thomas, P., Picard, F., Hirsch, E., Chatel, M. & Marescaux, C. (1998). Autosomal dominant nocturnal frontal lobe epilepsy. Reviews in Neurology, 154, 228–35. Tinuper, P. & Baruzzi, A. (1999). Seizures during sleep. In Epilepsy: Problem Solving in Clinical Practice, ed. D.Schmidt & S. Schachter, pp. 5–17. London: Martin Dunitz. Tinuper, P., Cerullo, A., Cirignotta, F., Cortelli, P., Lugaresi, E. & Montagna, P. (1990). Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures. Epilepsia, 31, 549–56. Tinuper, P., Plazzi, G., Provini, F., Cerullo, A. & Lugaresi, E. (1997). The syndrome of nocturnal frontal lobe epilepsy. In Somatic and Autonomic Regulation in Sleep, ed. E. Lugaresi & P.L. Parmeggiani, pp. 125–35. Milano: Springer. Vigevano, F. & Fusco, L. (1993). Hypnic tonic postural seizures in healthy children provide evidence for a partial epileptic syndrome of frontal lobe origin. Epilepsia, 39, 110–19. Wada, J.A. & Purve, S.J. (1984). Oral and bimanual-bipedal activity as an ictal manifestation of frontal lobe epilepsy. Epilepsia, 25, 668. Wada, J.A. (1988). Nocturnal recurrence of brief, intensely affective vocal and facial expression with powerful bimanual, bipedal, axial, and pelvic activity with rapid recovery as manifestations of mesial frontal lobe seizure. Epilepsia, 29, 209. Waterman, K., Purves, S.J., Kosaka, B., Strauss, E. & Wada, J.A. (1987). An epileptic syndrome caused by mesial frontal lobe seizure foci. Neurology, 37, 577–82. Weiland, S., Witzemann, V., Villarroel, A., Propping, P. & Steinlein, O. (1996). An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics. FEBS Letters, 398, 91–6. Williamson, P.D., Spencer, D.D., Spencer, S.S., Novelly, R.S. & Mattson, R.H. (1985). Complex partial seizures of frontal lobe origin. Annals of Neurology, 18, 497–504.

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Motor cortex hyperexcitability in dystonia Mark Hallett Human Motor Control Section NINDS, National Institutes of Health, Bethesda, MD, USA

Clinical features of dystonia Dystonia is a disorder characterized by involuntary movements of sustained muscle contractions, causing prolonged movements or abnormal postures. Movements are often twisting in nature, meaning rotatory about the long axis of a body part. Some patients may also have quick movements, called myoclonic dystonia, or tremor, but ordinarily there will have to be some sustained movements for dystonia to be recognized as such. These quick movements particularly might be confused with epileptic phenomena. Dystonia can be present during rest, but in general is more likely to appear when the patient is engaged in voluntary activity. Voluntary movements are slow, clumsy, and characterized by overflow (excessive activity in muscles not needed for the task). Dystonia can be present in any part of the body, and can be classified as focal, segmental, multifocal, generalized, or hemidystonia. Focal means that one body part is affected and includes conditions such as blepharospasm, oromandibular dystonia, adductor spasmodic dysphonia, spasmodic torticollis, and writer’s cramp. Segmental implies two or more contiguous regions such as involvement of a whole limb with the associated part of the trunk. Hemidystonia denotes one side of the body. Hereditary childhood onset dystonia (idiopathic torsion dystonia, DYT1) most commonly starts between 6 and 12 years of age with dystonia of the foot while walking. The illness is then slowly progressive and becomes generalized. The disorder is usually autosomal dominant with reduced penetrance both in Jews and nonJews (Bressman et al., 1994a). The abnormal gene, located on chromosome 9q, produces a protein called torsin A, whose function is not yet known (Ozelius et al., 1997). Genetic testing is possible. There are also other genes for autosomal dominant dystonia, even with clinically similar presentations (Bressman et al., 1994b). Segawa’s disease or hereditary progressive dystonia with marked diurnal Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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fluctuation is another childhood onset, autosomal dominant disorder with a number of clinical characteristics that are helpful in diagnosis. The disorder is much better in the morning and after a rest. Signs and symptoms are generalized and there is often an appearance of spasticity as well as dystonia. These patients respond well to small doses of levodopa. The etiology for the disorder is most commonly a mutation in the GTP cyclohydrolase I gene which leads to a deficiency in the production of dopamine (Ichinose et al., 1994), but mutations in the tyrosine hydroxylase gene can also be responsible (Ludecke et al., 1995). A number of other types of dystonia are genetic. Myoclonic dystonia is an autosomal dominant syndrome where symptoms include dystonic myoclonus as well as more prolonged spasms (Gasser et al., 1996). Tremor, similar to essential tremor, may also be present. There is often a marked response to ethanol. There are some families with autosomal recessive inheritance of torsion dystonia, but this is rare. There is an X-linked, recessive dystonia-parkinsonism called Lubag (Waters et al., 1993), primarily found in the Philippine Islands. Dystonia can also be psychogenic (Lang, 1995). The focal dystonias are usually sporadic and occur in later life. Patients may have more than one focal dystonia, although progression to generalized disease is uncommon. There may be a genetic basis, but, if so, the penetrance is very reduced. One family with spasmodic torticollis has a genetic linkage to chromosome 18p (Leube et al., 1996). Secondary dystonia can be caused by a variety of neurologic disorders including Parkinson’s disease, Wilson’s disease, gangliosidoses, leukodystrophies, Leigh’s disease, Hallervorden–Spatz disease, the juvenile form of Huntington’s disease, corticobasal ganglionic degeneration and brain lesions. The overwhelming preponderance of lesions that cause dystonia are in the basal ganglia or its pathways. Lesions in the putamen, caudate and thalamus can give rise to dystonia (Marsden et al., 1985; Pettigrew & Jankovic, 1985; Bathia & Marsden, 1994). Dystonia can be a manifestation of a paroxysmal disorder. These disorders are covered elsewhere in this volume, but it is worth noting here that paroxysmal dystonia can be a manifestation of epilepsy. It is now recognized that paroxysmal nocturnal dystonia is really a frontal lobe epilepsy syndrome. Additionally, however, dystonic posturing can be a component of a partial seizure. Limb rigidity contralateral to a mesial temporal lobe seizure focus is a common feature (Williamson et al., 1998), and may actually help to separate this site of origin from a neocortical temporal focus, where such dystonia is less common (Foldvary et al., 1997). Mesial temporal origin with spread into the basal ganglia for dystonia is suggested with subdural recordings (Kotagal et al., 1989), SPECT (Newton et al., 1992), and PET (Dupont et al., 1998). The ‘4-hemi’ syndrome of posthemiplegic hemidystonia, hemiatrophy and partial seizures commonly has lesions in the basal ganglia

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(Thajeb, 1996). Of course, other parts of the brain may also generate dystonic postures. Hemitonic seizures with arm elevation and paroxysmal hemispasm may arise from a supplementary motor area (SMA) focus (O’Neil et al., 1991). Physiology How the central nervous system produces dystonia has been mysterious. It seems appropriate to start by examining the involuntary movements themselves. Several observations over many years have shown that dystonic movements are characterized by an abnormal pattern of EMG activity with cocontraction of antagonist muscles and overflow into extraneous muscles. Cohen and Hallett (1998) reported detailed observations on 19 patients with focal dystonias of the hand, including writer’s cramp and cramp in piano, guitar, clarinet, and organ players. Five features, identified by physiological investigation, were indicative of impaired motor control. The first was cocontraction, which could be in the form of a brief burst or continuous. In repetitive alternating movements at a single joint, antagonist muscles typically alternate firing. The dystonia patients might cocontract even with such quick movements. The second feature was prolongation of EMG bursts. In movements made as quickly as possible, EMG bursts normally last no longer than about 100 ms. The patients had bursts of 200 or 300 ms as well as very prolonged spasms. A third feature was tremor. A fourth was lack of selectivity in attempts to perform independent finger movements, and a fifth was occasional failure of willed activity to occur. Rothwell and colleagues (1983) reasoned that the important problem of excessive cocontraction could be due to deficient reciprocal inhibition, a fundamental process represented at multiple levels of the central nervous system. Reciprocal inhibition is represented even in the spinal cord and can be studied as a spinal reflex. Reciprocal inhibition can be evaluated in humans by studying the effect of stimulating the radial nerve at various times prior to producing an H-reflex with median nerve stimulation. The radial nerve afferents come from muscles that are antagonist to median nerve muscles. Via various pathways, the radial afferent traffic can inhibit motoneuron pools of median nerve muscles. Reciprocal inhibition is reduced in patients with dystonia, including those with generalized dystonia, writer’s cramp, spasmodic torticollis, and blepharospasm (Rothwell et al., 1983; Nakashima et al., 1989a; Panizza et al., 1989, 1990; Deuschl et al., 1992; Chen et al., 1995). Valls-Solé & Hallett (1995) have evaluated the effects of radial nerve stimulation on the EMG activity of the wrist flexor muscles during a sustained contraction. A sequence of inhibition, excitation and inhibition was found, and the first inhibitory period was reduced in patients with simple writer’s cramp. This demonstrates reduced reciprocal inhibition during movement. Other spinal and brainstem reflexes have been studied, and a common result is

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that inhibitory processes are reduced. Another example that has been extensively studied is the blink reflex. Abnormalities of blink reflex recovery were first identified for blepharospasm (Berardelli et al., 1985), and have also been demonstrated in generalized dystonia, spasmodic torticollis, and spasmodic dysphonia (Cohen et al., 1989). In the last two conditions, abnormalities can be found even without clinical involvement of the eyelids. Similarly, abnormalities are seen with perioral reflexes (Topka & Hallett, 1992) and exteroceptive silent periods (Nakashima et al., 1989b). Reduction of spinal cord and brainstem inhibition is an important mechanism in dystonia, but the fundamental disturbance would more likely be an abnormal supraspinal command signal than disordered spinal circuitry. Sensory dysfunction

On first appearance, dystonia is a movement disorder. It is characterized by abnormal postures and movements. Sensation seems normal. There are clues, however, that sensory function may not be completely normal and that sensory features are important (Hallett, 1995). Since the sensory system is an important influence on the motor system, abnormalities of the sensory system could be relevant in causing motor dysfunction. Sensory tricks can relieve a dystonic spasm. The most commonly noted is the geste in spasmodic torticollis where, for example, a finger placed lightly on the face will neutralize the spasm. Such tricks are seen in all forms of dystonia. Pressure on the eyelids might improve blepharospasm, a toothpick in the mouth might relieve tongue dystonia, and sensation applied to parts of the arm might improve a writer’s cramp. On the other hand, sensory stimulation might trigger dystonia. This might be called a reverse geste. Examples include a tart taste producing tongue dystonia or a loud noise producing spasmodic torticollis. Sensory symptoms may well precede the appearance of dystonia (Ghika et al., 1993). Common examples would be a gritty sensation in the eye preceding blepharospasm and irritation of the throat preceding spasmodic dysphonia. Photophobia is an example of distorted sensation. In some situations, patients may say that they made voluntary repetitive movements in order to relieve the sensory symptom, but the movements eventually got out of voluntary control. Abnormal sensory input might well be a trigger for dystonia. Trauma to a body part is often a precedent to dystonia of that part. A blow to the head might precede torticollis, irritations of the eye are common in blepharospasm, and a deep cut of the hand might occur just before writer’s cramp develops. There may be an important problem with processing muscle spindle input. In patients with hand cramps, vibration can induce the patient’s dystonia (Kaji et al., 1995b). Cutaneous input similar to that which produces the sensory trick can reverse the vibration-induced dystonia. Conversely, both action-induced and

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vibration-induced dystonia can be improved with lidocaine block of the muscle that reduces sensory input. The brain response to somatosensory input is abnormal in dystonia. This can be demonstrated with PET studies (Tempel & Perlmutter, 1990, 1993) and evoked potential studies using EEG (Reilly et al., 1992). In addition, studies of sensory receptive fields of thalamic neurons in humans with dystonia show expanded regions where all cells respond to the same passive movement (Lenz et al., 1999). Mapping of cortical sensory areas of the different fingers is abnormal in dystonia; this is potentially consistent with the idea that there is abnormal cortical plasticity (Bara-Jimenez et al., 1998). Lastly, there is some evidence that there might be subtle abnormalities of sensation in patients with dystonia. The best evidence is for an abnormality of kinesthesia, the sense of movement of body parts (Grunewald et al., 1997) and cutaneous sensation (Bara-Jimenez et al., 2000). Cortical motor dysfunction

There are several abnormalities of the cortical motor system that suggest something is deficient. Movement-related cortical potentials associated with self-paced finger movement in patients with hand dystonia show a diminished NS’ component (thought to be generated in the motor cortex) (Deuschl et al., 1995; van der Kamp et al., 1995). A focal abnormality of the contralateral central region was confirmed with an analysis of event-related desynchronization of the EEG prior to movement, which showed a localized deficiency in desynchronization of beta frequency activity (Toro et al., 2000). These results are consistent with reduced excitability of the primary sensorimotor region. Feve et al. (1994) studied movement-related cortical potentials in patients with symptomatic dystonia including those with lesions in the striatum, pallidum and thalamus. With bilateral lesions, patients showed deficient gradients for the bereitschaftspotential and NS’ bilaterally and lack of vertex predominance for the bereitschaftspotential and contralateral predominance for NS’. With unilateral lesions, the problem was worse for the symptomatic hand. These results confirm reduced excitability of the primary sensorimotor cortex, but are more extensive than what Deuschl et al. (1995) found for their more mildly affected patients with idiopathic dystonia. The contingent negative variation (CNV) is the EEG potential that appears between a warning and a go stimulus in a reaction time task. The CNV shows deficient late negativity with head turning in patients with torticollis (Kaji et al., 1995a) and for hand movement in patients with writer’s cramp (Ikeda et al., 1996). The late negativity represents motor function similar to the movement-related cortical potential. Ceballos-Baumann et al. (1995) have studied voluntary movement in patients

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with dystonia using blood flow PET. The motor task was a freely chosen direction of joystick movement with pacing tones every 3 seconds. Depressed activity compared with normal was seen in the caudal SMA and bilateral primary sensorimotor cortex. Significant overactivity compared with normal was present in many sites including the contralateral lateral premotor cortex, rostral SMA (or pre-SMA), anterior cingulate area, ipsilateral dorsolateral prefrontal cortex and contralateral lentiform nucleus (primarily the putamen). Studies by this same group with handwriting in patients with focal hand dystonia yielded similar results (CeballosBaumann et al., 1997). Ibáñez et al. (1999) looked at several manual tasks in patients with focal hand dystonia using blood flow PET. Controls and patients were scanned during sustained contraction, tapping and writing with the right hand. In controls and patients, significant increases of rCBF were observed for each of the tasks in areas already known to be activated in motor paradigms. The betweengroup comparison disclosed less activation in writer’s cramp patients for a number of areas for all three tasks. This decrease reached significance for the somatosensory cortex during the sustained contraction task and for the premotor cortex bilaterally, cingulate cortex and SMA during writing. There are a number of studies pointing to hyperexcitability of the motor cortex. Transcranial magnetic stimulation (TMS) shows increased excitability of the motor cortex (Ikoma et al., 1996). There was no change in the motor threshold, nor was there any abnormality of the motor evoked potential (MEP) size with increase in the level of background contraction. There was, however, an abnormal increase in MEP size with increasing stimulus intensity (Fig. 8.1). Ikoma et al. (1995) and Byrnes et al. (1998) also found enlarged motor maps for dystonic muscles. Another result pointing to hyperexcitability of the motor cortex is that intracortical inhibition is deficient in patients with hand dystonia. Ridding et al. (1995) studied intracortical inhibition with the ‘double pulse paradigm’. MEPs are inhibited when conditioned by a prior subthreshold TMS stimulus to the same position at intervals of 1 to 5 ms. Inhibition was less in both hemispheres of patients with focal hand dystonia (Fig. 8.2). Inhibition can also be evaluated with double pulses at longer intervals with the muscle under study either at rest or contracted. Chen et al. (1997b) investigated this type of inhibition in patients with writer’s cramp and found a deficiency only in the symptomatic hand and only with background contraction. This abnormality is particularly interesting since it is restricted to the symptomatic setting, as opposed to many other physiological abnormalities in dystonia that are more generalized. Chen et al. (1997b) also found that the silent period following a MEP was slightly shorter for the symptomatic hemisphere in patients with focal hand dystonia. A nonsignificant trend was also seen by Ikoma et al. (1996) earlier. Moreover, the silent period is shorter during a dystonic contraction than during a voluntary

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Fig. 8.1

Change in the mean percentage of the area of the MEP to the M wave (MEP area%) with increasing stimulus intensity on the dominant side of normal subjects and the affected side of patients with dystonia. The different curves are for different levels of facilitation. (From Ikoma et al., 1996, with permission.)

movement with the same intensity (Filipovic et al., 1997). These results also indicate a deficiency of inhibition. All these results fit together with the hypothesis that deficient inhibition leads to motor cortex hyperexcitability. The hypothesis would be a suitable explanation for the excessive movement seen in patients with dystonia. Strong evidence for lack of cortical inhibition leading to a disturbance of motor function similar to dystonia was obtained by Matsumura et al. in several primate studies (Matsumura et al., 1991, 1992). In the first study, the authors showed that local application of bicuculline, a GABA antagonist, onto the motor cortex led to disordered movement and changed the movement pattern from reciprocal inhibition of antagonist muscles to cocontraction (Matsumura et al., 1991). In the second study, they showed that bicuculline caused cells to lose their crisp directionality, converted unidirectional cells to bidirectional cells, and increased firing rates of most cells including making silent cells into active ones (Matsumura et al., 1992).

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(a)

(b)

Fig. 8.2

Time course of paired pulse effects. (a) Raw data traces from a control subject (top set of three traces) and a representative patient with writer’s cramp (bottom set of two traces). These data were obtained after left hemispheric stimulation and responses were recorded in the relaxed right first dorsal interosseus muscle. In both the control subject and the patient the subthreshold conditioning stimulus evoked no response in the target muscle (see top trace), whereas the test stimulus evoked a clear EMG response of approximately 1 mV (peak to peak amplitude). In the control subject when the conditioning stimulus was given 2 ms before the test stimulus there was clear suppression of the response (bottom trace for the control subject). In the case of the patient there was much less suppression of the test response when conditioned at an interstimulus interval of 2 ms (see bottom trace). (b) Data obtained across all interstimulus intervals in controls and patients (stimulation of both left and right hemisphere). (From Ridding et al., 1995, with permission.)

Motor cortex excitability in epilepsy

Is the hyperexcitability of the motor cortex seen in dystonia related to the hyperexcitability of epilepsy? There are two problems with this question. First, any hyperexcitability might not affect the motor cortex directly unless there is generalized spread. Secondly, most patients with epilepsy are on antiepileptic drugs and these drugs can affect excitability. Drugs that affect Na and Ca channels such as phenytoin, carbamazepine and lamotrigine raise the threshold for TMS to produce MEPs (Ziemann et al., 1996b; Chen et al., 1997a). Drugs that promote GABA action such as lorazepam, vigabatrin, valproate and baclofen increase intracortical inhibition (Reutens et al., 1993; Ziemann et al., 1996a,b). In one study of idiopathic generalized epilepsy, patients were studied prior to starting anticonvulsant drugs. The investigators found that the MEP threshold

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was reduced (Reutens et al., 1993). Two studies have looked at intracortical inhibition with the double-pulse technique. Brown et al. (1996) studied patients with cortical myoclonus, some of whom also had epilepsy, and Caramia et al. (1996) studied patients with juvenile myoclonic epilepsy. Both found reduced intracortical inhibition. Hence, while more data should be obtained, it is possible that patients with epilepsy show both decreased motor threshold and intracortical inhibition. This differs from the findings in dystonia where the motor threshold is normal, and may be the reason that patients with dystonia are not generally epileptic. Origin of the abnormality in the basal ganglia

As noted earlier, most of the clinical evidence points to the basal ganglia as the site of pathology in dystonia. The full effect of the basal ganglia upon the cortex is unknown, but there is some evidence that the basal ganglia do affect cortical inhibition. The first line of evidence of this influence is the effect of basal ganglia disorders on the silent period following TMS. In Parkinson’s disease the silent period is shorter than normal and can be improved with dopaminergic treatment (Cantello et al., 1991; Priori et al., 1994). In Huntington’s disease, the silent period is longer than normal (Roick et al., 1992). Moreover, the clinical assessment of degree of chorea correlates with silent period length. The second line of evidence is the dopaminergic control of short interval, intracortical inhibition. Bromocriptine given to normal subjects will increase the amount of inhibition (Ziemann et al., 1997). Thirdly, thalamocortical influences on the cortex can be both excitatory and inhibitory, and, in some circumstances, the inhibitory influence is more profound (Ashby et al., 1995). It is not unreasonable to think therefore, that if cortical inhibition is diminished in dystonia the basal ganglia could be responsible. There is an interface between dystonia and epilepsy noted in the clinical section; dystonic posturing of a limb can be an epileptic manifestation. In the case of mesial temporal lobe foci, dystonia may result when the epileptic activity invades the basal ganglia. Hence, it is possible that the epileptic activity in this circumstance leads to phenomena similar to those seen in patients with dystonia. A comment on treatment For generalized dystonias, whether or not there is diurnal fluctuation, the first trial of therapy should be levodopa since it would be important not to miss a doparesponsive patient (Fletcher et al., 1993). If improvement does occur, it is often dramatic. Failing that, trials of anticholinergic agents should be next; trihexyphenidyl is commonly chosen. Dose should be very gradually escalated to very high levels (Fahn, 1987). These drugs should modulate the basal ganglia to produce inhibition.

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Drugs promoting GABA action should be the next consideration. That such drugs are useful is compatible with the physiology reported above that inhibition is deficient. A benzodiazepine, such as diazepam, can be added, usually maintaining some level of the anticholinergics. Baclofen should be the third drug to add (Greene & Fahn, 1992). If baclofen does not work orally, consideration should be given to intrathecal baclofen, similar to its use in spasticity (Ford et al., 1996). For severe generalized dystonias unresponsive to standard therapies, surgical intervention can be considered. Thalamotomy may be useful using the target of Vop, just anterior to VIM, the target for tremor (Cardoso et al., 1995). Pallidotomy or deep brain stimulation of the pallidum seems promising in early trials (Lozano et al., 1997; Ondo et al., 1998). How surgery works is unclear, but the findings are consistent with a primary role of the basal ganglia. For focal manifestations, injection of botulinum toxin into the muscles responsible for the abnormal postures can be very effective and is often considered the first choice (Jankovic & Hallett, 1994). Acknowledgement Some of the material in this chapter was taken from previous chapters about dystonia (Hallett, 1995; Hallett, 1998a,b).

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9

The paroxysmal dyskinesias Nardo Nardocci1, Emilio Fernandez-Alvarez2, Nicholas W. Wood3, Sian D. Spacey3 and Angelika Richter4 1

Department of Child Neurology, Istituto Neurologico C. Besta, Milan, Italy Servicio de Neuropediatria, Hospital de San Juan de Dios, Esplugues Barcelona, Spain 3 Department of Clinical Neurology, Institute of Neurology, London, UK 4 Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hanover, Germany 2

Introduction Paroxysmal dyskinesias (PDs) refer to relatively brief attacks of abnormal movements and postures with return to normal between episodes. The abnormal movements consist of dystonia, choreo-athetosis, and ballism, often in combination. The duration is variable, from very short attacks lasting a few seconds to prolonged ones, lasting several hours. The frequency is variable, as is the side of the body involved. PDs can be sporadic or familial with autosomal dominant inheritance or can be symptomatic of different conditions (Bressman et al., 1988; Fahn, 1994; Demirkiran & Jankovic, 1995). Since the first description by Mount and Reback (1940), numerous reports of patients with PDs have followed and several classifications, based on duration of attacks and etiology have been proposed (Lance, 1977; Goodenough et al., 1978; Fahn, 1994). The most recent one classifies PDs according to the precipitating events and distinguishes the following forms: paroxysmal kinesigenic dyskinesias (PKD), paroxysmal non-kinesigenic dyskinesias (PNKD), paroxysmal exertioninduced dyskinesias (PED), paroxysmal hypnogenic dyskinesias (PHD) (Demirkiran & Jankovic, 1995). The purpose of the chapter is to describe the clinical features of the classical forms of PDs including benign paroxysmal torticollis of infants (BPT) and paroxysmal tonic up-gaze deviation of infants (PTUDI) and to review the more recent data on pathophysiology of PDs as derived from genetic studies and from animal model.

Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Clinical features Paroxysmal kinesigenic dyskinesia (PKD)

Most cases of PKD are idiopathic, both familial with autosomal dominant pattern of inheritance or sporadic, but cases of symptomatic PKD are reported (Fahn, 1994; Marsden, 1996; Demirkiran & Jankovic, 1995; Hwang et al., 1998). The commonest cause is multiple sclerosis but rarer causes include head injury, strokes affecting the thalamus and putamen, hypoparathyroidism, hyperthyroidism, HIV infection and perinatal hypoxia (Fahn, 1994; Marsden, 1996; Demirkiran & Jankovic, 1995; Yen et al., 1998; Mirsattari et al., 1999). PKD has been described in association with congenital or acquired medullary abnormalities (Cosentino et al., 1996; Riley, 1996). There is an unexplained male predominance for this condition. The onset usually occurs in late childhood or adolescence, but an earlier or later occurrence has been described (Williams & Stevens, 1963; Demirkiran & Jankovic, 1995). Attacks are precipitated by sudden movement, usually after the patient has been sitting for some time, and consist of any combination of dystonic, choreic, ballistic or athetoid movements. Such dyskinesias can appear on one side of the body or can be bilateral. A sensory aura to the attack, consisting of paresthesia, stiffness or tension sensation is reported (Marsden, 1996). Patients may be unable to speak, but there is never any alteration of consciousness. The attacks are brief, usually lasting only seconds, but rarely they can last up to several hours (Demirkiran & Jankovic, 1995). The attacks can be frequent, occurring up to 100 times per day. The frequency and the severity of attacks may diminish with age. In idiopathic PKD general neurologic examination, interictal and ictal EEG recordings and neuroimaging are normal (Fahn, 1994; Marsden, 1996; Demirkiran & Jankovic, 1995). No specific abnormalities were discovered in the brains of two autopsied PKD patients (Kertesz, 1967; Stevens, 1966). PKD responds to treatment with anticonvulsants, and carabamazepine has been the drug most commonly used. Paroxysmal non-kinesigenic dyskinesia (PNKD)

The majority of cases of PNKD are idiopathic and show an autosomal dominant pattern of inheritance. However, symptomatic PNKD is described due to multiple sclerosis, perinatal hypoxia, stroke or psychogenic (Bressman et al., 1988). The age of onset is variable ranging between 1 and 77 years (Fahn, 1994; Demirkiran & Jankovic, 1995). The attacks can be precipitated by alcohol, coffee or tea and by fatigue and excitement. Attacks are characterized by any combination of abnormal movements, last minutes to hours and may occur as infrequently as once a year or as often as 20 times a day (Fahn, 1994; Marsden, 1996; Demirkiran & Jankovic, 1995). In idiopathic form of PNKD general neurologic examination, interictal and ictal EEG are normal, as brain computer tomography (CT) or magnetic resonance imaging (MRI) scans. The histopathological findings in two cases were normal

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(Lance, 1977). PNKD does not respond to anticonvulsant as well as in PKD. Clonazepam appears to be the most successful agent in reducing the frequency of attacks, but a number of other drugs including Gabapentin (Chudnow et al., 1997) have been tried, sometimes with success. Paroxysmal exertion induced dyskinesia (PED)

PED is a rare disorder and was first described by Lance (1977) under the term of Intermediate Paroxysmal non-kinesigenic dystonic-choreoathetosis. PED is sporadic (Nardocci et al., 1989; Wali, 1992; Bhatia et al., 1997) or familial with usually an autosomal dominant pattern of inheritance (Lance, 1977; Plant, 1984; Nardocci et al., 1989; Kluge et al., 1998). In all patients the attacks are precipitated by prolonged exercise (walking or running from 5 to 20 minutes) and sometimes by passive movement (Plant, 1984). The age of onset ranges between 1 and 30 years. The attacks last from a few seconds up to 2 hours with a frequency between 100 per day (Demirkiran & Jankovic, 1995) and two per month (Fahn, 1994). In the majority of patients the attacks are characterized by pure dystonia with an unilateral, generalised or focal involvement of the body (Demirkiran & Jankovic, 1995; Bhatia et al., 1997). As in other PDs, general neurologic examination, interictal EEG and, when performed, ictal EEG and neuroimaging are normal. Anticonvulsants are not as helpful as in PKD. Paroxysmal hypnogenic dystonia (PHD)

PHD is characterized by the occurrence of involuntary movements only during sleep (Lugaresi & Cirignotta, 1981; Lugaresi et al., 1986). Most patients show an autosomal dominant inheritance (Horner & Jackson, 1969; Fish & Marsden, 1994; Demirkiran & Jankovic, 1995) but sporadic occurrence has been described. The movements appear to be a mixture of dystonia, athetosis and some more rapid flinging movements. The attacks usually last from 15 seconds up to 2 minutes (Lugaresi & Cirignotta, 1981; Fish & Marsden, 1994), and attacks up to 50 minutes have been described (Lugaresi et al., 1986). Both nocturnal and diurnal short duration attacks are reported in a few patients (Horner & Jackson, 1969; De Saint-Martin et al., 1997). Many patients respond to anticonvulsants and recent studies strongly suggest that PHD is a form of frontal lobe epilepsy (Tinuper et al., 1990; Oguni et al., 1992; Meierkord et al., 1992; Fish & Marsden, 1994; Hirsch et al., 1994). Benign paroxysmal torticollis of infants (BPT)

BPT is a transient paroxysmal disorder of infants (Fernàndez-Alvarez, 1998) initially reported in 1969 by Snyder. Episodes of latero, retro or torticollis are the dominant sign (Chutorian, 1974; Sanner & Bergstrom, 1979; Deonna & Martin, 1981). Duration of attacks may vary from minutes to several days and rarely to 2 weeks. Often episodes appear in the morning (Hanukoglu et al., 1984) and may be

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precipitated by changes in posture (Cataltepe & Barron, 1993). Most episodes are accompanied at the onset of the episode by irritability, pallor, vomiting and ataxia. The latter may be the dominant feature (Deonna & Martin, 1981) and sometimes the only manifestation after several episodes of torticollis (Hanuklogu et al., 1984). Neurologic examination between attacks is normal. In more than half of the cases the episodes begin before 3 months of age sometimes as early as in the first week of life (Sanner & Bergstrom, 1979; Hanuklogu et al., 1984) or as late as the age of 30 months (Snyder, 1969). Attacks tend to occur frequently at onset (1–2 monthly) and often with strikingly regular occurrence. They disappear spontaneously before the age of 5 years. Girls are more affected than boys (3:1). A few cases are familial (Lipson & Robertson, 1978; Sanner & Bergstrom, 1979; Deonna & Martin, 1981; Roulet & Deonna, 1988). EEG and neuroimaging are normal. Auditory function and vestibular test have been found to be abnormal by Snyder (1969), but normal by others (Deonna & Martin, 1981; Bratt & Menelaus, 1992). The physiopathology is unclear but vestibular dysfunction is probable. To the title of his paper, Snyder added ‘A possible form of labyrinthitis’. Deonna and Martin (1981) followed patients with BPT in whom the episodes of torticollis were replaced by typical migraine or who developed migraine years after BPT, and, moreover, some children remember a headache in the episodes of torticollis when they are able to express themselves. In at least one case, episodes of vomiting, later followed by headache were observed (Roulet & Deonna, 1988). Familial antecedents of migraine are frequent (Deonna & Martin, 1981; Roulet & Deonna, 1988; Olivan Gonzalvo, 1996). Some patients develop benign paroxysmal vertigo later (Basser, 1964; Dunn & Snyder, 1976) suggesting a vestibular disturbance and a possible pathogenetic link with migraine (Eeg-Olofsson et al., 1982). Differential diagnosis may be difficult in the first attack occurring in a previously healthy infant, and especially if it starts in the newborn period, because BPT is not usually considered at this age. Differential diagnosis also includes dystonic reactions to drugs (Casteels-van Deale, 1979), posterior fossa tumours, cervical spine abnormalities, ocular co-ordination defects and Sandifer syndrome. When the paroxysmal features are confirmed and the child is neurologically normal between episodes, the diagnosis becomes easier. Paroxysmal tonic upgaze deviation of infants

This entity was described in 1988 by Ouvrier and Billson. Some observations (Ahn et al., 1989; Deonna et al., 1990; Echenne & Rivier, 1992; Gieron & Korthals, 1993; Campistol et al., 1993; Sugie et al., 1995; Ruggieri et al., 1998; Guerrini et al., 1998) and a large series (Hayman et al., 1998) have been reported. The disorder is characterized by prolonged episodes lasting hours, rarely days (Deonna et al., 1990; Gieron

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& Korthals, 1993) of sustained or intermittent upward gaze deviation and downbeating nystagmic jerks on attempts to look downward, but with normal horizontal eye movements. The episodes frequently disappear or are alleviated with sleep and are aggravated during daytime with fatigue or infections. Their onset is in the first months of life (most between 4 and 10 months) and experience a spontaneous remission in a few years (30 months in the case of Deonna et al., 1990). Some cases (Ouvrier & Billson, 1988; Deonna et al., 1990) may present, in addition, with episodes of dragging of a limb while others have ataxia during the episodes (Echenne & Rivier, 1992; Campistol et al., 1993). The disorder disappeared between 1 month to 6 years but in one case lasted only 2 days (Hayman et al., 1998). Recurrences with a modified form have been reported (Hayman et al., 1998). Psychomotor retardation or language delay affects up to 60–79% of cases (Hayman et al., 1998). In the cases of Campistol et al. (1993) and Guerrini et al. (1998) a positive family history suggested possible autosomal dominant inheritance but multiple siblings in two families have also been reported (Hayman et al., 1998). Laboratory, neurophysiological and neuroimaging examination are normal. Only one patient with MRI images suggestive of periventricular leukomalacia in spite of a normal perinatal history has been reported (Sugie et al., 1995). Pathological study of one case was normal (Ouvrier & Billson, 1988). -Dopa treatment (150 mg/day) in a few cases (Ouvrier & Billson, 1988; Campistol et al., 1993) resulted in disappearance of the episodes (in 15 days and 3 months in the two cases of Campistol et al., 1993) but this drug has been ineffective in others (Hayman et al., 1998; Ruggieri et al., 1998). Pathophysiology The pathophysiology of PDs is still unknown and the relationship between PDs and epilepsy has not been ruled out. The earliest descriptions of PDs were reported as subcortical epilepsy and reflex epilepsy. However, the extrapyramidal nature of the attacks, the absence of alteration of consciousness during the episodes, the lack of ictal electroencephalographic abnormalities argues against the hypothesis that PDs represent a form of epilepsy. Recent clinical and experimental data from animal models provide further insight on pathophysiology of these group of disorders suggesting that PNKD, PKD, PED, and PHD may result from different pathophysiological mechanisms (Luders, 1996). Animal models of paroxysmal dyskinesias In animals (rodents, cats, monkeys) dyskinetic syndromes can be experimentally induced by drugs or neurolesions (Crossman, 1987; Lorden, 1995; Richter & Loscher, 1998). Those experimental animal models have given insights into the

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neural mechanisms of movement disorders and particularly of basal ganglia functions and dysfunctions. However, animal models of inherited paroxysmal dyskinesias, helpful to increase the knowledge of the pathophysiology and to improve therapies of these movement disorders, are restricted to one rodent model, the genetically dystonic hamster (gene symbol dtsz), in which attacks of dystonic and choreoathetotic movements occur in the absence of any lesions in brain and spinal cord (Loscher et al., 1989; for review, see Richter & Loscher, 1998). The mutant dtsz hamster shows several features in common to PNKD (Demirkiran & Jankovic, 1995; Richter & Loscher, 1998). Like in humans with PNKD, dtsz hamsters exhibit attacks of choreoathetotic and dystonic movements which are precipitated by stress and caffeine, last several hours without alterations of consciousness and without ictal and interictal EEG changes in cortical areas, hippocampus, striatum, globus pallidus or nucleus ruber (Richter & Loscher, 1998). Altered EMG patterns found in dtsz hamsters are comparable to those determined in patients with dystonia (Loscher et al., 1989). As observed in patients with PNKD, dyskinesia in dtsz hamsters can be aborted by sleep (Fahn, 1994; Richter & Loscher, 1998). Parallel to clinical observations, anticonvulsants, like phenytoin and carbamazepine, are not effective and may even worsen dystonia, while benzodiazepines, gabapentin or neuroleptics exert beneficial effects (Richter & Loscher, 1998). The comparable response to drugs suggests that the hamster model is suitable for preclinical drug testing. Dyskinesia in dtsz hamsters shows an age-dependent time course with maximum expression between the 30 to 40 days of life, followed by a decrease of severity until complete remission at age of about 10 weeks. This age-dependence may resemble transient paroxysmal dystonias in infancy as described above (see BPT and paroxysmal tonic upgaze deviation of infants). Observations of recurrence of attacks in pregnant dtsz hamsters and the induction of dystonia by drugs (e.g. lamotrigine) in older animals, however, argue against a complete remission of dyskinesia in this animal model. With regard to relapses of age-dependant dystonia during pregnancy, parturition and nursing in dtsz hamsters (Khalifa & Iturrian, 1993; Loscher et al., 1995), it is interesting to note that in female patients menses may precipitate or worsen dystonic attacks (Demirkiran & Jankovic, 1995). In order to identify brain regions of abnormal neuronal activity during the expression of severe dystonia, the [3H]2-deoxyglucose (2-DG) uptake was examined in 75 brain regions of dtsz hamsters in comparison to non-dystonic control hamsters (Richter et al., 1998). The 2-DG uptake, reflecting altered synaptic activity, was dramatically increased in the nucleus ruber (159% over control). Further increases were detected in the ventral nuclei of thalamus (19–42%) and the medial vestibular nucleus (23%), while the deep cerebellar nuclei were found to be structures of most marked decreases of 2-DG uptake (30%) in dystonic brains. This

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decrease may reflect reduced synaptic activity of GABAergic neurons, leading to enhanced excitatory cerebellar output to the red nuclei, thalamic and vestibular nuclei. However, increased 2-DG uptake in the dorsomedial striatum indicates involvement of basal ganglia, possibly leading to the observed changes in the thalamus. By recent single unit recordings in anaesthetized dtsz hamsters enhanced neuronal activity was found in the dorsomedial striatum (Genert et al., 1999). Furthermore, in this subregion decreased dopamine D1 and D2 receptor binding became evident in mutant hamsters (Nobrega et al., 1996). Most neurochemical changes were found in the striatum and thalamic nuclei of the mutant hamster (Richter & Loscher, 1998). In line with pharmacological findings, which indicated that dopaminergic overactivity and impaired GABAergic inhibition play a critical role in the pathophysiology, neurochemical changes of the GABAergic and dopaminergic system became evident by recent studies, including different methods. Decreased GABA levels and reduced expression of the GABA-synthetizing enzyme glutamic acid decarboxylase were found in the striatum of dtsz hamsters (Richter & Loscher, 1998). Increased affinity and density of benzodiazepine binding sites in the striatum is possible due to upregulation (Pratt et al., 1995). These changes disappeared in parallel with remission of stress-inducible dyskinesia, implicating a causal relationship between these changes and dystonia. Significantly increased binding to the picrotoxin site of GABAa receptor was found in several brain regions of dtsz hamsters suggesting dysfunction of the GABAa receptor complex (Nobrega et al., 1995). Determinations of dopamine and its metabolites as well as tyrosine hydroxylase immunohistochemistry failed to disclose any changes (Richter & Loscher, 1998), but receptor analyses of dopamine receptor density revealed selective changes in subregions of the caudate-putamen, in the nucleus accumbens and substantia nigra pars reticulata in mutant hamsters (Nobrega et al., 1996). With regard to pharmacological examinations, decreased D2 binding has been interpreted to be related to decreases in presynaptic receptors, leading to increased dopamine release in subregions of the striatum which possibly results in downregulation of postsynaptic D1 and D2 receptors. In summary, the findings in the hamster model suggest (i) that basal ganglia dysfunction and abnormal thalamocortical activity seem to be critically involved in paroxysmal dyskinesias, although changes in cerebellum, red nucleus and brainstem may contribute to the clinical manifestation and (ii) a crucial role of disturbances of the GABAergic and dopaminergic system. Genetics of paroxysmal dyskinesias Progress in our understanding of the genetic basis of these disorders is providing new insights into the pathophysiology. However, the genetic developments do not

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clearly fall within the clinical classification system described above. We discuss here the linkage studies and possible candidate genes for these conditions. Paroxysmal non-kinesiogenic dyskinesia (PNKD) The majority of cases of PNKD has been familial and demonstrates an autosomal dominant pattern of inheritance. Penetrance is incomplete and estimates have ranged from 79–90% (Fink et al., 1996; Fouad et al., 1996; Jarman et al., 1997a, Raskind et al., 1998). Using data combined from all the PNKD kindreds with an unequivocal PNKD phenotype a penetrance of 84% has been calculated (Jarman et al., 1997a). A PNKD locus was first mapped to the distal region of chromosome 2q by Fink et al. (1996) and Fouad et al. (1996). Fink mapped the PNKD locus to a 15 cM region between markers D2S164 and D2S159 and Fouad to a 10 cM interval between markers D2S128 and D2S126. Jarman et al. (1997a) subsequently narrowed the region by mapping to a 4cM region bound by D2S295 and D2S377. The 4cM region identified by Jarman et al. lies within the regions identified by Fink and Fouad et al. There is further evidence of genetic homogeneity following a report by Raskind et al. (1998), who also localized the gene to a 5 cM region between flanking markers D2S164 and D2S377. Raskind et al. looked for a common mutational origin in PNKD and compared haplotypes in their family with those described by Fink but were unable to identify a shared region in or near the critical region on chromosome 2q31–36 (Raskind et al., 1998). These data together with the fact that the four families are derived from diverse geographic areas suggests that the disease arose de novo in each family. Despite the studies in these four independent families the genetic and physical distances remain large and therefore the number of potential genes is great. The genes that have been identified in other paroxysmal disorders (e.g. some epilepsies, episodic ataxia type I and II) are ligand or voltage-gated channels. Therefore, it is a reasonable hypothesis that mutations in ion channels are likely to explain many of the other paroxysmal movement disorders. Initial linkage studies by Raskind et al. (1998) excluded the cluster of potassium channels (KCNA5, KCNA6, KNA1) and a calcium channel (CACNL1A1) on 12p13. Following identification of linkage of PNKD to 2q, ion channels that are known to lie within this region have become the prime candidates. The delta subunit of the nicotinic acetylcholine receptor (CHRND) has been assigned to chromosome 2q36–q37. It is interesting to note that a mutation in another subunit of the neuronal nicotinic acetylcholine receptor, the alpha 4 subunit, is a cause of autosomal dominant nocturnal frontal lobe epilepsy (Steinlein et al., 1995). Although there are no EEG changes in PNKD, it has been proposed that it may represent a form of

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epilepsy as there are some clinical similarities. However, Jarman et al. (1997a) were able to exclude CHRND as a candidate gene for PNKD as they found at least two recombination events between CHRND and PNKD in their family (Zmax3.49 at P0.001). Perhaps the most promising candidate gene is SLC4A3. SLC4A3 is a membranebound protein that functions as a chloride/bicarbonate anion exchanger and an alkali extruder. SLC4A3 maps to the region between D2S126 and D2S164 at 2q36 (Su et al., 1994). Jarman et al. (1997a) identified no recombinations between PDC and SLC4A3 and therefore could not exclude this as a putative candidate. The SLC4A3 anion exchanger is widely expressed on neurons throughout the brain with highest expression in the deep pontine grey matter, the caudal medulla and in the substantia nigra (Alper, 1991). It plays a role in the regulation of intracellular chloride concentrations, cell volume and in regulation of intracellular pH (Kopito et al., 1989). The function of this gene is of particular interest in considering reports of PNKD patients responding to acetazolamide treatment. Acetazolamide produces a mild metabolic acidosis by inhibiting excretion of hydrogen ions in the renal tubule and could therefore be acting to correct an abnormal intracellular pH in these patients. Paroxysmal choreoathetosis and spasticity Aubuger et al. (1996) identified a family with autosomal dominant paroxysmal choreoathetosis and spasticity in which linkage was shown to a 2cM region on 1p. They noted this was close to a cluster of potassium channel genes but to date no mutation has been described. Paroxysmal kinesigenic choreoathetosis (PKC) This is the commonest form of paroxysmal dyskinesia. Under the classification system of Demirkiran and Jankovic (1995) this condition is also known as paroxysmal kinesigenic dyskinesia (PKD). To date, no linkage has been established in families with pure PKC (see below). The episodic nature and its response to anticonvulsants suggests that this condition may also be a channelopathy. However, there are no studies which have successfully linked the PKC phenotype to any of the known ion channels. Paroxysmal exercise-induced dykinesia (PED) and epilepsy Szepetowski and colleagues (1997) reported several autosomal dominant families with benign infantile convulsions in whom a paroxysmal dyskinesia was noted. In

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approximately half of these cases the attacks of dystonia were exercise induced. They provided evidence of linkage to the pericentromeric region of chromosome 16, with a lod score of 6.76 at 0. Guerrini et al. (1999) have reported a pedigree with autosomal recessive rolandic epilepsy and paroxysmal exercise-induced dystonia and writer’s cramp. They also have been shown to be linked to the same region. Both studies give most prominence to the epilepsy, but the occurrence of the paroxysmal movement disorder is noteworthy. It seems most likely that these two conditions are caused by the same mutation and therefore it fuels the debate about the nature of epilepsy and PDs. Hereditary geniospasm This is an unusual movement disorder causing episodes of involuntary tremor of the chin and the lower lip. Episodes start in early life and may be precipitated by stress. Jarman et al. (1997b) assigned linkage to 9q13–q21 in one family, whilst excluding this region in a second family, providing evidence of genetic heterogeneity. In summary, there are now several loci known for some of the PDs. No genes have yet been identified but there is strong circumstantial evidence that many, if not all of these disorders, will be due to ion channel mutations. As ion channels are also implicated in many of the Mendelian epilepsies, knowledge of these genes will not only shed light on the pathophysiology, but may lead to a major reorganization in our approach to the relationship between these disorders. Acknowledgements S.D.S. is funded by the McLaughlin Foundation, Canada (N.W. Wood and S.D. Spacey).

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Normal startle and startle-induced epileptic seizures Peter Brown1, David R. Fish1 and Frederick Andermann2 1 2

MRC Human Movement and Balance Unit, Institute of Neurology, London, UK Department of Neurology, Montreal Neurological Hospital and Institute, McGill University, Québec, Canada

Normal startle response The normal human startle response consists of a brief flexion response, most marked in the face and upper half of the body, elicited by an unexpected auditory, or sometimes somaesthetic, visual or vestibular stimulus. Activity is most prominent in orbicularis oculi and sternocleidomastoid. Habituation of the normal generalized startle response is rapid, although the blink reflex tends to persist. Studies in animals suggest that the startle response originates in the lower brainstem. The short latency startle response to sound persists after decerebration (Forbes & Sherrington, 1914; Szabo & Hazafi, 1965). Lesioning experiments in the rat have implicated the medial bulbopontine reticular formation, particularly the nucleus reticularis pontis caudalis, as the primary centre subserving the acoustic startle reflex (Szabo & Hazafi, 1965; Hammand, 1973; Leitner et al., 1980; Davis et al., 1982). Thus electrical stimulation of the nucleus reticularis pontis caudalis elicits short latency startle-like responses (Davis et al., 1982). If the medial pontomedullary reticular formation is the primary centre subserving the acoustic startle reflex, the efferent limb of the reflex may be provided by the bulbobulbar and reticulospinal pathways originating in this area. In particular, Shimamura and Livingston have identified a spino-bulbo-spinal reflex system relayed in the medial medullary reticular formation in cats, the efferent limb of which is formed by the moderately slowly conducting component of the medial reticulospinal pathway, running in the ventrolateral funiculus (Shimamura & Livingston, 1963; Shimamura & Kogure, 1979; Shimamura et al., 1964). This efferent pathway may form the basis of the audio-spinal reflex response, believed to underlie the auditory startle reflex in animals (Wright & Barnes, 1972).

Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Table 10.1. The etiology of the pathologically exaggerated startle response a

ii(i) Hereditary hyperekplexia i(ii) Symptomatic hyperekplexia Static encephalopathies Static perinatal encephalopathy without tonic spasms Postanoxic encephalopathy Post-traumatic encephalopathy Brainstem encephalopathy or encephalitis Sarcoidosis Viral encephalomyelitis, including HIV encephalopathy Encephalomyelitis with rigidity Paraneoplastic ?Multiple sclerosis Structural Brainstem hemorrhage or infarct Psychiatric Post-traumatic stress disorder Gilles de la Tourette syndrome (iii) Idiopathic hyperekplexia Note: a Adapted from Brown et al. (1991).

It seems likely that the startle response has a similar origin in man. Thus the startle reflex is said to exist in anencephalic infants (Edinger & Fisher, 1913), and patients with an exaggerated startle reflex often have pathology involving the brainstem (Table 10.1). Presumably the latter leads to a disinhibition of the medial caudal reticular formation. In addition, physiological studies of the human startle also support the contention that the startle response has a brainstem origin. Physiological studies of the normal startle reflex

The constancy of reflex EMG activity in orbicularis oculi has led some authors to consider this the first and most important event in the normal auditory startle reflex (Landis & Hunt, 1939; Wilkins et al., 1986; Chokroverety et al., 1992). Although certainly prominent in the observed startle response, the blink may represent a simultaneously elicited but different reflex to the generalized startle (Brown et al., 1991b). The auditory blink reflex may be seen without any other manifestation of the startle response, and, unlike the normal startle reflex, does not readily habituate. When seen in the context of a startle response, the latency of the

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blink reflex is much shorter than the latency to onset of EMG activity in other cranial muscles. In particular, the latency of mentalis, which has a similar innervation and peripheral efferent conduction time to orbicularis oculi, exceeds that of orbicularis oculi by about 20 ms. When a true startle response is elicited by unexpected auditory stimulation, the duration of the EMG activity in orbicularis oculi is much longer. These observations led Brown et al. (1991b) to suggest that the early latency auditory blink reflex is physiologically separate from the generalized startle reflex. These authors argued that the true startle response in orbicularis oculi is of longer latency, usually beginning during the normal auditory blink reflex. Discounting the auditory blink reflex in orbicularis oculi as separate (although temporally overlapping with the startle reflex), Brown et al. found the earliest recorded EMG activity in the generalized startle response was in sternocleidomastoid, where responses could be recorded 40 to 136 ms (median 58 ms) after an auditory stimulus (Brown et al., 1991b). EMG activity in mentalis occurred later, and in masseter later still. Valldeoriola et al. (1997) also found that activity in sternocleidomastoid preceded that in masseter. Comparable findings were made by Matsumoto et al. (1992), when considering startles in which sternocleidomastoid, masseter and orbicularis oris were active together. The pattern of activation of cranial nerve innervated muscles recorded by these different authors is the reverse of the rostro-caudal recruitment seen in cortical reflex myoclonus, or following magnetic stimulation of the motor cortex. Given the approximately similar peripheral efferent conduction delays to masseter, orbicularis oculi, mentalis and sternocleidomastoid, such a pattern of muscle recruitment to auditory stimulation is consistent with an origin for the startle reflex in the lower brainstem, with propagation rostrally to the seventh then fifth cranial nerve nuclei (Brown et al., 1991b). A similar pattern of activation of cranial nerve innervated muscles is seen in brainstem reticular reflex myoclonus, where myoclonic activity is propagated rostrally from a myoclonic generator in the lower brainstem (Hallett et al., 1977). The latencies of the startle response in trunk and limb muscles increase with the distance of their segmental innervation from the caudal brainstem. The proximal arm muscles are activated before those of the hand, and the cervical paraspinal muscles are activated before the abdominal recti. Responses in the legs are seen only occasionally in normal subjects when sitting relaxed, and are at longer latency than those of the arms (Chokroverety et al., 1992; Brown et al., 1991b). The difference in latency between sternocleidomastoid and rectus abdominis is 16ms or so longer than the difference in latency between these muscles when they are activated by magnetic stimulation of the motor cortex. This is consistent with a slow conduction velocity in the spinal efferent pathways utilized by the startle response. In addition, the latency to onset of EMG activity in the intrinsic hand muscles is disproportionately long, even when allowance is made for the apparent slowness of conduction in spinal efferent pathways (Brown et al., 1991b;

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Matsumoto et al., 1992). This suggests that the pathways responsible for activation of these muscles differ, at least in part, from those underlying the rest of the startle reflex. In summary, the electrophysiological evidence is generally consistent with the mediation of the auditory startle reflex in man by an efferent system with its origin in the caudal brainstem. The spinal projections of this system may be relatively slowly conducting, and distributed predominantly to axial muscles, similar to the efferent limb of the spino-bulbo-spinal reflex in animals. The complexity of the normal startle response

Although the available evidence is largely consistent with an origin for the human auditory startle response in the reticular formation of the medial caudal brainstem, the form of the response is complicated and varies under different conditions. Alertness, emotional state, stimulus strength and repetition, the presence of tonic voluntary muscle activity, posture and incipient movement may all modify the response (Wilkins et al., 1986). Stimulus repetition is a particularly important parameter. The normal auditory startle reflex habituates within two to six trials, with the stimulus presented every 20 minutes or so (Brown et al., 1991b). The plasticity of the startle response argues against the simple notion of a single volley in an efferent system originating in the brainstem, as may occur in brainstem reticular reflex myoclonus (Hallett et al., 1977). Instead, it seems more likely that the efferent response to a startling stimulus consists of a series of volleys, each of which may be independently modulated under different circumstances (Brown et al., 1991a). The complexity of the organization of the efferent system is matched by that of the inputs bearing on the bulbospinal reticular formation. The latter receives not only direct subcortical inputs, such as from the lateral lemniscus or the inferior colliculus, but also indirect inputs from the cerebral cortex, limbic system and basal ganglia. In particular, the motor cortex is likely to exert a tonic inhibitory effect on the startle reflex, as the latter can be exaggerated on the hemiparetic side following hemispheric strokes involving the contralateral motor cortex and its efferent pathways (Voordecker et al., 1997). In contrast, the basal ganglia may have a facilitatory effect on the startle response, which in part seems to be under dopaminergic control (Delwaide et al., 1993; Vidailhet et al., 1992). Startle provoked epileptic seizures (SPES) The electroclinical features of approximately 100 patients with SPES have been reported in the literature (Brown et al., 1991c; Alajouanine & Gastaut, 1955; Gastout & Tassinari, 1996; Aguglia et al., 1984; Saenz-Lope et al., 1984; Kolbinger

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et al., 1990; Guerrini et al., 1990; Chauvel et al., 1992; Manford et al., 1996; Oguni et al., 1998). The prevalence is difficult to estimate, although it is probably less than 1% of patients with epilepsy. The patients with SPES form a somewhat heterogeneous group with a wide range of etiologies, most of which have been acquired preperinatally. Typically such patients present with clinical seizures suggesting ictal involvement of the motor/supplementary motor areas. Some of the seizures are provoked by sudden unexpected stimuli, usually a loud noise. Virtually all patients report additional spontaneous seizures. The semiology of provoked and spontaneous seizures is usually similar. The sensitivity to unexpected stimuli is often a transient features in the overall seizure history. Prevalence

There have been no population-based series of SPES. Case series from specialized centres are likely to over-report the prevalence due to referral bias. Gastaut and Tassinari (1966) estimated that approximately 5% of patients with epilepsy had provoked seizures, the commonest mechanism for which was obviously photosensitivity. Manford et al. (1996) studied the electroclinical features of 252 patients attending a specialized epilepsy centre with features to suggest temporal or frontal lobe epilepsy. Of these highly selected patients, 19/252 (7.5%) had a history of SPES. It may be that amongst patients with frontal lobe epilepsy the proportion with SPES is higher than typically recognized because, for some patients, the history of SPES is transient. Patients with Down’s syndrome may form another subgroup with an increased prevalence of SPES (Guerrini et al., 1990), although in these patients the seizure type is more often myoclonus or absence, with generalized spike-and-wave discharges on the EEG. Etiology

Historical series of SPES were mostly derived from surgical material. Many of these patients had gross neurological deficits, especially hemiplegia due to major destructive/atrophic lateralized lesions. Chauvel et al. (1992) reviewed the history and investigative findings in 20 patients with somatomotor seizures triggered by sensory stimuli. Nineteen of these had clinical or radiological findings to indicate a cerebral structural lesion. Eighteen of these patients had an etiology which was considered to have occurred before the age of 2 years, and in most were thought to be ‘congenital’. Seventeen of the patients had a hemiplegia, some with an associated hemisensory deficit, and three had a hemianopia. Eleven of the patients had mental retardation. The principal radiological finding was of a gross unilateral hemispheric lesion – hemicranial atrophy, cerebral atrophy, / an associated porencephalic cyst. These lesions were mostly evident in the motor and premotor areas. The strictly lateralized findings may have reflected the requirements of presurgical

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selection. Manford et al. (1996) identified 11/19 patients with mental retardation or neurological deficits present from birth, and five with neuroimaging evidence of malformations of cortical development. However, only 5/19 patients had a hemiplegia, 3/19 had bilateral neurological deficits, 11/19 had no gross neurological deficit, and only 6/19 had mental retardation. Presumably these differences reflected the different population studied – Manford et al. selected patients attending predominantly medical rather than pre/post surgical clinics. The proportion of patients with areas of cortical maldevelopment may be underestimated by Manford et al., because not all patients had high resolution MRI. This was undertaken in five neurologically normal subjects and three with neurological deficits. Of the eight patients MRI revealed porencephaly (one patient), cortical maldevelopment (six patients) and was normal in only one patient. The areas of cortical maldevelopment would probably not have been evident on CT. They involved the lateral premotor cortex in three patients and the perisylvian cortex in the other three – one of which was bilateral. These two series provide strong evidence for the high proportion of patients with SPES who have a preperinatal aetiology for their epilepsy, but some of these cases have relatively mild (if any) neurological/intellectual abnormalities. The identified structural abnormalities most often involve the motor/premotor (including lateral as well as mesial dorso frontal) areas of cortical maldevelopment. Provocative stimuli

SPES are most often seen in response to sudden unexpected loud noises. Chauvel et al. (1992) noted that natural sounds as compared with pure tones or clicks were more effective stimuli. Manford et al. (1996) noted that all 19 patients they reported with SPES had a history of seizures provoked by sudden unexpected noise. In addition 6/19 had seizures provoked by unexpected somatosensory stimuli, for example an unexpected tap on the shoulder or catching the paretic foot while walking. Visual stimuli are less effective. Manford et al. identified the possible occurrence of this provocative stimulus in only 3/19 patients, and the effects were less reproducible than with the auditory or somatosensory stimuli. The sensitivity to sudden unexpected stimuli is often a transient feature in the overall seizure history. In 9/19 of the patients reported by Manford et al. spontaneous seizures occurred for some years before patients experienced SPES. One patient with seizure onset age 1 year only developed SPES after a change in seizure pattern age 25 years, while in 2/19 patients SPES no longer occurred by the time of interview, i.e. they had been present previously but resolved leaving only spontaneous seizures. Ictal semiology

For an individual patient, the ictal semiology of SPES and spontaneous seizures is usually similar. Chauvel et al. (1992) reported semiology that included head and

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eye turning (12 patients), clonic or tonic–clonic movements (17 patients), affecting the upper limb (six patients), both upper and lower limbs (five patients) both sides of the body (five patients) or one side of the face (one patient). In addition speech arrest was seen in 18 patients, preserved awareness in nine patients, bilateral mydriasis in ten patients and flushing in nine patients. Manford et al. (1996) also noted predominant focal motor activity with 16 patients having ictal tonic motor activity which was focal in 14. Five patients had focal somatosensory onset before the motor activity. Manford et al. also reported three patients with different ictal semiology: one patient with absences, one patient with generalized tonic–clonic seizures, and one patient with complex partial seizures manifest by giggling and behavioural automatisms. Seizure frequency is often high. Manford et al. reported that all the patients in their series had at some stage suffered more than one seizure per day, and 10/19 had suffered more than ten seizures in a day. In keeping with extratemporal seizures most were brief: only 4/19 reported habitual seizures that lasted for more than 1 minute, and most were less than 30 seconds. The ictal semiology in most patients with SPES therefore overall is in keeping with seizures involving primarily the motor or premotor cortex. In some patients the startle seizure may represent a uniform motor seizure induced via a long-loop reflex, whereas in others there may be a brief (exaggerated) startle reponse prior to the habitual seizure (Chauvel et al. (1992)). EEG findings

Manford et al. (1996) reported interictal spiking in 10/19 patients with SPES, slow wave abnormalities in 12/19 and five patients with normal interictal records. The distribution of interictal spikes varied both within and between patients but predominately involved frontal, central or temporal regions. Ictal scalp EEGs were available in 7/19 patients. As would be expected with seizures showing such prominent motor activity most had their onset obsured by muscle artefact. One showed focal 12–16 Hz rhythmic activity over the left mid frontal region. Chauvel et al. (1992) reported SEEG recordings in 18 patients with SPES. Implantations included frontal, parietal and sometimes temporal regions. No difference was found between triggered and spontaneous seizures, in keeping with the clinical observation of similar ictal semiologies patterns varied between patients but always involved primary and secondary motor areas, with various degrees of overlap. One patient showed isolated involvement of the lateral frontal cortex, and three patients showed epileptogenic areas restricted to the mesial frontal cortex, in the remaining 14 patients the epileptogenic cortex included both mesial and lateral frontal areas. Chauvel et al. concluded that SPES represented seizures arising from MI–MII areas. Temporal lobe structures were not usually involved, and if so this was seen late.

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Neurodiological findings

CT is likely to reveal the etiology in those cases with gross atrophic lesions. However, Manford et al. stress the need to investigate patients with high resolution MRI given the high incidence of areas of cortical maldevelopment. These lesions are often subtle, and they may be missed on routine imaging, or their true extent not identified. This is of particular importance in patients undergoing presurgical evaluation. Thin contiguous T1 weighted slices may be needed to identify such lesions. This may be aided by three-dimensional reconstruction of the cortical pattern or special sequences such as FLAIR. Surgical treatment

Successful surgical treatment of SPES has been reported (Chauvel et al., 1992; Oguni et al., 1998). Evaluation will follow the usual principles of concordance of data from different investigative modalities and extent of feasible resection. Oguni et al. (1998) reported two patients with SPES and infantile hemiplegia due to gross contralateral hemispheric lesions. Both suffered from tonic postural seizures provoked by sudden unexpected somatomensensory stimuli applied to the paretic side, and resulted in significant falls and injuries. Both underwent corpus callosotomy and resection of the motor and premotor epileptogenic lesions. One also had multiple subpial transection of the primary motor cortex. Both showed significant improvements in quality of life and seizure control at follow-up beyond 2 years. Conclusions on SPES

SPES usually occur in patients with congenital lesions involving the motor/premotor cortex. They may be done to the junction of polymodal sensory afferents and limbic inputs in the perisylvian, supplementary motor and lateral premotor cortex. The pathophysiology may relate to variable changes given that SPES may occur as a transient phenomenon in patients with fixed motor deficits due to congenital underlying lesions involving these areas. Presumably the congenital nature of most identified etiologies provides the possibility of plasticity within these and other areas which may underlie the susceptibility to such provoked seizures.

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Normal startle and startle-induced seizures Brown, P., Day, B.L., Rothwell, J.C., Thompson, P.D. & Marsden, C.D. (1991a). The effect of posture on the normal and pathological auditory startle reflex. Journal of Neurology, Neurosurgery and Psychiatry, 54, 892–7. Brown, P., Rothwell, J.C., Thompson, P.D., Britton, T.C., Day, B.L. & Marsden, C.D. (1991b). New observations on the normal auditory startle reflex in man. Brain, 114, 1891–902. Brown, P., Rothwell, J.C., Thompson, P.D., Britton, T.C., Day, B.L. & Marsden, C.D. (1991c). The hyperekplexias and their relationship to the normal startle reflex. Brain, 114, 1903–28. Chauvel, P., Trottier, S., Vignal, J.P. & Bancaud, J. (1992). Somatomotor seizures of frontal lobe origin. Advances in Neurology 57, 185–232. Chokroverety, S., Wakzak, T. & Hening, W. (1992). Human startle reflex: technique and criteria for abnormal response. Electroencephalography and Clinical Neurophysiology, 85, 236–42. Davis, M., Gendelman, D.S., Tischler, M.D. & Gendelman, P.M. (1982). Primary acoustic startle circuit: lesion and stimulation studies. Journal of Neuroscience, 2, 791–805. Delwaide, P.J., Pepin, J.L. & Maertens de Noordhout, A. (1993). The audiospinal reaction in Parkinsonian patients reflects functional changes in reticular nuclei. Annals of Neurology, 33, 63–9. Edinger, L. & Fisher, B. (1913). Ein mensch ohne grosshirn. Pflugers Archive European Journal of Physiology, 152, 535–62. Forbes, A. & Sherrington, C.S. (1914). Acoustic reflexes in the decerebrate cat. American Journal of Physiology, 35, 367–36. Gastaut, H. & Tassinari, C.A. (1966). Triggering mechanisms in epilepsy: the electroclinical point of view. Epilepsia, 7, 86–138. Guerrini, R., Genton, P., Bureau, M., Dravet, C. & Roger, R. (1990). Reflex seizures are frequent in patients with Down’s syndrome and epilepsy. Epilepsia, 31, 406–17. Hallett, M., Chadwick, D., Adam, J. & Marsden, C.D. (1977). Reticular reflex myoclonus: a physiological type of human post-hypoxic myoclonus. Journal of Neurology, Neurosurgery and Psychiatry, 40, 253–64. Hammond, G.R. (1973). Lesions of the pontine and medullary reticular formation and prestimulus inhibition of the acoustic startle reaction in rats. Physiology and Behavior, 10, 239–43. Kolbinger, H., Zierz, S., Elger, C.E. & Penin, H. (1990). Startle-induced seizures and their relationship to epilepsy: three case reports. Journal of Epilepsy, 3, 237. Landis, C. & Hunt, W.A. (1939). The Startle Pattern. New York: Farrar and Rinehart. Leitner, D.S., Powers, A.S. & Hoffman, H.S. (1980). The neural substrate of the startle response. Physiology and Behavior, 25, 291–7. Manford, M.R.A., Fish, D.R. & Shorvon, S.D. (1996). Startle provoked epileptic seizures: features in 19 patients. Journal of Neurology, Neurosurgery and Psychiatry, 61, 151–6. Matsumoto, J., Fuhr, P., Nigro, M. & Hallett, M. (1992). Physiological abnormalities in hereditary hyperekplexia. Annals of Neurology, 32, 41–50. Oguni, H., Hayashi, K., Usui, N., Osawa, M. & Shimizu, H. (1998). Startle epilepsy with infantile hemiplegia: report of two cases improved by surgery. Epilepsia, 39, 93–8. Saenz-Lope, E., Herranz, F.J., & Masdeu, J.C. (1984). Startle epilepsy: a clinical study. Annals of Neurology, 16, 78–81.

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11

Hyperekplexia: genetics and culture-bound stimulus-induced disorders Andrea Bernasconi, Frederick Andermann and Eva Andermann Department of Neurology, Montreal Neurological Hospital and Institute, McGill University, Québec, Canada

Abnormal, excessive startle is a feature of three distinct conditions: hyperekplexia or startle disease, jumping (the jumping Frenchmen of Maine), and startle epilepsy. The mechanisms of normal / startle and startle epilepsy are reviewed by Brown et al. (this volume). Clinical presentation Kirstein and Silverskiold (1958), first described startle disease. Two sisters, their father, and the daughter of one of the sisters suffered from sudden violent falls precipitated by stress, fright, or surprise. Three of these family members also had nocturnal myoclonus. The authors cautiously considered the disorder to represent an unusual, genetically determined form of drop seizures. In a letter to Lancet, Kok and Bruyn (1962), drew attention to a hereditary disease affecting 29 individuals in six generations of a German–Dutch family with 127 members. Suhren et al. (1966), described this family in much greater detail. The affected individuals had a strikingly excessive response to startle elicited by visual, auditory, and proprioceptive stimuli that failed to produce a response in most normal individuals. These authors coined the term hyperekplexia, i.e. excessive jerking to describe the condition. The disorder occurs in two forms: a minor form in which the response is quantitatively different from normal, i.e. the startle response is more violent; and a major form in which there are also additional clinical symptoms. In the major form, patients, when startled, experience momentary generalized muscular stiffness with loss of voluntary postural control causing them to fall as if frozen, with their arms at their sides, unable to carry out protective movements. As soon as they hit the ground, muscle tone and control of voluntary movements return, and there is never evidence of loss of consciousness. In the major form, there is a transient generalized hypertonia during infancy. On neurological examination, Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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generalized stiffness is described in newborns with the major form (Suhren et al., 1966). As babies, when awakened or handled, affected individuals have an immediate increase in muscle tone in flexion. This abnormality diminishes as spontaneous activity increases during the first year of life. Adults with the major form often walk with a stiff-legged, mildly wide-based gait without signs of ataxia. Some adult patients report episodes of a sensation of muscle stiffness or slowness of movement (Dooley & Andermann, 1989), and they often have spontaneous and usually nocturnal clonus (Suhren et al., 1966; Andermann et al., 1980; Bernasconi et al., 1996). In some patients there are features of more diffuse cerebral involvement with developmental delay (Andermann et al., 1980). The symptoms usually respond dramatically to clonazepam (Andermann et al., 1980; Bernasconi et al., 1996; Ryan et al., 1992; Tijssen et al., 1997), and the clinical evolution is usually favourable. However, the excessive backward jerking of the head elicited by tapping the forehead or nose (Shahar et al., 1991), generally persists. The infants have a high incidence of umbilical and other hernias, previously noted by Suhren et al. (1966), and probably related to their hypertonicity. Apnea due to spasm of respiratory muscles may also occur, and sometimes lead to the children’s death (Suhren et al., 1966; Ryan et al., 1992a, b; Vigevano et al., 1989; Kurczynski, 1983). Exceptionally, the symptoms of startle disease will arise later in life (Suhren et al., 1966; Dooley & Andermann, 1989). Dooley & Andermann (1989) studied an adolescent boy with normal neonatal history, who developed falling attacks as well as generalized stiffness which made it impossible for him to take part in sports. Hyperekplexia shows an autosomal dominant, and at times recessive, inheritance pattern, with nearly complete penetrance and variable expression in most dominant pedigrees. However, a positive family history may be difficult to elicit in this condition because of the phenotypic variation. In the first family we described (Andermann et al., 1980), the disorder was obvious in the proband and her sister. Only the minor form was present in both children of one of the probands, and only when they were ill. For years, it was impossible to obtain a history of abnormal startle from either of the probands’ parents. Eventually, it became clear that the mother startled excessively and literally jumped off her chair when the telephone rang. In the second family reported by us, initially no other member was found to be affected by either the major or the minor form, even on intensive questioning. However, many years later, a sister was found to have excessive startle. Lack of expression in families may be explained by difficulty in eliciting a positive family history unless all family members are interviewed individually, by a new mutation in the proband, or by lack of penetrance of the gene in other family members. Apart from families with the hereditary form of hyperekplexia, sporadic cases with the major form have been described (Shahar et al., 1991; Gastaut & Villeneuve,

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1967; Boudouresques et al., 1964; Saenz-Lope et al., 1984; Andermann & Andermann, 1986; Hayashi et al., 1991; Dubowitz et al., 1992; Stephenson, 1992; Berthier et al., 1994). Gastaut and Villeneuve (1967) presented in detail 12 patients with sporadic startle disease. The authors stressed the psychogenic precipitation of startle and falling. Eleven of their patients had falling attacks and, in at least one, these were identical to those occurring in familial cases. The authors felt that their patients were different from those described by Suhren et al., although it seems likely that at least some of them had the same disorder, but without an obvious family history. There is no good evidence that patients with sporadic startle disease differ from the familial cases described by Suhren et al. (1966), as Gastaut and Villeneuve (1967), have suggested. Our own cases, familial or sporadic, appeared to have the same syndrome. These two forms would thus appear to represent a single genetically determined disorder. Genetics Hyperekplexia is the first human disease shown to result from mutations within a neurotransmitter gene. A number of large families have been described in which the condition segregates in an autosomal dominant fashion with almost complete penetrance. Different missense mutations in the GLRA1 gene, Arg271Leu (Shiang et al., 1993), Arg271Gln (Shiang et al., 1993, 1995; Schorderet et al., 1994; Rees et al., 1994; Tijssen et al., 1995a, b; Elmslie et al., 1996), Tyr279Cys (Shiang et al., 1995), Gln266His (Milani et al., 1996), Lys276Glu (Seri et al., 1997) and Pro250Thr (Saul et al., 1999), have been identified in families with the autosomal dominant form of hyperekplexia. In addition to individuals with the dominant form, two recessive cases, both offspring of consanguineous parents, have been described (Rees et al., 1994). In one patient, a recessive point mutation, Ile244Asn (Rees et al., 1994) was detected, whereas the other patient carried a homozygous deletion encompassing exons 1 to 6 of the GLRA1 gene (Brune et al., 1996). Vergouwe et al. (1999) described the genetic marker and mutation analysis of a family in which two different, but on their own apparently non-pathogenic, missense mutations in the GLRA1 gene caused the hyperekplexia phenotype in compound heterozygous individuals. Using systematic linkage analyses in several unrelated families with the major form of hyperekplexia, Ryan et al. (1992a, b), identified the locus of the major form of hyperekplexia on the distal portion of the long arm of chromosome 5 (5q33–q35), an area which contains the genes for several neurotransmitter receptors, including glycine receptors. These glycine receptor subunits in the mammalian CNS are found in brainstem, spinal cord and brain (Matzenbach et al., 1994). Autoradiographic studies in the mouse CNS using 3H-strychnine as a ligand

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(White et al., 1990), have demonstrated that the highest densities of binding sites were seen in the somatic motor and sensory areas. Sequence analysis of the gene encoding for the 1 subunit of the inhibitory glycine receptor (GLRA1) in humans revealed two different missense mutations, occurring in the same base pair of exon 6 of GLRA1. These mutations replace arginine at position 271 with either leucine or glutamine (G1192A and G1192T) (Rees et al., 1994; Shiang et al., 1995; Elmslie et al., 1996). GLRA1 is a constituent of the inhibitory glycine receptor in the mammalian central nervous system and is antagonized by strychnine, which in sublethal doses in the mouse causes hypertonia and an exaggerated startle response comparable to the symptoms in hyperekplexia (Ryan et al., 1994; Kingsmore et al., 1994). Agonist binding to GLRA1 initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential (Grenningloh et al., 1987). These mutations reduce the glycine sensitivity of GLRA1 (Rajendra et al., 1994; Langosch et al., 1994), and result in the redistribution of GLRA1 singlechannel conductances to lower conductance levels (Rajendra et al., 1995). We analysed this gene in a family of Swiss–Italian origin and found a G1192A mutation changing an ARG to a LEU codon in three affected females with major startle disease (Bernasconi et al., 1996; Schorderet et al., 1994). The major and minor forms of startle disease can occur in the same family, as illustrated in the large family reported by Suhren et al. (1966), and those reported by Andermann et al. (1980) Andermann and Andermann (1984, 1986) and by Dooley and Andermann (1989). The minor form of the disease, which must be distinguished from psychogenic startle, consists only of excessive startle (Suhren et al., 1966; Andermann et al., 1980; Vigevano et al., 1989; Kurczynski, 1983). A parent with the minor form can have children with the major form and vice versa, but siblings tend to be affected to the same degree. Therefore it is likely, as Suhren et al. (1966) have suggested, that these two forms represent different phenotypic expressions of the same (autosomal dominant) gene. Recent reports, however, showed that only clinically typical or major hyperekplexia is consistently associated with GLRA1 (G1192A) mutations (Shiang et al., 1995). Tijssen et al. (1995a, b), reanalysed the family described by Suhren et al. in 1966, and observed that patients with the minor form never transmitted the major form. They found the mutation of the GLRA1 receptor only in patients with a major form of the disorder, and postulated that the minor form could represent a variant of the physiological startle reaction. Not all cases of hyperekplexia have a family history of the disorder. These sporadic cases could be due to new mutations, non-penetrance in one of the parents or recessive transmission, or be phenocopies caused by organic diseases. The observation that mutations in GLRA1 in mice can produce startle syndromes with recessive patterns of transmission (Ryan et al., 1994; Buckwalter et al., 1994), suggests that recessive inheritance might account for at least some of the sporadic cases of

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hyperekplexia seen in humans. Based on clinical observations, Hayashi et al. (1991) and Hayashi and Kajii (1993), suggested the possibility of recessive transmission of the disorder in some families. Rees et al. (1994), reported a different mutation in the same exon of GLRA1 (T1112A, which results in the substitution of asparagine for isoleucine at position 244 of the mature protein) also causing a recessive form of the disease in a 22-year-old girl with major startle disease . We recently examined four individuals from four families with major form of hyperekplexia. None of our patients with familial and sporadic hyperekplexia nor their examined relatives had the previously described point mutations of the glycine receptor GLRA1 (Bernasconi et al., 1996; Shiang et al., 1993; Rees et al., 1994; Shiang et al., 1995; Vergouwe et al., 1997). It is therefore evident that the clinical phenotypes of hyperekplexia, both the major and the minor form, as well as familial and sporadic cases can result from more than one genetic abnormality, indicating genetic heterogeneity. In addition, the two strains of mutant mouse that resemble the startle disease phenotype have a genetic defect involving two different genes, coding for the 1-subunit (Ryan et al., 1994) and the -subunit (Kingsmore et al., 1994; Becker et al., 2000) of the glycine receptor, respectively. Therefore, it is possible that other mutations can be found in genes coding for the different subunits of the glycine receptor in human hyperekplexia syndromes (Shiang et al., 1995). Pathophysiology of the excessive startle reaction and myoclonus Spontaneous clonic jerks occur frequently in hyperekplexia (Suhren et al., 1966; Dooley & Andermann, 1989; Andermann et al., 1980; Saenz-Lope et al., 1984). Suhren et al. (1966) and Gastaut and Villeneuve (1967), suggested that, as jerking of the legs occurred only at night, it presumably represented an exaggerated form of hypnagogic myoclonus. Two of our patients had such attacks in the daytime as well, and all limbs were involved, though the legs always more than the arms. When the attacks occurred at night, the patients woke with a feeling described as unsteadiness, similar to their diurnal state when unexpected stimuli would be particularly likely to provoke a fall. The jerking would last for several minutes. There were no electrographic features to suggest an epileptic etiology. Clinically, these attacks strongly resembled spontaneous generalized clonus, were most marked in the lower extremities and were usually triggered by emotion. De Groen and Kamphuisen (1978), studied the periodic nocturnal myoclonic jerks of one of Suhren and Bruyn’s patients. They concluded that these were due to spontaneous arousal reactions caused mainly by increase in excitability of motor neurons, hyperexcitability of the brainstem arousal system, and markedly increased influence of respiratory variables on reticular hyperexcitability.

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In their review, Wilkins et al. (1986), suggested that hyperekplexia could represent the known combination of reticular and cortical reflex myoclonus as described by Hallett et al. (1979). They tentatively concluded that hyperekplexia should be considered as an independent phenomenon within the spectrum of stimulussensitive myoclonic disorders. The electroencephalographic correlates of startle were similar in the patients reported by Suhren et al. (1966), Andermann et al. (1980) and Gastaut and Villeneuve (1967). The EEG response consisted of an initial spike recorded from the centroparietal vertex followed by a short-lasting train of slow waves, and then by desynchronization of background activity lasting 2–3 s. This complex discharge may represent an evoked response to various sensory stimuli. The motor response in the normal auditory startle reflex in man is organized in the medial reticular formation, which may be activated by subcortical or cortically relayed afferent inputs. Testing spinal inhibitory pathways in five patients with hereditary hyperekplexia, Floeter et al. (1996), found definite abnormalities only in one of the two forms of inhibition mediated by glycinergic interneurons. Therefore, spasticity, hyperreflexia, and muscle stiffness in patients with hyperekplexia are probably not related to spinal hyperexcitability. On the other hand, the clonus (Suhren et al., 1966; Dooley & Andermann, 1989; Andermann et al., 1980), the EEG abnormalities (Suhren et al., 1966; Dooley & Andermann, 1989; Andermann et al., 1980), the shortened latency of the blink reflex (Brown et al., 1991) and the large somatosensory evoked potentials (Brown et al., 1991; Fariello et al., 1983; Markand et al., 1984), may indicate that the excessive startle reflex is related to increased cortical (Markand et al., 1984) or reticular neuronal excitability (Matsumoto et al., 1992). Studying saccadic eye movements, Tijissen et al. (1995a, b) found no evidence of a lack of cortical inhibition in hyperekplexia. On the other hand, some observations support the hypothesis of a lack of inhibition by higher cortical centres (Suhren et al., 1966). Fariello et al. (1983), reported a patient in whom an infarction involving the subthalamic nucleus and the dentatorubroventrolateral thalamic pathway led to the reappearance of preexisting hyperekplexia. He postulated that the interruption of thalamic pathways can eliminate the descending inhibition of the startle reflex. Hochman et al. (1994), reported a sporadic case of hyperekplexia with decreased cerebral blood flow in the frontal lobe using SPECT, and assumed that this abnormality could represent a ‘functional cortical lesion of a descending pathway that normally inhibits the startle reflex’. Physiological studies have focused on brainstem and spinal mechanisms in startle disease. However, the startle reflex is thought to activate frontal abnormalities, and both reticular and cortical mechanisms may contribute to the startle reaction (Chauvel et al., 1992). We used proton magnetic resonance spectroscopic imaging (MRSI) to assess in vivo cortical neuronal involvement in hyperekplexia

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(Bernasconi et al., 1998). Cerebral neuronal function was measured in four unrelated patients with hyperekplexia and 20 healthy controls. All patients had the major form of the disorder. The neuronal marker N-acetylaspartate (NAA), choline-containing compounds (Cho) and creatine (Cr) were measured in frontal, central and parietal areas. The MRSI showed a reduction of the relative resonance intensity of NAA/CrCho in frontal and central regions in three patients, and in the right frontal region of the fourth. In one patient, a second MRSI showed normal relative NAA resonance intensities over both temporal lobes and from the brainstem. In two subjects the topography of EEG abnormalities in frontal lobes coincided with the MRSI findings. Therefore, our MRSI study indicates the presence of frontal neuronal dysfunction in hyperekplexia. Whether this represents a cortical dysfunction or epiphenomenon of diencephalic or brainstem abnormalities remains open. However, the observation of normal proton MRSI in the temporal regions and brainstem in one of the patients seems to concur with the hypothesis of a facilitatory role of cortical dysfunction within areas of sensory-motor representation in the generation of the pathological startle reaction in hyperekplexia. The excessive backward jerking of the head elicited by tapping the forehead or nose observed in many patients represents a peculiar sensibility to sensory stimuli of the central face area (Shahar et al., 1991; Bernasconi et al., 1998), and may be related to the cortical dysfunction within areas of sensorimotor representation. This is in keeping with the fact that patients with startle provoked epileptic seizures show preponderance of EEG and structural abnormalities within the frontal and central regions (Chauvel et al., 1992; Manford et al., 1996; Aguglia et al., 1984; see also Chapter 10 by Brown et al.). Therefore, the results of our MRSI study support the concept of a common pathway in the pathophysiology of epileptic and nonepileptic startle disorders. Cortical myoclonus may represent an enhancement of sensory inputs to the motor cortex or abnormal relays within the sensory–motor cortex (Obeso et al., 1985; Reutens et al., 1993). Magnetoencephalography studies in patient with cortical myoclonus showed that an abnormal sensory–motor cortex can contribute to the generation of the cortical myoclonus (Uesaka et al., 1996), and that anomalies of the motor cortical inhibition facilitate the spread of the myoclonic activity responsible for generalized jerks (Brown et al., 1996). Therefore, in our patients with hyperekplexia and spontaneous clonus, the cortical abnormalities detected with MRS could also contribute to the generation of the clonus. Cortical excitability A history of generalized seizures that are independent of startle episodes were seen in about 20% of one series (Saenz-Lope et al., 1984), and a family history of

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seizures is not uncommon. EEG between episodes is often normal, although nonspecific changes can be seen. Suhren et al. (1966) considered the disorder to be non-epileptic. However, epileptogenic EEG abnormalities were found in several of their patients who fell, and many had excessive slow activity which they attributed to the repeated head injuries. Some patients, though, display evidence of more widespread cerebral dysfunction, not explainable by a maturational defect in a specific system alone, and unlikely to be due merely to the repeated falls. One of the patients of Andermann et al. (1980), had an active generalized slow spike-wave discharge and another had a parietal sharp wave focus: neither had epileptic seizures or episodes other than the specific clinical phenomena just described. Indeed, the spike-wave discharge was blocked by startle. Several of the patients reported by Gastaut and Villeneuve (1967) had a low convulsive threshold, and one had seizures as well. Four of their patients had, or were suspected to have, mild mental retardation. Low average intelligence was also encountered in two of the three patients of Andermann et al. (1980) with the major form, suggesting diffuse cerebral dysfunction. Treatment At the present time clonazepam, a benzodiazepine agonist, appears to be the drug of choice in the treatment of hyperekplexia. Clonazepam reduces the frequency and magnitude of startle responses, and diminished the frequency of falls (Andermann et al., 1980; Bernasconi et al., 1996; Ryan et al., 1992; Tijssen et al., 1997; Morley et al., 1982; Kelts & Harrison, 1988). Clonazepam potentiates, by unknown mechanisms, the neurotransmitter gamma-aminobutyric acid (GABA). In small doses (0.1 mg/kg), clonazepam abolishes the falling attacks and greatly reduces the episodic jerking. Although clonazepam does not cause the startle response to return to normal, its effect is greater than that of diazepam, and appears to be sustained. Excessive backward jerking of the head elicited by tapping the forehead or nose persists, and appears to represent residual reticular reflex myoclonus. Under conditions of exceptional emotional stress, falling or nocturnal leg jerking occasionally recur. Valproic acid abolished the clinical manifestations in a patient studied by Dooley and Andermann (1989). Alcohol, phenobarbital, phenytoin, primidone, chlordiazepoxide, and vigabatrin (Stephenson, 1992), although they have some effect on the falling attacks, startle and repetitive jerks, are not the drugs of choice for treatment of this disorder. According to Saenz Lope et al. (1984), 5-hydroxytriptophan and piracetam may also be helpful. In some cases, reduction or elimination of the abnormal startle response may not be the end of the problem, and the patient can be left with residual difficulties caused by secondary handicaps which may be more difficult to treat. These include anxiety disorders due to fear of falling,

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secondary depression and alcohol problems. In some individuals, hyperekplexia can result in extreme isolation and distress both for patients and their families. Differential diagnosis The diagnosis of startle disease should not be difficult if one is aware of this syndrome. Unfortunately, it is common to find that the condition has been previously misdiagnosed and treated, even as hysteria or malingering. The condition is probably rare, and one would suspect that it is commonly misdiagnosed as epilepsy, as it was at first in most patients. The mainstay of diagnosis is a clear history with corroboration from an observer or, better still, direct observation of an episode following a stimulus such as a loud noise. Preserved consciousness and the absence of EEG evidence for an epileptic attack, allows hyperekplexia to be distinguished from startle epilepsy and drop attacks. Hypertonia in infancy is easily misinterpreted as spastic quadriplegia. The most puzzling symptom is the unsteady gait which the physician may attribute to a cerebellar disorder instead of the uncertainty and fear of falling, which actually causes it. The course of the condition is variable. Some patients with early onset eventually improve, whereas in others the symptoms only arise or increase later in life. In our patients there has been little change over the years, although on the whole the manifestations were more severe in childhood, when the hypertonicity was striking and the falls frequent. The disorder is not entirely benign considering the risk of sudden death in infancy attributable to spasm of respiratory muscles and also the possible complication of hernias. When intelligence is normal and the symptoms are successfully treated, people affected with this disorder lead normal lives. Genetic counselling and close supervision during delivery of babies at risk and during infancy are indicated. Early descriptions of stimulus-induced startle disorders include the jumping Frenchmen of Maine (Beard, 1978; Stevens, 1965; Kunkle, 1965; Howard & Ford, 1992; Saint-Hilaire et al., 1986), Latah and Myriachit (Hammond, 1984; Yap, 1952). These three entities were respectively described in the North Eastern USA, Malaysia, and Siberia. The features of jumping (the jumping Frenchmen of Maine) are excessive startle, echolalia, and automatic obedience. Echopraxia also occurs. In addition to violent startle, a loud cry, expletive swearing or coprolalia, dropping objects or a fighting posture may occur. This entity is quite different in its manifestations from the usual continuum of childhood tics that culminate in Tourette’s syndrome of tic convulsif. Beard (1978) was aware of the hereditary nature of the disorder. Among 50 affected people he studied, there were 14 affected members in four families. The heredity of the condition suggests autosomal dominant inheritance with variable expressivity. The condition is not confined to the French Canadian group who settled in Northern Maine. Saint-Hilaire et al. (1986)

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confirmed the existence of the disorder many years later in the Beauce region, a district of Quebec. Beard was aware of latah (ticklish), a Malay disorder featuring echopraxia, excessive startle, and swearing. Myriachit (to act foolishly) is a condition encountred in Siberia and other parts of Asia and Africa. People with myriachit also display echopraxia, echolalia, and excessive startle as prominent features (Hammond, 1884). During a voyage to Malaysia in 1952, Yap (1952) observed three patients who showed echolalia, echopraxia, and automatic obedience. Excessive startle was alluded to in some patients and coprolalia was often a feature. At least one of the subjects was very ticklish. Simons (1980), distinguishes three phases: first, the startle response; secondly, the attention capture which corresponds to expletive, echopraxia and automatic obedience; and thirdly, an elaboration of some of the responses into intentionally amusing performances. This readiness or willingness to perform is not a feature of jumping, which is considered a disability in North American society. From this accounts it seems that jumping, myriachit, and latah may well represent the same basic pathophysiological disorder of the nervous system since excessive startle, echolalia, echopraxia and automatic obedience are present in all three. It is, however, also clear that there is a considerable and variable cultural overlay to these conditions in the different populations in which they occur. Similar diseases have been described in other populations as well and because of variation in elaboration, they are described as ‘culture-bound’ syndrome (Simons, 1996).

R E F E R E N C ES

Aguglia, U., Tinuper, P. & Gastaut, H. (1984). Startle induced epileptic seizures. Epilepsia, 25, 712–20. Andermann, F. & Andermann, E. (1984). Startle disease, or hyperekplexia [letter]. Annals of Neurology, 16, 367–8. Andermann, F. & Andermann, E. (1986). Excessive startle syndromes: startle disease, jumping, and startle epilepsy [Review]. Advances in Neurology, 43, 321–38. Andermann, F. & Andermann, E. (1988). Startle disorders of man: hyperekplexia, jumping and startle epilepsy. [Review]. Brain and Development, 10, 213–22. Andermann, F., Keene, D.L., Andermann, E. & Quesney, L.F. (1980). Startle disease or hyperekplexia: further delineation of the syndrome. Brain, 985–97. Beard, G.M. (1978). Remarks on jumpers or jumping frenchman. Journal of Nervous and Mental Diseases, 5, 526. Becker, L., Hartenstein, B., Schenkel J., Kuhse J., Betz, H. & Weiher, H. (2000). Transient neuromotor phenotype in transgenic spastic mice expressing low levels of glycine receptor betasubunit: an animal model of startle disease. European Journal of Neuroscience, 12, 27–32.

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12

Myoclonus and epilepsy Renzo Guerrini1, Paolo Bonanni2, John Rothwell3 and Mark Hallett4 1

Neurosciences Unit, Institute of Child Health, The Wolfson Centre, London, UK Institute of Child Neurology and Psychiatry, University of Pisa, Italy 3 MRC Human Movement and Balance Unit, Institute of Neurology, London, UK 4 Human Motor Control Section NINDS, National Institutes of Health, Bethesda, MD, USA 2

Historical note

The term myoclonus covers a group of neurophysiologically diverse phenomena, of heterogeneous etiology, whose common semiological element is represented by involuntary, jerky movements, most frequently involving antagonist muscles (Marsden et al., 1982). Myoclonus originates from abnormal muscle activation in the form of brief electromyographic (EMG) bursts (positive myoclonus) or, more rarely, from a brief interruption of ongoing EMG activity (negative myoclonus) (Marsden et al., 1982). Clinical phenomenology of myoclonus may also result from a combination of a myoclonic jerk plus postmyoclonic muscle inhibition (Guerrini et al., 1994a). The nosologic boundaries between myoclonus and epilepsy have been the subject of discussion since the earliest clinical descriptions. Reynolds (1861) observed the frequent association between epilepsy and ‘clonic spasms’, interpreting the latter as interseizure phenomena. Friedreich (1881) coined the term ‘paramyoclonus multiplex’ to describe a sporadic, non-progressive form of myoclonus. Subsequently, a series of conditions revealing a close association between epilepsy and myoclonus were described: familial myoclonic epilepsy (Unverricht, 1891), epilepsia partialis continua (Kojewnikow, 1895), and non-progressive myoclonic epilepsy (Rabot, 1899). The first attempt at classification was undertaken by Lundborg (1903), who subdivided myoclonus into three etiological categories: (i) symptomatic myoclonus, which should include, for example, postencephalitic myoclonus (Dubini, 1846); (ii) essential myoclonus (the appropriate category for Friedreich’s paramyoclonus multiplex); and (iii) familial myoclonic epilepsy (subdivided into non-progressive and progressive forms). Later, Muskens (1928) highlighted a close nosologic link between myoclonus and epilepsy, and coined the term Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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‘fragments of epilepsy’ to designate the myoclonic jerks of patients with epilepsy. Since then, many other conditions in which myoclonus is a significant symptom have been reported, allowing the following etiological classification of myoclonus to be drawn up (Marsden et al., 1982; Fahn et al., 1986): (i) physiologic myoclonus (sleep-related, hiccup, myoclonus induced by anxiety or exercise); (ii) essential myoclonus (subjects without other neurological signs); (iii) epileptic myoclonus (conditions in which the predominant element is epilepsy); (iv) symptomatic myoclonus (conditions in which the predominant element is encephalopathy). According to Marsden et al. (1982) and Fahn et al. (1986), the first category of epileptic myoclonus comprises ‘fragments of epilepsy’, and includes forms that originate from an isolated spike discharge in the motor cortex (isolated epileptic myoclonic jerks, epilepsia partialis continua, idiopathic stimulus-sensitive myoclonus, photosensitive myoclonus, myoclonic absences in Petit Mal). Three additional categories are: (i) the childhood myoclonic epilepsies [benign myoclonus of infancy, infantile spasms, myoclonic astatic epilepsy (Lennox–Gastaut), cryptogenic myoclonic epilepsy (Aicardi, 1980), awakening myoclonus epilepsy of Janz]; (ii) the benign familial myoclonic epilepsy (Rabot, 1899); and (iii) the progressive myoclonus epilepsies (PMEs): Baltic myoclonus (Unverricht–Lundborg). Since this is an etiological classification, the myoclonus appearing in conditions that belong to different categories could share common neurophysiological mechanisms. Moreover, concepts on nosology of myoclonic epilepsies have evolved considerably in recent years (Commission, 1989, 1997). The study of the temporal relationship between neuronal and muscle events has permitted a neurophysiological classification of myoclonus (Marsden et al., 1982) into cortical and subcortical, according to the site of origin. In cortical myoclonus the jerk is generated by a discharge originating from the cerebral cortex. This type of myoclonus is closely related to epilepsy. The interictal spike is the surface correlate of a hypersynchronous paroxysmal depolarization shift, which, if originating from a discrete group of neurons in the motor cortex, can trigger myoclonus. Rhythmic recurrence of this phenomenon may lead to epilepsia partialis continua. Local diffusion can trigger a seizure with Jacksonian march, while spread throughout both hemispheres can result in a generalized seizure. Hallett (1985) described epileptic myoclonus as a ‘fragment of epilepsy’ with an EEG correlate distinct from non-epileptic myoclonus, which has no correlate. He proposed a physiological classification which included the following categories: (i) cortical reflex, representing a fragment of partial epilepsy with hyperactivity of the motor cortex; (ii) primary generalized, signifying a fragment of idiopathic generalized epilepsy, with generalized hyperactivity of the cortex driven by subcortical stimuli; and (iii) reticular reflex, which represents a fragment of generalized epilepsy with hyperactivity of the reticular formation of the medulla. Evidence that cortical myoclonus belongs to a spectrum of manifestations of epi-

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lepsy is provided by descriptions of patients with reflex or spontaneous myoclonus, associated with epilepsia partialis continua, Jacksonian motor seizures, myoclonic absences, myoclonic status, and generalized tonic–clonic seizures, in various combinations (Hallett et al., 1979; Obeso et al., 1985; Ikeda et al., 1990; Guerrini et al., 1996). Cortical myoclonus is accompanied by facilitation of inter- and intrahemispheric spread of the excitation (Brown et al., 1991a; Guerrini et al., 1996), which may play a key role in the transition from ‘fragment of epilepsy’ to a full seizure. Epileptiform discharges time locked with the EMG silent period are present in epileptic negative myoclonus (ENM) (Cirignotta & Lugaresi, 1991; Guerrini et al., 1993), which has been described in patients with motor cortex epilepsy, either idiopathic or symptomatic (Guerrini et al., 1993). Clinical neurophysiology of epileptic myoclonus Although the relationships between myoclonus and epilepsy have now been partially elucidated, the use of the term ‘epileptic myoclonus’ is still confusing. Some authors define as epileptic myoclonus that which occurs within the setting of epilepsy (Patel & Jankovic, 1988). Others define as epileptic myoclonus those forms in which a paroxysmal depolarization shift is thought to be the underlying neurophysiological substrate, irrespective of which population of neurons (cortical or subcortical) is primarily involved (Hallett, 1985). Epileptic myoclonus (EM) can be comprehensively defined as an elementary electroclinical manifestation of epilepsy involving descending neurons, whose spatial (spread) or temporal (self-sustained repetition) amplification can trigger overt epileptic activity. Frequently, the EEG correlate of epileptic myoclonus can be detected only by using jerk-locked (EEG or MEG) averaging. According to the above definition, epileptic myoclonus includes positive and negative cortical myoclonus, thalamo-cortical myoclonus and reticular myoclonus (Table 12.1). Clinically, epileptic myoclonus may be positive or negative. It is focal if it involves a restricted, usually distal, group of muscles, multifocal when asynchronous focal jerks involve different body areas; or generalized when jerks involve most body segments in an apparently synchronous manner. Furthermore, it may be spontaneous, or reflex if induced by movement or by sensory or visual stimuli. Finally, as regards periodicity, epileptic myoclonus may be rhythmic or arrhythmic. The neurophysiological characteristics of EM are: (i) duration of the myoclonic EMG burst ranging between 10 and 100 ms; duration of the EMG silent period of negative myoclonus, ranging from 50 to 400 ms; (ii) synchronous EMG bursts or silent periods on antagonist muscles; (iii) presence of an EEG correlate detectable by routine surface EEG or burst-locked EEG averaging. The EEG correlate is time

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Table 12.1. Relation of myoclonus to epilepsy

Epilepsy

Fragment of epilepsy

rhythmic repetition Cortical myoclonus

spread

generalization

EPC

FBCM or CT

Jacksonian seizure

generalization

Epileptic myoclonus

Thalamo-cortical myoclonus

I Generalization

locked in cortical reflex myoclonus and in primary generalized epileptic myoclonus. Secondarily generalized epileptic myoclonus, as defined in this chapter has a time-locked EEG correlate but temporal relationships between EEG and EMG event may vary according to pattern of muscle pread. No time-locked EEG event has yet been demonstrated in reticular reflex myoclonus. Cortical myoclonus Clinical findings

Cortical myoclonus can be positive or negative; focal, multifocal or generalized; spontaneous or reflex; rhythmic or arrhythmic. Neurophysiologic findings Origin Cortical myoclonus originates from abnormal neuronal discharges in the sensorimotor cortex. Abnormally firing motoneurons may be primarily hyperexcitable or may be driven by abnormal inputs originating from hyperexcitable parietal (Deuschl et al., 1991) or occipital (Kanouchi et al., 1997) neurons. Each jerk represents the discharge from a small group of cortical motoneurons somatotopically connected to a group of contiguous muscles. A cortical potential that is temporally and consistently correlated with the myoclonic potential, and localized on the contralateral sensorimotor region, can be demonstrated by EEG, MEG or JLA (Shibasaki & Kuroiwa, 1975; Hallett et al., 1979; Shibasaki et al., 1991; Mima et al., 1998). In some patients with focal myoclonus, epilepsia partialis continua and partial motor seizures, excision of a small cortical region, identified by electrophysiological recordings as the area of

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origin of the myoclonic discharges, leads to remission of symptoms (Kugelberg & Widén, 1954; Cowan et al., 1986; Legatt et al., 1996). However, in epilepsia partialis continua, the cortical site of origin of the myoclonic discharges and the site of origin of the associated partial seizures do not necessarily coincide (Commission, 1997). In patients with PMEs, the polarity of the premyoclonic potential as detected by JLA is positive (Shibasaki et al., 1978, 1991; Hallett et al., 1979; Kelly et al., 1981; Obeso et al., 1985; Kakigi & Shibasaki, 1987; Ikeda et al., 1990, 1995; Toro et al., 1993). In contrast, in patients with Alzheimer’s disease, Down syndrome, and in some patients with Lennox–Gastaut syndrome, there is a negative sharp wave associated with myoclonus (Ugawa et al., 1987; Wilkins et al., 1984, 1985). Mima and coworkers (1998) used MEG and EEG to study patients with cortical myoclonus caused by PMEs, familial cortical myoclonic tremor (defined in this chapter as autosomal-dominant cortical reflex myoclonus and epilepsy), cortico-basal degeneration, Alzheimer’s disease, and Lennox–Gastaut syndrome. In all patients, jerklocked MEG averaging revealed cortical activities associated with myoclonic jerks. The estimated generator of the earliest peak of the premyoclonus cortical activity was localized at the contralateral precentral gyrus. As judged from the direction of the elctrical current, surface positive activity was detected in PMEs, familial cortical myoclonic tremor and cortico basal degeneration and negative activity in Alzheimer’s disease and Lennox–Gastaut syndrome. According to Mima and colleagues (1998), the negative premyoclonic potential may be generated by a hyperexcitable motor cortex, through a mechanism of epileptogenesis, i.e. the PDS is widely distributed within the motor neocortex. The positive polarity potential is thought instead to be generated by a PDS restricted to the deep layers (probably in lamina V) of the motor cortex (Obeso et al., 1985; Mima et al., 1998). However, there is good evidence from other authors (Cowan et al., 1986; Legatt et al., 1996) that cortical hyperexcitability may reside in sensory or parietal regions rather than motor cortex. If this were the case, then it is conceivable that premyoclonic potentials of opposite polarity could occur simply because of the reversal in anatomic orientation of pyramidal cells in motor and sensory parts of the central sulcus. In cortico basal degeneration and Alzheimer’s disease, averaging EEGs could not detect cortical activity associated with myoclonic jerks. Jerk-locked MEG is more sensitive than jerk-locked EEG averaging, at least in some patients, in detecting cortical activity associated with myoclonus (Mima et al., 1998), possibly because the magnetic fields are not attenuated by the skull. Induction mechanisms

In patients with cortical reflex myoclonus, appropriate stimuli administered to a resting somatic segment produce a reflex muscle response (jerk), which in normal

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subjects can only be detected during voluntary contraction. The normal reflex pattern consists of an H response after 28 ms and a long latency reflex (LLR II) at 50 msec. An earlier reflex component at 42 ms (LLR I) is present in 30% of normal subjects, and at 70 ms an additional LLR III may occur (Deuschl et al., 1987). The reflex jerk was originally called a C- (cortical)-reflex, as it was presumed to be cortically mediated (Sutton & Mayer, 1974). Electrical or mechanical stimulation of a relevant nerve produces a reflex response that has a latency of 30–50 ms for the upper limb, and 60–70 ms for the lower limb. If the afferent (N20 of SEPs) and efferent motor evoked potentials (MEPs) from transcranial magnetic stimulation (TMS) conduction times are subtracted from these latencies, the cortical relay time (CRT) is obtained, corresponding to the intracortical transmission time of myoclonic activity. SEPs of giant amplitude are often observed in patients with cortical reflex myoclonus. The giant components are most often P25/P30 (P1) and N35 (N2) (Rothwell et al., 1986), and their generators are localized close to the central sulcus (Shibasaki et al., 1985; Ikeda et al., 1995). Since the subcortical components and the first cortical component (N20) have normal amplitude, an abnormality of intracortical inhibition following arrival of the first volley of thalamo-cortical activity could be the cause both of the abnormal enlargement of the giant SEPs components and of activation of descending motor outputs leading to the C-reflex (Rothwell et al., 1986). The striking resemblance in latency and morphology of the giant SEPs to the myoclonus related cortical spike suggests that both originate from common cortical mechanisms (Shibasaki et al., 1991). In the typical forms of CRM, the reflex jerk has a latency of 50 ms and the CRT has a mean duration of 7 ms (Thompson et al., 1994a). Typical CRM can be observed in patients with focal cortical lesions (Sutton & Mayer, 1974), spinocerebellar degeneration (Chadwick et al., 1977; Hallett et al., 1979; Obeso et al., 1985), multiple system atrophy (Obeso et al., 1985; Chen et al., 1992; Rodriguez et al., 1994), cerebral anoxia (Hallett et al., 1979; Young & Shahani, 1979), childhood metabolic degenerations such as neuronal ceroid lipofuscinosis and sialidosis (Shibasaki et al., 1985; Deuschl et al., 1987), Alzheimer’s disease, Down syndrome (Wilkins et al., 1984; Ugawa et al., 1987) and mitochondrial disorders (Rosing et al., 1985; So et al., 1989, Thompson et al., 1994b). If the latency of the reflex myoclonus is reduced to 40 ms, that is to say 10 ms shorter than usual and 2 ms longer than the sum of the afferent and efferent times to and from the cortex, CRM is defined as atypical. Atypical forms have been observed in patients with epilepsia partialis continua (Chauvel et al., 1978; Kelly et al., 1981), postanoxic myoclonus (Chadwick et al., 1977), PMEs (Shibasaki et al., 1985; Deuschl et al., 1987), neuronal ceroid lipofuscinosis (Shibasaki et al., 1985), Huntington disease (Carella et al., 1993) and corticobasal degeneration (Thompson et al., 1994a).

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It has been hypothesized that the different patterns of abnormality in CRM might be explained by differences in the processing and relay of sensory information in thalamo-cortical pathways (Thompson et al., 1994a; Deuschl et al., 1987). In the typical forms, CRM may involve abnormal relays through the sensory cortex to the motor cortex, either directly or via cerebellar-thalamo-cortical projections (Rothwell et al., 1986; Thompson et al., 1994a). In the atypical forms, myoclonus may represent enhancement of a direct sensory input to the motor cortex (Thompson et al., 1994a). A form of CRM characterized by more prolonged C-reflex latency has recently been described in Rett syndrome (Guerrini et al., 1998a). Clinically, myoclonus is multifocal, predominating distally, and arrhythmic. A positive potential, localized on the contralateral centro-parietal area, precedes myoclonus with a latency of 347 ms for the forearm muscle. This is compatible with cortico-motoneuronal conduction. The N20-P30 and P30-N35 components of the SEPs have significantly increased amplitude. In addition, the latency of the N20 component is delayed, and the N20-P30-N35 interval is significantly increased and has expanded morphology. The latency between electrical stimulation (median nerve) and onset of reflex myoclonus is 655 ms when the recording is made from the abductor pollicis brevis (APB) muscle. Topographic mapping of the SEP voltage shows, for the P30 component, a field distribution very similar to that of the premyoclonic potential. The CRT has a duration of 284 ms; a value which is 3–4-fold higher than that observed in PMEs myoclonus epilepsy (Thompson et al., 1994a). It is therefore probable that in Rett syndrome the following sequence of events occurs: slight delay in central conduction of the impulse afferent to the sensorimotor cortex (N20), slowing of the processing of the afferent impulse (interval N20–P30; mean11 ms), delay in cortico-cortical transmission to the precentral neurons subserving movement of the stimulated body segment (latency increase P30 – C reflex; mean32 ms), and rapid descending volley to the spinal motoneurons. Thus the premyoclonic EEG and the corresponding P30 wave would represent a discharge arising from the postcentral neurons and subsequently activating slowly the motor efferences through connections with the precentral neurons (Uesaka et al., 1996). Intracortical conduction time could be particularly prolonged on account of the synaptic abnormalities present in the brain of patients with Rett syndrome (Belichenko et al., 1994). One particular form of CRM may be induced by photic stimuli, in idiopathic generalized epilepsies (benign myoclonic epilepsy, juvenile myoclonic epilepsy), in idiopathic generalized photosensitive epilepsies, or in some forms of cryptogenic epilepsies (myoclonic–astatic epilepsy, severe myoclonic epilepsy). The most active frequency of stimulation is between 10 and 20 Hz. The ratio between stimulus

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(flash) and reflex response (jerk) is not constant and is only partly time-locked. Responses are usually symmetric and predominate in the upper limbs. In most cases they are mild, only producing head-nodding and slight arm abduction. More generalized jerks, involving the face, trunk and legs, may occasionally cause the patient to fall. Isolated myoclonic jerks occur without loss of consciousness. However generalized jerks may be repeated, especially if the stimulus is protracted. In this situation consciousness may be impaired and a generalized tonic–clonic seizure may follow. The relationship of myoclonic jerks to the stimulus is complex. Sometimes there is no definite time relationship. On other occasions the jerks may be repeated rhythmically with the same frequency as the stimulus or at one of its subharmonics (Walter, 1949). If the triggering stimulus is prolonged, the clinical response may translate into a generalized convulsion (Gastaut & Tassinari, 1966). In patients with diffuse degenerative brain damage (Shibasaki & Neshige, 1987; Artieda & Obeso, 1993) or with occipital lesions (Kanouchi et al., 1997), when IPS is performed at low frequencies (0.5–3 Hz) each flash may provoke a frontal giant potential which is time locked to the stimulus and precedes by 15 ms a myoclonic jerk localized in the face or spreading from the face in a rostro-caudal pattern. Further repetition of the stimulus may induce a generalized tonic–clonic seizure (Artieda & Obeso, 1993). The potential evoked on the occipital cortex may be normal or giant. Since the occipital response precedes the giant frontocentral response by 4 ms, which may correspond to the time required for the impulse to pass from the occipital to the frontal cortex, long pathways of occipito-frontal intracortical transfer have been hypothesized (Pandya & Kuypers, 1969). Study of the recovery cycles of the EEG components in response to pair of flash stimuli has shown that components on the central regions recover more rapidly than those on the occipital regions. Brain-mapping analysis indicates that the frontal activity correlated with the myoclonus originates in the premotor and motor cortices. Therefore, hyperexcitability of the visual cortex was not considered an essential prerequisite in this type of myoclonus by some authors (Shibasaki & Neshige, 1987; Artieda & Obeso, 1993). The orbitofrontal photomyoclonic response, which is widely described in the EEG literature in patients undergoing intermittent photic stimulation (synonyms: frontopolar response, recruiting response, photo-oculoclonic response), is probably a form of photic cortical reflex myoclonus which may be observed in normal individuals. The frequency IPS range of flashes effective in triggering it is usually between 8 and 20 Hz. This type of response is usually not seen in children. Patients present with rapid myoclonic jerking of the periorbital muscles producing fluttering of the eyelids and blinking which is synchronous with the flashes. There may be vertical oscillations of the eyeballs. Amplitude of the response increases progressively during the first flashes, reaching a maximum within a few seconds. The maximal

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amount of muscle activity is initially observed in the inferior orbicularis oculi muscles with subsequent irradiation to other facial muscles, the frontal and occipital areas and the neck (Bickford et al., 1952). Further spread may be seen if IPS stimulation is protracted. The response is blocked by opening of the eyes or cessation of IPS. Although the pathophysiology and significance of the orbitofrontal photomyoclonic response have long been disputed, our current understanding indicates it to be an expression of cortical myoclonus (Chatrian & Perez-Borja, 1964) within the spectrum of photic cortical reflex myoclonus (Artieda & Obeso, 1993). Photic CRM provides a clear example of how a single jerk (fragment of epilepsy) can gradually translate into overt seizure activity, through a temporal summation effect of the triggering stimuli. Rhythmic or arrhythmic recurrence

A focal spike generated in the sensorimotor cortex can produce a focal myoclonic jerk. Rhythmic or arrhythmic jerk recurrence may lead to epilepsia partialis continua (Marsden et al., 1982). The cortical origin of myoclonus in epilepsia partialis continua has been widely demonstrated (Thomas et al., 1977; Obeso et al., 1985; Cowan et al., 1986; Chauvel et al., 1992; Legatt et al., 1996; Cockerell et al., 1996). However a subcortical origin has also been proposed, at least in some patients showing basal ganglia or cerebellar lesions and no jerk-locked EEG activity (JuulJansen & Denny-Brown, 1966; Kristianasen & Henriksen, 1971; Botez & Brossard, 1974; Colamaria et al., 1988; Cockerell et al., 1996). Bilateral, rhythmic, virtually continuous myoclonus at 11–18 Hz is typically observed in Angelman syndrome (AS) (Guerrini et al., 1996). The jerks are spontaneous at rest and, if particularly intense, may produce dystonic posturing of the upper limbs or the feet. A cortical transient in the contralateral sensorimotor cortex precedes each EMG burst by an interval consistent with rapid corticomotoneuronal conduction (20–30 ms) (Fig. 12.1). Clinical and neurophysiological characteristics suggest a high propensity for intra-hemispheric and inter-hemispheric cortical spread of myoclonic activity (Fig. 12.1). There is no giant SEP and lack of C-reflex hyperexcitability correlates with the absence of reflex jerks. The post MEP silent period has short duration and testifies to a deficit of inhibitory cortical mechanisms (Jay et al., 1991; Inghilleri et al., 1998). The pattern of myoclonus observed in Angelman syndrome suggests that small areas within the motor cortex are able independently to produce hypersynchronous, rhythmic neuronal discharges recruiting muscle activity similar to tremor. Distal myoclonic jerks can convert into overt generalized myoclonic status (Guerrini et al., 1996) (Fig 12.2.). As this pattern of myoclonus is observed in all patients with AS, irrespective of their genetic class, mutations in the ubiquitin 3A gene must play a direct role in its genesis. Transition to overt seizure activity in AS may, in turn, be facilitated by reduced representation

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Fig. 12.1

Patient with Angelman syndrome. Back-averaged EEG activity (n100) preceding the onset of a brief EMG burst. EMG activity in the left wrist extensor precedes that of the contralateral homologous muscle by about 8 ms. The same time difference is found between the premyoclonus EEG transients recorded from the right central (C4) and left central (C3) areas.

of GABAA subunit receptors, as demonstrated by the much more frequent and severe epilepsy observed in patients bearing a chromosome 15q11–13 deletion, leading to reduction of gene product (see Angelman syndrome in the following section on ‘Epileptic syndromes and neurological disorders with cortical myoclonus’, and in Chapter 2 by Olsen and De Lorey). A rhythmic pattern of cortical myoclonus, bearing some similarities to that seen in AS, may be observed in association with different clinical conditions. SchulzeBonhage and Ferbert (1998) described a patient who developed cortical action tremor and focal motor seizures of the left hand, following a right parietal infarction. Wang and coworkers (1999) reported cortical tremor appearing after surgical removal of a frontal lobe meningioma. A similar rhythmic pattern was produced as a reflex response to tapping on the forehead or by sudden acoustic stimuli in a boy with Down syndrome (Guerrini et al., 1990). We recently observed a patient with tuberous sclerosis who developed rare partial motor seizures and seemingly rhythmic, bilateral hand myoclonus, at 6–7 Hz. Brain MR imaging showed numerous cortical tubers, involving the sensorimotor cortex bilaterally (Fig. 12.3(a)). Jerk-locked EEG averaging uncovered an

Fig. 12.2

Patient with Angelman syndrome. Surface EEG–EMG recording during myoclonic status epilepticus. Rhythmic 10 Hz sharp activity, with fronto-central predominance, accompanies rhythmic diffuse jerking having the same frequency as the ictal EEG activity. Jerks are visible on either the EMG (right deltoid) and the right mid- and posterior temporal EEG channels. Sharp waves and myoclonic potentials are time locked at the beginning of the discharge. EEG–EMG relationships become less clear when rhythmic sharp waves are progressively intermingled with slow wave activity.

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2 µV

L. Ext 15 µV

L. Flex

(a) R. Ext

50 ms 25 yrs INPL-Pisa NS R

Fig. 12.3

Patient with Tuberous sclerosis. (a) Brain MRI shows a cortical tuber involving the right motor cortex that is contralateral to the monoclonus leading side. (b) Back-averaged EEG activity (n100) preceding the onset of a brief EMG burst. EMG activity in the left wrist extensor precedes that of the contralateral homologous muscle by about 10 ms. The same time difference is found between the premyoclonus EEG transients recorded from the right frontal (Fp2) and left frontal (Fp1) areas.

interside latency of roughly 10 ms between jerks and a leading hemisphere (Fig. 12.3(b)). SEPs had normal amplitude and there was no C-reflex at rest. Cortical tremor, in the form of postural or action tremor, and showing the neurophysiological characteristics of reflex cortical myoclonus, can also be observed in patients with PMEs (Ikeda et al., 1990; Toro et al., 1993) or with a form of autosomal dominant epilepsy mainly described in Japan (Terada et al., 1997; Okuma et al., 1998; Elia et al., 1998). Rhythmic cortical excitation could originate from rhythmic generators within layers IV and V of the motor cortex (Connors & Amitai, 1997). Alternatively, cortical neurons could be driven by a subcortical generator. Mechanisms of spread

Facilitation of interhemispheric and intrahemispheric spread of cortical myoclonic activity through transcallosal or intrahemispheric cortico-cortical pathways seems to play a major role in producing generalized or bilateral myoclonus (Brown et al.,

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1991a). Spread of cortical myoclonic activity can also underlie the transition from a ‘fragment of epilepsy’ to epilepsy. In patients with cortical myoclonus, bilateral jerks are not synchronous. EMG activity in ipsilateral muscles under stimulation or during movement preceded that in the contralateral muscles by a delay (10 ms) that is appropriate for transcallosal transfer of the excitation (Shibasaki et al., 1978; Wilkins et al., 1984). The latencies pertaining to EMG activity of the muscles on a given side are consistent not only with the length of the descending motor pathway, but also with an extra delay due to spread within the motor cortex itself (Brown et al., 1991a). Intrahemispheric spread follows a somatotopic pattern and could be attributed to cortico-cortical connections (Brown et al., 1991a). Interhemispheric spread of myoclonic activity is also observed in Angelman syndrome, in which the myoclonic jerks usually start in one hand and spread to the contralateral hand (Guerrini et al., 1996) with a stable interside latency (Fig. 12.1). In some patients with cortical reflex myoclonus with various etiologies, myoclonic activity remains localized in the segment stimulated (Brown et al., 1991a). Lack of any spread is particularly evident in Rett syndrome (Guerrini et al., 1998a), and might be evidence of severely reduced horizontal cortico-cortical transmission. Rothwell and Brown (1995) and Brown and colleagues (1996) demonstrated abnormalities of ipsilateral and transcallosal inhibition which could facilitate the spread of myoclonic activity. Patients with multifocal myoclonus were defined as ‘non-spreaders’ and patients with generalized myoclonus as ‘spreaders’. Motor thresholds to single transcranial magnetic shocks were higher in ‘non-spreaders’ than ‘spreaders’ or controls. This increase in the motor threshold was attributed to an increase in cortico-cortical inhibitory mechanisms. In addition, paired transcranial magnetic stimuli showed that ‘spreaders’ had less ipsilateral inhibition at interstimulus intervals of 1–6 ms and less transcallosal inhibition across inhibitory timings (10–14 ms) compared with ‘non-spreaders’. Although abnormalities in cortico-cortical and transcallosal inhibition may facilitate spreading of myoclonic activity, they do not appear to play a role in the production of generalized seizures, which were present to the same extent in both groups. There was no difference in inhibitory mechanisms between patients with and without epilepsy (Brown et al., 1996). It is likely that myoclonic activity descends from the sensorimotor cortex through the rapid conduction pyramidal pathways (Hallett, 1985). This hypothesis is supported by the fact that: (i) the time interval separating activation of two muscles involved in the spontaneous or reflex myoclonic jerk is similar to the time interval measurable between the same muscles by TMS; (ii) the latency separating the pre-myoclonic EEG potential and the P30 component of the onset of the myoclonic jerks is similar to the latency of the MEP for that muscle obtained by TMS (Toro & Hallett, 1997).

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Epileptic negative myoclonus

Brief (50–200 ms) and irregular muscle inhibitions during maintenance of a posture, visible as EMG silent periods, give rise to asterixis (Young & Shahani, 1986), a phenomenon observed in patients with metabolic encephalopathies or with focal lesions of the sensorimotor cortex (Young & Shahani, 1986; Degos et al., 1979). Asterixis is one of the expressions of negative myoclonus (Fahn et al., 1986). Asterixis is usually multifocal in distribution but may affect a single somatic segment. In some patients jerk-locked EEG averaging shows a contralateral cortical transient time locked with the EMG silent period (Ugawa et al., 1989; Artieda et al., 1992). Recently, Shibasaki and colleagues (1994) have described cortical reflex negative myoclonus limited to muscles of one limb in patients affected by PMEs. A similar phenomenon is seen in epileptic negative myoclonus (see also Chapter 6), in which 50–400 ms periods of muscle inhibition with focal, multifocal or bilateral distribution are time-locked to sharp wave or spike-wave discharges on the contralateral central areas (Guerrini et al., 1993; Shibasaki, 1995). Clinically, it may be difficult to differentiate positive and negative epileptic myoclonus, as silent periods of sufficient duration may cause sudden lapses in posture, followed by brisk jerky movements which represent attempts to resume the original posture. Epileptic negative myoclonus is etiologically heterogeneous, and may be observed in idiopathic epilepsy, in association with cortical dysplasia, or may be precipitated by adverse reaction to antiepileptic drugs (Guerrini et al., 1993, 1998b). Shewmon and Erwin (1988) studied a visual-related task in patients with occipital spike-andwave discharges as a model aimed at demonstrating that each ‘interictal’ paroxysmal EEG discharge may disrupt a specific cortical function for a length of time corresponding to its duration. According to this model, epileptic negative myoclonus is the clinical counterpart of spike-and-wave discharges involving neurons in the sensorimotor cortex. When the paroxysmal abnormalities are very frequent, anatomic-specific dysfunction of the higher cortical functions may also appear (see Chapter 6). EMG silence, in selected muscles, with a duration of 50–300 ms, may be triggered either by stereotaxic stimulation of the boundary region between the thalamus and the capsula interna (Pagni et al., 1964), or by transcutaneous electrical or transcranial magnetic stimulation of the motor cortex (Marsden et al., 1973). Therefore interpretation of such inhibitory motor phenomenona does not necessarily require disinhibitory (Engel, 1995) ictal activation of ‘negative’ motor areas (Hallett, 1995). It is sufficient to assume hypersynchronous ictal inhibition in ‘primary’ motor cortex neurons. The myoclonic jerks produced by the postural lapses and subsequent postural recovery, typical of epileptic negative myoclonus, seems to be different from post-myoclonic atonic phenomena, which are usually

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generalized (Guerrini et al., 1994a). Gastaut and Regis (1961) showed that ‘inhibition of muscle tonus can immediately follow the myoclonias of Petit Mal and may be so pronounced as to cause a fall’ and that ‘myoclonia always corresponds to the polyspikes whereas the tonic inhibition corresponds to the slow waves which follow them’. We now know that several epileptic syndromes featuring violent myoclonic jerks, followed by a transient (100–400 ms) inhibition, are characterized by myoclono-atonic falls, e.g. benign myoclonic epilepsy, myoclono-astatic epilepsy, myoclonic Lennox–Gastaut syndrome. Postural lapses, preceded by EMG bursts or occurring as merely inhibitory phenomena, have also been described as being associated with periodic slow-wave complexes in subacute sclerosing panencephalitis (Hamoen et al., 1956; Cobb, 1966). Lapses lasting up to 400 ms have also been described during diffuse sharp-wave bursts in infantile spasms (Hakamada et al., 1981). Patients with intention and action myoclonus described by Lance and Adams (1963) showed myoclonic bursts followed by muscle inhibition which, outlasting the EMG burst, could contribute significantly to the clinical picture. Patients with PMEs may present with similar manifestations (Roger et al., 1992; Shibasaki et al., 1994). Epileptic syndromes and neurological disorders with cortical myoclonus Cortical action / reflex myoclonus

Postanoxic (or posthypoxic) encephalopathy is characterized by dysarthria, ataxia, pyramidal signs, rigidity, epilepsy, and myoclonus, the last of which may be a predominant feature. Usually myoclonus is both spontaneous and action-activated, multifocal, and generalized, and is extremely disabling in patients who have suffered severe anoxia. Lance and Adams (1963) provided the first description of postanoxic myoclonus and showed the existence of EMG silence following the jerks as postmyoclonic atonia responsible for the postural lapses often seen in these patients. Postanoxic myoclonus may be of several physiologically distinct types. It may be cortical in origin and involve the sensorimotor cortex and rapidly conducting pyramidal pathways (Hallett et al., 1979; Young & Shahani, 1979). More rarely the myoclonus may be of brainstem origin, either as exaggerated startle reflex or as reticular reflex myoclonus (Hallett et al., 1977; Brown et al., 1991b). Forty per cent of patients with postanoxic myoclonus suffer from generalized epileptic seizures.

Postanoxic encephalopathy

Progressive myoclonus epilepsies This group of diseases is characterized by progressive myoclonus, generalized, tonic-clonic seizures and neurological deterioration (Commission, 1989). Onset is most frequent in late childhood or adolescence (Roger et al., 1992). The best known forms are Unverricht-Lundborg disease, Lafora disease, neuronal ceroidolipofuscinosis, type III Gaucher disease,

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infantile and juvenile GM2-gangliosidosis and some mitochondrial encephalopathies, sialidosis, dentatorubro-pallidoluysian atrophy (Roger et al., 1992). Specific mutations have been defined in Unverricht–Lundborg disease (Pennacchio et al., 1996), ceroid lipofuscinoses 3 or Spielmayer Voight syndrome within Batten’s disease (Lerner et al., 1995), sialidosis (Mueller et al., 1986), dentadorubropallidoluysian atrophy (Ueno et al., 1995), the mitochondrial syndrome MERRF (Shoffner et al., 1990; Shoffner & Wallace, 1992) and Lafora’s disease (Minassian et al., 1998a, 1999; Serratosa et al., 1999). Onset features comprise myoclonus and rare generalized tonic-clonic seizures. In the early stages, the myoclonus may be clinically and polygraphically indistinguishable from that of idiopathic myoclonic epilepsies (Roger et al., 1992; Guerrini et al., 1998c). The tonic–clonic seizures can occur without any warning or after a long build-up of myoclonus. The EEG shows generalized polyspike and spike-andwave discharges frequently precipitated by photic stimulation. With gradual progression of the disease, background activity becomes progressively slower (Roger et al., 1992). Common to all such syndromes is cortical reflex myoclonus, which is manifested with the classic combination of action myoclonus, spontaneous jerks, giant SEPs and C-reflex at rest, and the premyoclonus spike. With progression of the disease, myoclonus becomes increasingly prominent and disabling. Some forms have distinctive features which usually become apparent at advanced stages. Prognosis depends on the underlying disease. Corticobasal degeneration is a progressive disorder with onset in the elderly. It is mainly characterized by limb apraxia, alien limb phenomenon, slowness and rigidity, cortical sensory defects, dysarthria and aphasia, hand dystonia, and stimulus-sensitive myoclonus. The evolution is slowly progressive. Myoclonus is defined as atypical (Thompson et al., 1994a) because the latency of the reflex jerks is reduced to 40 ms (upper limb), that is to say 10 ms shorter than usual and only 2 ms longer than the sum of the afferent and efferent times to and from the cortex. In this case myoclonus may represent enhancement of a direct sensory input to the motor cortex (Thompson et al., 1994a). No seizures have been described.

Corticobasal degeneration

Alzheimer’s disease Alzheimer’s disease may show spontaneous and actioninduced myoclonus or, more typically, small amplitude jerks, with irregular twitching of the hand muscles, producing a tremulous appearance. Although myoclonus may be an early sign, it is most often a late manifestation (Wilkins et al., 1984; Hauser et al., 1986). Cortical–reflex myoclonus in Alzheimer’s disease is

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considered to be neurophysiologically typical (Wilkins et al., 1984; Ugawa et al., 1987), although the cortical relay time may be particularly long. The estimated number of Alzheimer’s disease patients developing myoclonus is about 10% and the ratio of patients developing seizures, mostly generalized, is similar (Hauser et al., 1986). There seems to be no increased risk of seizures in patients with myoclonus . Huntington’s disease In Huntington’s disease action myoclonus is a rare symptom, but a few patients have been described in whom myoclonus was the primary manifestation. Atypical cortical–reflex myoclonus can be observed (Carella et al., 1993; Thompson et al., 1994c). Seizures are a rare complication of Huntington’s disease and are mainly seen in cases of juvenile onset. Focal cortical repetitive myoclonus Epilepsia partialis continua Epilepsia partialis continua, also called ‘Kojewnikow’s syndrome’ (Kojewnikow, 1895), is characterized by almost continuous, rhythmic muscle jerks affecting a limited part of the body for a period of hours, days, or even years (Commission, 1989), and is associated with unilateral somatomotor seizures. The myoclonic jerks have a frequency of about 1–2/s and may persist during sleep. In most cases neurophysiologic analysis of myoclonic jerks uncovers a cortical origin, either spontaneous or reflex. At least two types of epilepsia partialis continua have been identified: the first is a form of non-evolutive motor cortex epilepsy which has various etiologies; the second shows a progression typical of Rasmussen’s encephalitis (Commission, 1989; Rogers et al., 1994). The first type of epilepsia partialis continua is symptomatic of fixed epileptogenic lesions involving the motor cortex which, in children, are due to ischemic or post-traumatic lesions or cortical dysplasia (Bancaud, 1992; Fusco et al., 1992; Kuzniecky & Powers, 1993), and in adults to vascular or tumoral insults of the rolandic cortex. A stable motor deficit usually pre-exists the onset of seizures. This type is characterized at onset by somato-motor seizures, frequently followed by permanent segmentary myoclonus resistant to drug treatment. Its course is not progressive (Bancaud, 1992), except in relation to the evolution of the causal lesion (Commission, 1989). A second type of epilepsia partialis continua is identified with Rasmussen’s syndrome; a form of chronic encephalitis affecting one hemisphere. An autoimmune etiology is hypothesized on account of the presence of antibodies to the anti-glutamate receptor 3 in some patients (Rogers et al., 1994; Krauss et al., 1996; Andrews et al., 1997). Onset occurs during childhood, with the appearance of epilepsia partialis continua and intractable focal, unilateral or generalized seizures, progressive hemiparesis, hemianopia and, eventually, cognitive deterioration. Magnetic resonance

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imaging shows progressive atrophy of the affected hemisphere. Pathological studies reveal inflammation with perivascular infiltrates and microglia nodules (Andrews et al., 1997). In a very small number of cases an analogous form of progressive epilepsia partialis continua may be observed in children with mitochondrial encephalopathy of the MELAS type (Bancaud, 1992). Rhythmic fast bursting cortical myoclonus Angelman syndrome Angelman syndrome is a neurogenetic disorder which derives from a defect in maternal chromosome 15q11–q13. Seventy per cent of patients present a cytogenetic or molecular deletion including three subunits of receptor A for -aminobutyric acid (GABAA) (subunits GABRB3, GABRA5 and GABRG3) and the gene UBE3A. Less frequently, AS is caused by uniparental paternal disomy (UPD), or mutations in the imprinting centre or in the UBE3A gene. Patients present with severe mental retardation, absence of language, microbrachicephaly, inappropriate paroxysmal laughter, epilepsy, EEG abnormalities, ataxic gait, tremor and jerky movements. Neurophysiologic and polygraphic investigations reveal a spectrum of myoclonic manifestations (Guerrini et al., 1996). All patients present with rapid distal jerking of fluctuating amplitude, which causes a sort of coarse distal tremor combined with dystonic limb posturing. Jerks occur at rest in prolonged runs. In addition, the majority of patients have myoclonic and absence seizures, as well as episodes of myoclonic status. Bilateral jerks of myoclonic absences show rhythmic repetition at 2.5 Hz and are time locked with a cortical spike. Interside latency of both spikes and jerks is consistent with transcallosal spread and spike-to-jerk latency indicates propagation through rapid conduction cortico-spinal pathway. In patients with a deletion, epilepsy is much more severe than in those without. It is therefore likely that in addition to UBE3A, other genes in 15q11–13 (especially GABRB3) could play a major role in epileptogenesis (Minassian et al., 1998b) (see Chapter 2). Autosomal dominant cortical reflex myoclonus and epilepsy Several families of Japanese origin have recently been described, with a dominant disorder characterized by cortical tremor, myoclonic jerks and generalized tonic–clonic seizures (Kuwano et al., 1996; Ikeda et al., 1990; Okino, 1997; Terada et al., 1997; Okuma et al., 1998). In spite of different names given to the condition, affected patients present very homogeneous characteristics: (i) autosomal dominant inheritance; (ii) adult onset (mean age 38 years, range: 19–73; (iii) non-progressive course; (iv) distal, fairly rhythmic myoclonus, enhanced during posture maintainance; (v) rare, apparently generalized seizures often preceded by worsening of myoclonus; (vi) absence of other neurological signs; (vii) generalized

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interictal spike-and-wave discharges; (viii) photoparoxysmal response; (ix) giant SEPs; (x) hyperexcitability of the C-reflex; (xi) cortical EEG potential time locked to the jerks. Linkage analysis in five of the Japanese kindreds, in two different studies, led to localization of the disease gene to chromosome 8q23.3–q24.1 (Mikami et al., 1999; Plaster et al., 1999). An Italian family with earlier age of onset (mean age9 years) and moderate mental retardation was reported by Elia and coworkers (1998). We recently observed an Italian family with 11 affected individuals (of whom 8 are living) over five generations, with the same clinical and neurophysiological characteristics as the Japanese families, but with variable severity of the associated generalized epileptic seizures. Since the severity of the condition appears to be variable and the main complaint was of major seizures, we propose to define this condition as ‘autosomal-dominant non-progressive cortical reflex myoclonus and epilepsy’. This disease is not limited to a geographical area and is probably underdiagnosed rather than extremely rare, as the cortical tremor is easily missed or interpreted as druginduced. We believe that many such patients may have been wrongly diagnosed as having juvenile myoclonic epilepsy (Panayiotopoulos et al., 1994). Epileptic syndromes with secondarily generalized epileptic myoclonus

SME is observed in 6–7% of children with seizure onset in the first 3 years of life (Dravet et al., 1992a). Up to 64% of patients have a family history of epilepsy or febrile convulsions (Dravet et al., 1992a). Onset of epilepsy occurs during the first year of life, in previously healthy children, with prolonged seizures during fever that rapidly become associated with non febrile attacks of the same type: generalized or unilateral, clonic or tonic–clonic, often prolonged, or repeated in status. By the fourth year of life, myoclonic and partial seizures, and atypical absences, also appear. EEG is normal at the beginning, but subsequently shows generalized discharges and multifocal abnormalities. Early photosensitivity is seen in some children. Neurological development appears delayed from the second year of life onwards. Seizures are particularly resistant to treatment. Epilepsy remains extremely active up to the age of 11–12 years; subsequently, there is a reduction in the frequency of seizures (Dravet et al., 1992a). Two main types of myoclonia are observed. Almost all children show arrhythmic distal jerks, manifested as twitching of fingers. In a small series of patients (Guerrini et al., 1998c), no C-reflex at rest or enlarged SEPs were found, and jerklocked back-averaged EEG did not reveal any time-locked activity. It therefore seems that these small jerks are either not produced in the cortex or result from discharges arising from such a small number of neurons that the electrical activity is

Severe myoclonic epilepsy (SME)

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Fig. 12.4

Generalized myoclonus in a patient with symptomatic SME. Back-averaging from seven myoclonic jerks of the left orbicularis oris. Averaging shows the tight relation between myoclonus and EEG spiking. Interside latency EEG discharges (12 ms) is compatible with interhemispheric spread. L. Massleft masseter; L. O. Orisleft orbicularis oris; L. Delt. left deltoid; L. APBleft abductor pollicis brevis; L. Quad.left quadriceps; R. Mass.right masseter; R. Delt.right deltoid; R. Quad.right quadriceps.

undetectable. In fact, since this clinical pattern of distal myoclonus is very similar to minipolymyoclonus of cortical origin (Wilkins et al., 1985) it is possible that a cortical origin could just not be demonstrated. Children with SME also have generalized jerks preceded by clearcut spike-and-wave discharges. Such jerks appear to originate from the spread of focal cortical myoclonic activity (Guerrini et al., 1998c). Indeed, when averaging EEG activity correlated to the first muscle to burst in a given generalized jerk, there is evidence for one leading hemisphere and for

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interhemispheric spread of cortical myoclonic activity (Fig. 12.4). If, on the other hand, single consecutive jerks are studied, the leading side shifts from one discharge to the next (Fig. 12.5). So there is preliminary evidence that in this cryptogenic epilepsy, myoclonus can originate, like the other seizure types, from multiple cortical areas. Lennox–Gastaut syndrome Lennox–Gastaut syndrome is included among the cryptogenic or symptomatic generalized epilepsies (Commission, 1989). Its prevalence is 2–3% in children with epilepsy (Beaumanoir & Dravet, 1992). In most cases it appears in children with diffuse brain damage, with onset at 3–5 years years of age (Beaumanoir & Dravet, 1992). The most typical seizures are tonic, atonic, or atypical absences. It is often difficult, or indeed impossible, to distinguish between atonic seizures and atypical absences with an atonic component. Other types of seizures which may occur in addition are myoclonic, generalized tonic–clonic, and partial. Seizures are almost always resistant to pharmacological treatment. Status is frequent. The interictal EEG shows generalized spike-waves with a frequency below 3 Hz, and often multifocal abnormalities with abnormal background activity. During sleep, all patients show typical rhythmic discharges at around 10 Hz, accompanying tonic seizures or without apparent clinical correlate. Myoclonus is not a prominent feature of Lennox–Gastaut syndrome (Gastaut, 1982), but some patients do exhibit myoclonic jerks. Neurophysiologic analysis of myoclonus in patients with symptomatic Lennox–Gastaut syndrome (Guerrini et al., 1998c) indicated that although jerks and the accompanying spike-and-wave discharges were apparently generalized (Fig. 12.6(a)), they showed interside latencies consistent with transcallosal spread (133 ms) and premyoclonus spike latencies consistent with cortical origin (189 ms). Topographic mapping showed a frontal distribution of the electrical field, probably because there is a fixed lesion involving this area and acting as a trigger (Fig. 12.6(b)). The major difference compared to SME was that in Lennox–Gastaut syndrome the leading side was constant, while in SME there was no evidence for a constant area of origin for myoclonus. One particular form of myoclonus encountered in different symptomatic conditions was described by Wilkins et al. (1985) and referred to as minipolymyoclonus. It is characterized by small focal jerks, predominating distally, frequently leading to individual tiny finger movements. Jerks can be seen synchronously in both hands. Back-averaged EEG demonstrated in some of the patients described by Wilkins et al. (1985) a bifrontal negative slow wave, preceding the jerks by 20–500 ms, and in other patients a sharper bifrontal negativity preceding the jerks by 40 to 70 ms. One remarkable case had a 8 Hz bifrontal rhythm, time-locked with the myoclonic jerks.

Fig. 12.5

Same patient as in Fig. 12.4. When single consecutive jerks are studied, the leading side shifts from one discharge to the next

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Although the original description indicated that minipolymyoclonus was related to primary generalized epileptic myoclonus, current clasification concepts indicate that some of the patients described had cryptogenic and symptomatic epilepsies. There is in fact a strong similarity between minipolymyoclonus and the pattern of distal myoclonus observed in patients with severe myoclonic epilepsy who often present with tiny irregular finger jerks, as well as in patients with Lennox–Gastaut syndrome who may have small jerks with a time-locked frontal potential and patients with Angelman syndrome, who show rhythmic bilateral hand jerking and a time-locked anterior 8 Hz rhythm (Guerrini et al., 1996). Idiopathic (primary) generalized epileptic myoclonus Clinical findings

This type of myoclonus is common to various epileptic syndromes, in which it may be observed either as the sole manifestation or in association with other seizure types. Clinically, myoclonus presents as generalized, spontaneous, predominantly arrhythmic jerks, with inconstant axial predominance. Depending on severity, patients may present with simple head nodding or raised shoulders, or may stagger or fall. Neurophysiologic findings

The generalized jerks appear to originate from afferent volleys from subcortical structures that act synchronously on a hyperexcitable cortex (Gloor, 1979; Hallett, 1985). As a consequence, muscles from both sides are activated synchronously, as in reticular myoclonus, and muscles innervated by the cranial nerves are involved through a rostro-caudal pattern of activation, as in cortical myoclonus. This suggests that the impulse generating myoclonus descends through the brainstem. The EEG correlate is a generalized spike-wave, in which the negative peak of the spike precedes the generalized jerks by 20–75 ms (Commission, 1997). Duration of the EEG transient is 30–100 ms, and that of the myoclonic potential is less than 100 ms. Epileptic syndromes and neurological disorders with primary generalized epileptic myoclonus Idiopathic generalized epilepsies

Two recognized syndromes exhibit generalized myoclonus as their main clinical manifestation (Commission, 1989; 1997): benign myoclonic epilepsy in infancy and juvenile myoclonic epilepsy (JME). Overlapping with these two forms of myoclonus is myoclonic-astatic epilepsy (MAE) (Commission, 1997). However, the latter is considered to be a cryptogenic or symptomatic generalized epilepsy, on account of the frequent presence of mental retardation, although no specific etiology has ever been demonstrated.

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F4

L. O. Oris L. Delt.

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(a) Seemingly bilateral synchronous myoclonic jerks in a patient with symptomatic Lennox–Gastaut syndrome. Each spike is followed by a myoclonic jerk. (b) Same patient as in A; backaveraging from seven myoclonic jerks of the right deltoid. Averaging shows the tight relation between myoclonus and EEG spiking. Interside latency EEG discharges

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Myoclonus and epilepsy Benign myoclonic epilepsy of infancy Dravet and Bureau defined this syndrome in 1981, after which only isolated case reports or small groups of patients were reported from Europe (Dalla Bernardina et al., 1983; Colamaria et al., 1987; SalasPuig et al., 1990a; Todt & Muller, 1992; Dravet et al., 1992b; c). This syndrome is, however, probably more frequent than is commonly recognized, with many cases possibly unreported in countries where polygraphic EEG is not carried out. Among patients with seizure onset in the first 3 years of life, BME represents 0.4% to 2% of cases (Dalla Bernardina et al., 1983; Dravet et al., 1992b; Guerrini et al., 1994b). Age at onset ranges between 4 months and 3 years. Rare cases with identical clinicoelectrographic characteristics and onset up to age 5 years have been recorded (Guerrini et al., 1994b). Some of the patients reported by Dravet and Bureau (1981) were mentally retarded when evaluated at ages of between 10 and 15 years (Dravet, 1990; Dravet et al., 1992b, c). Mild to moderate forms of mental retardation as the only neurological manifestation are difficult to identify in the first year of life before the onset of myoclonus, and can be associated with fixed encephalopathies with a genetic basis. Seizures consist of generalized myoclonic jerks, brief, isolated or repeated in series of 2 or 3. Intensity and frequency vary not only from patient to patient but also within the same patient. In the mildest cases, jerks are identified polygraphically, but do not cause significant clinical changes. Jerks occurring during sleep are often mistaken for sleep myoclonus. If the child is standing or sitting, the jerks often cause nodding with upward gaze deviation and eyelid myoclonia, accompanied by slight arm abduction or elbow bending. Staggering may occur, especially up to the second year of life, when walking is still unstable. Though falls are unusual, when they occur the child falls on its buttocks and then gets up immediately to continue whatever it was doing. In most cases, the jerks occur many times per day. The myoclonic jerks are usually the only ictal manifestation, although a few patients from the series of Dravet and colleagues (1992b) had generalized tonic–clonic seizures in adolescence after therapy was withdrawn. Neurophysiology of myoclonus reveals symmetric, rostrocaudal muscle activation and a premyoclonus negative spike preceding jerks by 302 ms (Guerrini et al., 1998c). Duration of the myoclonic jerk is roughly 100 ms.

Caption to fig. 12.6 (cont.) (16 ms) is compatible with interhemispheric spread and premyoclonus spike latency (18  9 ms) is consistent with cortical origin. On the right, voltage field mapping of the positive spike on F3 (at the time point indicated by the vertical line), shows the focal distribution of the EEG activity related to myoclonic jerks. L. O. Orisleft orbicularis oris; L. Delt.left deltoid; R. O. Orisright orbicularis oris; R. Delt.right deltoid.

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The same type of generalized epileptic myoclonus can be encountered in children with mental retardation in the context of static encephalopathies of different genetic etiologies. Its neurophysiologic features and good outcome are the same as those observed in BME (Guerrini et al., 1994b). Therefore the simple, generalized myoclonic jerk can either be the expression of different epileptogenic genetic abnormalities or the nonspecific result of a low seizure threshold, a ‘fragment of epilepsy’ (Fahn et al., 1986). In most cases of BME, myoclonic seizures have no triggering factors. About 10% of affected children exhibit photic-induced jerks (Dravet et al., 1992b; Guerrini et al., 1990) clinically indistinguishable from spontaneous jerks. Some children have reflex myoclonus triggered by tactile or sudden acoustic stimuli, which may be associated with spontaneous jerking (Revol et al., 1989; Deonna & Despland 1989; Ricci et al., 1995). Hence, these are forms of BME with reflex seizures, or true reflex epilepsies.

Reflex form of benign myoclonic epilepsy in infancy

Juvenile myoclonic epilepsy Juvenile myoclonic epilepsy has a prevalence of between 3.4 and 11.9% (Genton et al., 1994) and represents 23.3 % of all idiopathic generalized epilepsies (Genton et al., 1994). Although a gene involved in JME has been linked to chromosome 6p, the syndrome appears to be genetically heterogeneous (Delgado-Escueta et al., 1994). Onset occurs at around age 14, with generalized myoclonus and generalized tonic–clonic seizures. Myoclonic jerks constitute the initial symptom in 54% of patients, and are bilateral, single or repetitive, arrhythmic, and more pronounced in the upper limbs. If intense, they may result in falls, but do not seem to be accompanied by loss of consciousness. They are characteristically concentrated in the minutes following wakening. In 5% of patients, generalized jerks are also triggered by IPS. In 7% of patients, there may be episodes of myoclonic status (Salas-Puig et al., 1990b), at times precipitated by inappropriate drug use, especially carbamazepine. Generalized tonic–clonic seizures are present in 84% of patients and represent the initial symptom in 35% of cases. They are often preceded by generalized myoclonic jerks. In 27% of patients, absences are also present, occurring infrequently (less than several times per week). Treatment with valproic acid in monotherapy or in association with clonazepam (CZP) leads to total control of seizures in 80 % of patients (Genton et al., 1994). Discontinuation of drug therapy is followed by a high rate of relapse (90%) (Genton et al., 1994). JME is apparently a lifelong condition, although there may be periods of remission and a decrease in seizure propensity with increasing age. Neurophysiologic analysis of myoclonus indicates that muscles from both sides are activated synchronously and muscles innervated by the cranial nerves are

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involved through a rostro-caudal pattern of activation. The EEG correlate is a generalized spike-wave, in which the negative peak of the spike precedes the generalized jerks by 30 ms (Guerrini et al., 1998c). Duration of the EEG transient is 100 ms, and that of the myoclonic potential is less than 100 ms. Myoclonic-astatic epilepsy (MAE) Epilepsy with myoclonic–astatic seizures is a generalized cryptogenic or symptomatic form with onset between 7 months and 6 years. Children with MAE have several types of seizures, including atypical absences, generalized clonic or tonic–clonic seizures, massive myoclonus and episodes of status epilepticus with erratic myoclonus and clouding of consciousness. Since the classification was published (Commission, 1989), there has been growing evidence that among children with myoclonic–astatic epilepsy, there is a large subgroup with idiopathic epilepsy or ‘primarily generalized seizures’ (Doose et al., 1970; Doose, 1985, 1992). Although the distinction between myoclonic–astatic epilepsy and Lennox–Gastaut syndrome is now accepted (Beaumanoir & Dravet, 1992; Dulac & N’Guyen, 1993), among patients previously included under the heading of MAE there still appears to be an overlap with other syndromes which feature myoclonus. In children whose only clinical feature is severe myoclonus and whose prognosis is favourable, the likely diagnosis is benign myoclonic epilepsy. Children who have frequent and prolonged unilateral alternating febrile and afebrile clonic seizures from the first year of life and myoclonic attacks after some years probably have severe myoclonic epilepsy in infancy (Dravet et al., 1992a). However, there continues to be a rather large subgroup of patients with ‘true myoclonic-astatic epilepsy’ (Dulac et al., 1990; Commission, 1997) who share some distinct electroclinical features but may have a variable outcome. The neurophysiology of myoclonus in MAE confirms this nosological interpretation (Guerrini et al., 1998c). Thus myoclonus may manifest in the form of bilateral synchronous single whole body jerks. As with myoclonus in BME and JME, this is consistent with the hypothesis of a thalamocortical volley. The jerks, which have a duration of 100 ms, are preceded by a negative EEG potential of 36 ms (Fig. 12.7). These children also show a peculiar form of myoclonic status, with the neurophysiological characters of erratic cortical myoclonus with multifocal jerking, increase in basic muscle tone and clouding of consciousness. Status may occur spontaneously or be precipitated by carbamazepine (Fig. 12.8(a), (b)). Epileptic syndromes with myoclonus of unclear neurophysiologic characterization Early myoclonic encephalopathy (EME) EME is a rare syndrome classified among the generalized symptomatic epilepsies with non-specific etiology (Commission, 1989). Its causes are multiple and of prenatal origin. Some inborn errors of

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Myoclonic Epilepsy MyoclonicAstatic astatic epilepsy F4 LD F3 RD

300 µV 100 ms

F4 LD F3 RD

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F4 LD F3 RD 150 µV

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Fig. 12.7

Generalized myoclonus in three children with MAE. Three or four single events are overlapped. Note the synchronous EMG bursting. L. Delt.left deltoid; R. Delt.right deltoid.

metabolism can provoke EME, such as methylmalonic acidemia and nonketotic hyperglycinemia. Onset is neonatal or occurs during the first month of life, with fragmentary, erratic and severe myoclonus, followed by partial seizures and tonic spasms. Fragmentary myoclonus involves the muscles of the face and the extremities, with multifocal distribution, leading to the description of ‘erratic’. The frequency of myoclonus varies from occasional to almost continuous. Neurological development is severely delayed, with marked hypotonia, impaired alertness and, often, vegetative state (Aicardi, 1992).

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The EEG is characterized by suppression bursts with bursts of spikes, sharp waves and slow waves, which are irregularly intermingled and separated by periods of electrical silence. Erratic myoclonus generally does not have an ictal EEG correlate. (Aicardi, 1992). Scher and Bergman (1986) studied patients with non-ketotic hyperglycinaemia, demonstrating that whole body myoclonus can be spontaneous or triggered by tactile–proprioceptive stimuli and is often associated with generalized EEG discharges. Spongy leucodystrophy of all myelinated tracts, especially of the reticular activating system, confirms the role of the non-specific diffuse somatosensory projection system in the generation of generalized myoclonus (Scher & Bergman, 1986). Myoclonic status in fixed encephalopathies This condition is seen exclusively in severe encephalopathies with profound cognitive deficit and hypotonia, and is characterized by recurrent, prolonged, and drug-resistant episodes of myoclonic status (Dalla Bernardina et al., 1992). About half the cases, reported by Dalla Bernardina et al. turned out to have Angelman syndrome (Dalla Bernardina et al., 2001). Associated seizure types include: partial motor, myoclonic absences, generalized myoclonias and, rarely, unilateral or generalized clonic seizures. Myoclonic status is characterized by almost continuous absences accompanied by erratic, distal, multifocal, frequent myoclonias, which sometimes become more rhythmic and diffuse. This condition may be insidious, because reduced awareness may be diffcult to recognize in severely mentally retarded children and associated jerks may be very mild, and become clearly detectable only during polygraphic EEG/EMG recordings. When the myoclonic jerks are rhythmic and bilateral, in bursts or continuous, they are closely related to 1.5–2.5 Hz spike-and-wave discharges (Guerrini et al., 1996). Sometimes, myoclonias are continuous but asynchronous in the different muscles involved. In this case the relationship between myoclonic jerks and paroxysmal EEG discharges is more difficult to appreciate on surface EEG (Dalla Bernardina et al., 1992). It is extremely important to recognize this condition, which can mimic a progressive encephalopathy. Epilepsy with myoclonic absences Epilepsy with myoclonic absences is currently classified among cryptogenic or symptomatic generalized epilepsies (Commission, 1989). Onset is at about age 7 years with absences recurring many times a day, accompanied by bilateral rhythmic jerks, involving the shoulders, arms or legs. There may be concomitant mild axial tonic contraction. Consciousness is cloudy (Tassinari et al., 1992) but not completely interrupted. Bilateral, synchronous and symmetric spike-wave discharges at 3 Hz accompany the absences. Myoclonic jerks

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Fig. 12.8

(a) Myoclonic status epilepticus precipitated by carbamazepine in a child with myoclonic–astatic epilepsy. Clinically, the child is unresponsive and shows multifocal and generalized jerks. The EEG shows diffuse slow waves, interspersed with diffuse or multifocal irregular slow spike and wave complexes. Simultaneous surface EMG shows arrhythmic, focal and generalized myoclonic potentials on a background of mild tonic contraction.

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Fig. 12.8

Average = 150

(b) Same patient as in Figure 12.8 (a) Back-averaged EEG activity (n150; rectified EMG) in relation to a spontaneous focal jerk involving left wrist extensor and flexors muscles (LWE and LWF). A positive–negative potential, well recognizable over the C4 electrode, precedes the jerk by 20 ms.

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have the same frequency as the EEG discharges. Absences are often resistant to treatment. Other types of seizures are observed only rarely. Evolution is variable: cognitive deterioration, evolution towards a different type of epilepsy, at times full recovery without sequelae. The physiology of myoclonus in epilepsy with myoclonic absences is difficult to study as this condition is rare, and in the majority of patients the jerks appear against a background of increased muscle tone (Guerrini et al., 1998c). Tassinari and co-workers (1995) found a close and constant relationship between the spikeand-wave complex and the jerk, in that the positive spike of the spike-and-wave complex is followed by a myoclonic jerk with a latency of 15–40 ms (proximal muscles). Reticular reflex myoclonus Reticular myoclonus presents most of the clinical and neurophysiological characteristics of epileptic myoclonus although it lacks a time-locked EEG correlate (Hallett, 1985). Clinical findings

Clinically, the myoclonias are generalized, with greater involvement of proximal and flexor muscles, spontaneous, or induced by somatosensory, auditory and visual stimuli, or by movement (Hallett et al., 1977; Hallett, 1985). Neurophysiologic findings

Reticular myoclonus is believed to originate from the brain stem reticular formation. This hypothesis is supported by the finding that when there is involvement of muscles innervated by the cranial nerves, the surface EMG shows activation, initially, of the trapezius muscle (XIth cranial nerve), followed by the sternocleidomastoid (XIth cranial nerve), the orbicularis oris (VIIth cranial nerve), and finally the masseter (Vth cranial nerve). The initial activation of the trapezius muscle suggests that the impulse generating the myoclonus originates from the medulla (Hallett et al., 1977). In addition, EEG or JLA allows demonstration of an EEG potential with wide distribution over the hemispheres and greater amplitude at the vertex, which is not time locked with the myoclonic potential but often follows muscle activation. These observations suggest that the spike is projected and is not directly responsible for the myoclonus (Hallett, 1985). The somatosensory-evoked potentials do not have increased amplitude. When the myoclonus is of the reflex type, it is possible to estimate the speed of conduction of the efferent bulbospinal motor pattern. The difference in latency between

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the different muscles activated may be similar to that between the same muscles when activation is obtained through TMS of the motor cortex (Brown et al., 1991b) when rapidly conducting bulbospinal motor pathways mediate the reflex jerks. However, slower conduction has also been observed, suggesting that there could be various subtypes of reticular reflex myoclonus, given that there are several descending reticular spinal systems with different conduction velocities (Rothwell et al., 1986). Patients have been described with postanoxic encephalopathy, and with a combination of cortical myoclonus and brainstem reticular reflex myoclonus (Chadwick et al., 1977; Hallett et al., 1979; Brown et al., 1991b). Clinically, there are both multifocal and generalized jerks. Cantello and coworkers (1997) found that in a series of patients with MERRF and Unverricht-Lundborg disease, the sum of afferent and efferent times to and from the cortex was longer than the latency of the reflex or spontaneous myoclonus. These authors hypothesized that the short-latency myoclonic discharge originated subcortically, at a site with sufficient somatotopic organization, to spread upward to produce a cortical potential and downward to the spinal cord to produce the jerk. Such a subcortical mechanism would be additional and not alternative to cortical reflex myoclonus. Although no hypothesis was formulated about the specific subcortical site of origin of myoclonus, a reticular origin was considered unlikely because of its focal nature. The patients studied had multifocal spontaneous, action and reflex jerks, but none presented with generalized jerks which is a frequent expressions of action myoclonus. However, in a subsequent study the same pattern of myoclonus was also observed in patients showing reflex generalized jerks consisten with reticular reflex myoclonus, in response to somatosensory stimulation (Cantello et al., 1997). One wonders whether a predominantly multifocal or generalized expression of reticular myoclonus is possible according to the underlying pathological substrate. Neurophysiological study of reticular reflex myoclonus is difficult, especially because of the coexistence of cortical myoclonus. Only a few patients have been reported. As a consequence its neurophysiological correlates and relationships with epilepsy are not fully understood. The presence of seizures in most reported patients indicates a close clinical association with epilepsy. Although an EEG spike is often associated with the myoclonic jerks, EEG and EMG events are not time locked, suggesting that the spike is projected, does not originate primarily in the cortex and is not directly responsible for the myoclonus (Hallett, 1985). Myoclonus produced in the cat after urea infusion (Zuckermann & Glaser, 1972) has been proposed as an animal model for reticular reflex myoclonus. Electrophysiological recording demonstrated this to be generated by by neuronal activity resembling paroxysmal depolarization shifts in the nucleus reticularis

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gigantocellularis. Cobalt injection at this level also causes myoclonus (Cesa-Bianchi et al., 1967). According to such a model, in humans paroxysmal depolarization shifts in the caudal brainstem reticular formation would generate a volley producing muscle recruitment down the spinal cord and up the brainstem as well as a projected EEG discharge. Reticular reflex myoclonus must be distinguished from hyperekplexia, in which the reflex jerks represent an exaggerated normal startle reflex. Neurophysiological investigation has shown that the origin of startle response is in the caudal brainstem, but, unlike reticular reflex myoclonus, utilizes slowly conducting bulbospinal motor pathways (Rothwell et al., 1986). Treatment and antiepileptic drug-induced myoclonus The treatment of myoclonus is largely empirical because there has been little progress in understanding its biochemical basis. In this section we discuss the therapeutic possibilities in accordance with the pathophysiological origin of myoclonus regardless of the etiology. Both cortical (positive and negative) and thalamo-cortical (idiopathic generalized epileptic) myoclonus respond to clonazepam (CZP) and sodium valproate (VPA) (Commission, 1997). In cortical myoclonus, CZP is the most effective drug but piracetam is the first choice because it is so well tolerated (Brown et al., 1993; Genton et al., 1999), even though very high doses are needed to achieve significant results (Koskiniemi et al., 1998) . Also primidone and acetazolamide and, recently, zonisamide may be useful used in combination with CZP or VPA (Commission, 1997). In posthypoxic action myoclonus, administration of 5-HTP, a precursor of serotonin, may produce dramatic improvement (Chadwick et al., 1977), but is rarely used because of side effects. In idiopathic generalized myoclonus, VPA is the drug of choice. In resistant cases ethosuximide may be a useful adjunct when used in combination with VPA or CZP (Commission on Pediatrics – Dulac et al., 1998). Antiepileptic drugs may aggravate or precipitate myoclonus, positive or negative. Although some anecdotal reports indicate that Lamotrigine (LTG) may be useful in some ‘myoclonic’ epilepsies, there is no convincing data on this. Recent evidence indicates that add-on LTG treatment may induce worsening in patients with SME (Guerrini et al., 1998d). De novo myoclonic status epilepticus has been reported following high-dosage LTG therapy in Lennox-Gastaut syndrome (Guerrini et al., 1999). Both CBZ and VGB can worsen or precipitate myoclonic seizures (Talwar et al., 1994; Viani et al., 1995).

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De novo appearance of myoclonic jerks was described in several reports on children or young adults with cryptogenic or symptomatic partial epilepsy treated with add-on VGB (Lortie et al., 1993; Marciani et al., 1995). Exacerbation of ENM has been reported in a few children with benign rolandic epilepsy (BRE) after CBZ or phenobarbital treatment (Guerrini et al., 1995, 1998b see also Chapter 6). Comment

Epileptic myoclonus can be divided on a neurophysiological basis into cortical, positive and negative, thalamo-cortical and reticular. Cortical epileptic myoclonus constitutes a fragment of partial or symptomatic generalized epilepsy; thalamocortical epileptic myoclonus is a fragment of idiopathic generalized epilepsy (Hallett, 1985). Reflex reticular myoclonus, which does not have a time-locked EEG correlate, represents the clinical counterpart of fragments of hypersynchronous epileptic activity of neurons in the brainstem reticular formation. Attempts have been made to elaborate a classification of childhood epilepsies in which myoclonus constitutes the clinically most relevant element (Aicardi, 1980; Commission, 1989, 1997). However, considerable confusion still persists in clinical practice, as many cases prove difficult to classify. Our classification of epileptic syndromes and neurogenetic syndromes with myoclonus, established on the basis of data on record in the literature and from personal observations, has utilized neurophysiologic criteria to constitute three main categories of epileptic syndromes or disorders with myoclonus characterized by (see Table 12.2): (i) cortical epileptic myoclonus: (ii) thalamo-cortical EM; (iii) forms that are neurophysiologically difficult to classify. Classifying epileptic syndromes with myoclonus using more rigorous neurophysiological criteria, in addition to classical clinical and EEG observations, may certainly help determine diagnosis and treatment in uncertain cases. Specific epileptic syndromes such as severe myoclonic epilepsy, Lennox–Gastaut syndrome and myoclonic–astatic epilepsy, which have in the past been lumped together and confused with one another under the definition of myoclonic epilepsies, show different neurophysiological patterns of myoclonus, in addition to specific clinical features, and different responses to treatment.

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Table 12.2. Neurophysiological classification of epileptic syndromes and neurological disorders with epileptic myoclonus

ii(i) Epileptic syndromes and neurological disorders with cortical myoclonus Cortical action / reflex myoclonus Postanoxic encephalopathy Progressive myoclonus epilepsies Cortico basal degeneration Alzheimer’s disease Huntington’s disease Focal cortical repetitive myoclonus Non progressive Epilepsia Partialis Continua Rasmussen syndrome Rhythmic fast bursting cortical myoclonus Angelman syndrome Autosomal dominant adult-onset non-progressive CRM and epilepsy Fixed encephalopathies of various etiology (tuberous sclerosis, Down syndrome, post traumatic) Progressive myoclonus epilepsies Secondarily generalized epileptic myoclonus Severe myoclonic epilepsy Lennox–Gastaut syndrome Progressive myoclonus epilepsies Drug-induced cortical myoclonus (positive or negative) Carbamazepine Lamotrigine Phenobarbital Vigabatrin i(ii) Epileptic syndromes or disorders with primary generalized epileptic (thalamo-cortical) myoclonus Idiopathic (primary) generalized epilepsies Benign myoclonic epilepsy of infancy Myoclonic–astatic epilepsy Juvenile myoclonic epilepsy Genetically based fixed encephalopathies with primary generalized myoclonus (iii) Epileptic syndromes or disorders with myoclonus still awaiting neurophysiological classification Early myoclonic encephalopathy Myoclonic status in fixed encephalopathies Epilepsy with myoclonic absences

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R E F E R E N C ES

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13

The spectrum of epilepsy and movement disorders in EPC Hannah R. Cock and Simon D. Shorvon University Department of Clinical Neurology, Institute of Neurology, London, UK

Introduction Since the first descriptions at the end of the last century of a ‘peculiar form of cortical epilepsy’ (Kojewnikow, 1895), there has been much written about what we now term epilepsia partialis continua (EPC). This initial description of ‘localized continuous clonic jerks’, intermingled in these cases with more typical spreading focal motor seizures of the Jacksonian type (Taylor, 1931), has been followed by numerous other case reports and series. There has been much debate concerning the most appropriate definition, and what pathophysiological mechanisms underlie this particular movement disorder. Now, over a century later, although much progress has been made, there are still many unanswered questions. This chapter will start by considering the definition and mechanisms underlying EPC, followed by a review of the current clinical literature in terms of etiologies, diagnosis, prognosis and treatment. EPC is undoubtedly rare. The only study from which epidemiological data can be inferred is that of Cockerell et al. (1996), which identified 40 cases in the United Kingdom over a 1-year period. This suggests an estimated minimum prevalence of less than 1 in a million, so most neurologists will have little if any clinical experience of the condition. The most frequent cause of EPC is Rasmussen’s encephalitis (Rasmussen et al., 1958; Andermann, 1991), accounting for 20–50% of EPC cases and predominantly affecting children (Dereux, 1955; Lohler & Peters, 1974; Cockerell et al., 1996). Definition and pathophysiology Kojewnikow (1895) in describing his four cases with frequent localized jerks continuing for years and uninfluenced by treatment, inaugurated the term ‘epilepsia corticalis sive partialis continua’, subsequently abbreviated to the terminology now Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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widely used. In this and subsequent series of a specific condition, later etiologically linked to Russian spring–summer encephalitis (Omorokov, 1927), the authors describe jerks of brief duration typically affecting agonist and antagonist muscles, with a rhythmic quality, persisting in sleep, worsened by action and stress, and continuing relentlessly over time. More recent definitions have changed little. That of Obeso et al. (1985) is probably the most widely accepted, proposing that EPC be defined as ‘spontaneous regular or irregular clonic muscle twitching of cerebral cortical origin, sometimes aggravated by action or sensory stimuli, confined to one part of the body and continuing for a period of hours, days or weeks’. The only remarkable modification here is the additional specification that EPC must be, by definition, of cortical origin. Extending this premise, most authorities would now accept that EPC, being of cortical origin, represents a form of focal motor status epilepticus (Thomas et al., 1977; Schomer, 1993; Shorvon, 1994; Treiman, 1995). In the series of Bancaud et al. (1982) EPC was further subclassified into two groups, still commonly referred to today. Eleven of their 23 patients corresponded to the classical description of Koljewnikow. This group had variable age of onset, rare somatomotor seizures, a sometimes long delay before the onset of EPC, normal neurological examination or a stable hemiplegia, normal psychometry and only localized EEG disturbances. In contrast Bancaud’s type 2 had early onset of EPC, other frequent seizure types, quite widespread localization of myoclonic jerks, and a progressive neurological syndrome commonly including hemiplegia, mental deterioration, behavioural abnormalities, and a characteristic EEG pattern with long subclinical paroxysms of slow spikes. This second group includes patients that would now be considered to have Rasmussen’s encephalitis. It is notable that, against the prevailing view of the times, that myoclonus arose from the hyperexcitability of anterior horn cells in the spinal cord, and despite lacking pathological evidence from his cases, Kojewnikow recognized the cortical origins or EPC at the outset (Kojewnikow, 1895). Later pathology (Omorokov, 1927) and early EEG studies supported this with frontal polyspikes and waves corresponding to time-locked peripheral motor jerks, in patients with either isolated myoclonic jerks (Grinkler et al., 1938) or EPC (Kugelberg & Widen, 1954). Depth electrode studies such as that by Bancaud et al. (1970), and the successful creation of an animal model by subpial injections of aluminium (Chauvel & Lamarche, 1975) or tetanus toxin (Louis et al., 1990) conformed to this opinion. However, it is clear that, in some patients, continuous jerking, indistinguishable from EPC, can arise from subcortical structures. Furthermore, in many cases, the site of origin is uncertain after routine investigations such as MRI and EEG have often failed to show any structural or epileptiform abnormalities in association with clinically definite EPC (Thomas et al., 1977; Cockerell et al., 1996). The idea that EPC can have subcortical origins was first instigated by Juul-Jensen and Denny-Brown in

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1966. In this case series, nine patients had large, predominantly acute lesions affecting cortical and subcortical structures, and EPC consistent with the previous clinical definitions, but with no time-locked associated EEG phenomena. Although recognizing that EPC can, in some conditions be associated with focal clinical seizures, the authors drew a sharp distinction between EPC and focal seizures, observing that EPC lacked the march of the clonic phase, and progression from tonic to clonic phases usually associated with focal motor seizures. JuulJensen and Denny-Brown suggested that the jerks in EPC were of subcortical origin, representing a disequilibrium in subcortical reflex activity whereby clonic jerks occurred due to the release of extrapyramidal mechanisms from their normal cortical control. In support, the authors also cite their own work on monkeys where spontaneous jerks had been observed after subcortical lesions in the cerebellum, thalamus and deep parietal lobe in the absence of any cortical pathology. Subsequent case reports of EPC in association with isolated subcortical lesions (Botez & Brossard, 1974), with more widespread pathologies affecting cortical and subcortical structures (Niedermeyer & Rocca, 1980), and one patient in which myoclonic jerking persisted during intraoperative cooling of the cerebral hemisphere (Kristiansen et al., 1971), have all been cited as further evidence for subcortical mechanisms. It does seem that some cases of what appears to be EPC can arise from subcortical structures, including the deep nuclei, brainstem, spinal cord or even peripheral nerves. Most cases are, however, cortical in origin and with the advent of newer recording techniques including jerk-locked EEG backaveraging (Shibasaki & Kuroiwa, 1975) abnormalities can now be demonstrated in most patients. Typically an EEG spike or sharp wave, clearly preceding the peripheral jerk by milliseconds can be demonstrated either by this or other techniques including depth electrode recording, stereo-EEG (SEEG) (Wieser et al., 1978), and intraoperative electrocorticography (Thomas et al., 1977; Baker et al., 1986; Cowan et al., 1986). More recently, dipole source localization of back-averaged EEG (Celesia et al., 1994) or magnetoencephalography (MEG) has been used to localize the source of the cortical discharge in more detail. A further source of discussion has been the difference, if any exists, between cortical myoclonus and cortically originated EPC. The clinical and neurophysiological characteristics of each are essentially the same, with the exception that EPC is, by definition, spontaneous, and myoclonus need not be. Both involve repetitive clonic jerking of a muscle or muscle group, may coexist with other seizure types, and may be exacerbated by peripheral stimuli, e.g. touch, movement. Neurophysiologically both have been associated with the EEG phenomena described above, and with pathological enlargement of the somatosensory evoked potential from the appropriate limb (Dawson, 1947; Rothwell et al., 1984; Cockerell et al., 1996). Obeso et

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al. (1985) concluded that EPC, cortical myoclonus and partial somatomotor seizures were all part of a spectrum of paroxysmal motor signs from the same (cortical) pathophysiological origins. The particular nature of EPC is thought to reflect the peculiar architecture of the motor cortex and of its special tight afferentefferent relations, supporting the activation of exacerbated long-loop reflexes (Chauvel et al., 1986; Cowan et al., 1986). In such a model the backward projection to the motor cortex would act simultaneously to reinforce focal excitation periodically and to circumscribe a ‘hot-spot’ of neuronal activity through a surrounding inhibition, which would prevent lateral spread (Biraben & Chauvel, 1997). A single pathological study suggested local impairment of inhibition in brain tissue resected from a patient with EPC and focal cortical dysplasia, rather than a ‘hot spot’. However the authors concede that their methods identified limited subpopulations of neurons, and surrounding ‘normal’ brain was not studied so limited conclusions can be drawn from this. The operational view of Obeso et al. (1985) has been endorsed by subsequent authors (Shorvon, 1994; Treiman, 1995). In this framework, the term EPC would be used for cases where the ‘cortical myoclonus’ or ‘focal motor seizure’ was spontaneous (non-reflex), repetitive and continuous for a period of at least hours. For cases which are clinically similar, but which are considered to be of extracortical origin as in 2 of the 16 cases described by Cockerell et al. (1996), it has been suggested that an alternative term, ‘myoclonia continua’, should be used. This maintains the premise that EPC by definition refers to ‘continuous muscle jerks of cortical origin’, which reflects the most widely accepted view, and the definition of Obeso et al. (1985). We concur with this view and feel that the term EPC should be restricted to cases with cortical origins. Factors which can help distinguish cortical EPC from other myoclonic movement disorders are given in Table 13.1. None the less, others still maintain the position that ‘EPC’ should be restricted to local and elementary motor signs as previously described, whether or not associated with spreading seizures, and regardless of the mode and pathways of propagation (Biraben & Chauvel, 1997). Etiology As mentioned in the introduction, up to 50% of cases of EPC, particularly in children, are associated with Rasmussen’s encephalitis. In published series including adult patients (Thomas et al., 1977; Cockerell et al., 1996; Gurer et al., 1999), cerebrovascular disease is the commonest identified cause accounting for 25 to 30% of all cases (Table 13.2). Tumours also feature commonly in these series and other case reports (Botez & Brossard, 1974). Not surprisingly, in these and with other etiologies, the frontal motor/premotor cortex is usually either directly affected or

Table 13.1. Characteristics of different forms of continuous localized myoclonus

Origin

Effect of movement

Stimulus sensitivity

Giant SEPs preceding myoclonus

Back-averaged cortical spike

EMG characteristic

Surface EEG

Cortical Basal ganglia Brainstem Spinal cord Peripheral nerve

Worsens Worsens No effect No effect Improves

Sometimes No No No No

Sometimes No No No No

Sometimes No No No No

Brief (50 ms) Long (100 ms) Brief (50–100 ms) Brief (50–100 ms) Brief (50–100 ms)

May be normal Normal Normal Normal Normal

Source: From Cockerell et al. (1996).

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Table 13.2. Summary of etiologies in a UK series of 36 patients with EPC

Etiology

n

%

Unknown

7

19

Rasmussen’s

7

19

Vascular disease Atherosclerotic SLE Angiits Arteriovenous malformation Cortical vein thrombosis

9 5 1 1 1 1

25 14 3 3 3 3

Multisystem disease Mitochondrial Alpers Unknown

4 1 1 2

11 3 3 5

Neoplastic disease Glioma Hemangioblastoma Meningioma

4 2 1 1

11 5 3 3

Perinatal birth injury

2

5

Metabolic (Hyperglycemia)

1

3

Trauma

1

3

Infectious (Creutzfeldt–Jakob)

1

3

Source: From Cockerell et al. (1996).

immediately adjacent to the main pathology. This was true of all eight patients in whom pathology was obtained in the series by Thomas et al. (1977). It seems that almost any process affecting this brain region, either structurally or metabolically can be associated with EPC (Table 13.3). In many cases the EPC is associated with other seizure types, which supports a cortical origin. Other neurological signs reflecting the underlying cause such as focal deficit, or altered consciousness may also be present. It should be noted that some of the early series, including that by Thomas et al. (1977) include cases of myoclonus secondary to global metabolic abnormalities such as hypoxia. These would not conform to current definitions of EPC. In patients with metabolic abnormalities the EPC can be due to coexistent focal pathology such as in most of the nine patients with diabetic non-ketotic hyperglycemia reported by Singh and Strobos (1980). Additional metabolic abnormalities in these patients included hyperosmolality and hyponatremia, which may

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also have contributed to the generation of EPC. In a proportion of cases in all the published series, however, the etiology remains obscure despite the advent of modern investigative techniques. Clinical features The clinical manifestations of EPC are varied, and this has led to diagnostic confusion in some cases, most commonly with other extrapyramidal movement disorders, tremor and non-cortical myoclonus (Biraben & Chauvel, 1997). Moreover, children with Rasmussen’s encephalitis can rarely present dystonia as a first symptom preceding the onset of focal motor seizures or EPC (Bhatjiwale et al., 1998). Although any muscle group may be involved, distal muscles are affected most commonly. Typically, there will be rhythmical repetitive jerking of a hand or foot with cocontraction of agonists and antagonists. In some patients several segments may be synchronously involved including the proximal muscles of the limb girdles, trunk or face. By definition, the jerking is spontaneous but it is frequently exacerbated by external stimuli such as touch or movement. It usually, though not always (Thomas et al., 1977), continues through sleep, although the amplitude may reduce. The interval between jerks is rarely more than a few seconds, and they may occur at rates of up to 15 Hz as recorded by EMG bursts. EPC may develop at any age, and may be an early or late feature in the course of the underlying disease, either in isolation, or in association with other seizure types depending on the etiology. The duration of a given episode can vary from hours to many years. Those resulting from vascular disease or other acute insults are perhaps more likely to remit (Thomas et al., 1977), although this is not universal (Cockerell et al., 1996). Intractability alone does not imply a sinister pathology, although the presence of progressive neurological deficits in association usually does, and the overall prognosis reflects that of the underlying cause. Investigation The neurophysiological features of EPC have been discussed above. All patients should have EEG and, if no focus is identified on routine recordings, EMG jerklocked back averaging studies should be undertaken. Only 7 of a total of 245 EEG recordings undertaken in the 32 patients reported by Thomas et al. (1977) were normal, although a definite focal discharge was rarely identified. Other associated EEG findings include generalized or focal slowing, periodic lateralized epileptiform discharges (PLEDs), background abnormalities, or isolated spikes/sharp waves. Abnormally enlarged SSEPs if present, help to provide evidence of cortical pathology if doubt still exists. Electrocorticography (EcoG) or depth electrode studies will

Table 13.3. Reported causes of EPC (non-Rasmussens)

Etiology Cerebrovascular disease

References

Subarachnoid hemorrhage Arteriovenous malformation Angiitis; Cortical vein thrombosis

Thomas et al. (1977); Pickut et al. (1995); Cockerell et al. (1996) Gurer et al. (1999) Thomas et al. (1977) Celesia et al. (1994); Cockerell et al. (1996) Cockerell et al. (1996)

Neoplasms

Primary CNS tumour Craniopharyngioma Metastases Paraneoplastic

Botez & Brossard (1974); Thomas et al. (1977); Cockerell et al. (1996) Colamaria et al. (1988) Gurer et al. (1999) Shavit et al. (1999)

Trauma

Head injury Perinatal injury

Thomas et al. (1977); Nobuhara et al. (1989); Cockerell et al. (1996) Cockerell et al. (1996)

Infectious

Russian spring–summer encephalitis Acute measles encephalitis Subacute sclerosing panencephalitis Cryptococcal meningitis Tuberculous meningitis; Hydatid cysts Progressive multifocal leukoencephalopathy HIV encephalopathy Creutzfeld–Jakob disease Hepatic encephalopathy Diabetic non-ketotic hyperglycemia Diabetic ketoacidosis Mitochondrial disease

Kojewnikow (1895) Alcardi et al. (1977); Colamaria et al. (1988); Chen et al. (1994) Lyon (1977); Colamaria et al. (1989); Gurer et al. (1999) Chalk et al. (1991) Gurer et al. (1999) Ferrari et al. (1998) Bartolomei et al. (1999) Cockerell et al. (1996) Thomas et al. (1977) Singh & Strobos (1980); Sabharwal et al. (1989); Cockerell et al. (1996) Tran et al. (1999) Andermann et al. (1986); Veggiotti et al. (1995); Cockerell et al. (1996); Elia et al. (1996); Schuelke et al. (1998) Boyd et al. (1986); Bourgeois & Aicardi (1992); Cockerell et al. (1996); Worle et al. (1998) Gambardella et al. (1998)

Metabolic

Atherosclerotic disease

Alper’s disease Kuf ’s disease Developmental

Focal cortical dysplasia Hemimegencephaly Polymicrogyria

Nordborg et al. (1987); Ferrer et al. (1992); Desbiens et al. (1993); Kuzniecky & Powers (1993); Legatt et al. (1996); Gurer et al. (1999) Ishii et al. (1995) Caraballo et al. (1999)

Inflammatory

Multiple sclerosis Sjorgren’s syndrome Systemic lupus erythematosis

Hess & Sethi (1990); Spatt et al. (1995) Bansal et al. (1987) Biraben & Chauvel (1997)

Toxic

Metrizamide cisternography Azlocillin/Cefotaxime

Shiozawa et al. (1981) Wroe et al. (1987)

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often demonstrate a focal discharge where routine tests have failed. However, these should only be undertaken in patients in whom therapeutic surgery is being considered, given the risks these procedures entail (Kugelberg & Widen, 1954; Bancaud et al., 1970; Wieser et al., 1978). Imaging should be undertaken in all patients, preferably by MRI, to look for focal structural lesions or evidence of more widespread disease process. More recently a variety of functional imaging techniques have been used, of particular interest as EPC represents a rare opportunity to gain images of the brain during a seizure discharge. Positron emission tomography (PET) has been reported to show high regional blood flow in an area of atrophied cortex, later confirmed as the electrical focus by EcoG. This was interpreted to reflect local vasodilation in response to the high metabolic demands of the discharging focus (Cowan et al., 1986). Confusingly FDG PET has showed both hypometabolic (Guttman et al., 1986; Swartz et al., 1989) and hypermetabolic (Hajek et al., 1991; Volkmann et al., 1998) regions corresponding to the focus of EPC, even with the same underlying pathology in some cases. The mechanistic significance of this is unclear, other than providing evidence that regional abnormalities are of localizing value. Other modalities such as single photon emission computerized tomography (SPECT) (Katz et al., 1990; Sztriha et al., 1994; Pickut et al., 1995), functional MRI (Fish et al., 1988; Jackson et al., 1994), and magnetic resonance spectroscopy (MRS) (Park et al., 1997) may also identify areas of activation corresponding to the EPC focus. In some instances this may be of value even where extensive EEG studies have failed to localize the source (Guttman et al., 1986; Katz et al., 1990). An interesting report which throws some light on mechanisms comes from Weishmann et al. (1997). Diffusion-weighted magnetic resonance imaging, sensitive to the molecular motion of water, was carried out during and after periods of EPC in a case of unknown etiology. Decreased diffusion was seen in the motor cortex of the affected right leg, with increased diffusion in the corresponding subcortical white matter. Both changes resolved following cessation of the EPC. The authors suggest that, during epileptic activity, water flux into cells in the area of maximal neuronal activity might cause shrinkage of the extracellular space, explaining a decrease in cortical diffusion. At the same time, the extracellular space in areas remote to neuronal activity would expand, explaining the increase in subcortical white matter. Of note the observed changes are quite different from those observed in ischemia, and not inevitably followed by cell death. Treatment EPC is notoriously pharmacoresistant, and case reports of successful treatment, such as that by Brandt et al. (1988) using nimodipine, are difficult to interpret as a

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proportion of cases spontaneously remit after variable time periods. Most of the conventional antiepileptics have been tried with carbamazepine, clonazepam, valproate and phenytoin reported to be of limited benefit, as have steroids (Cockerell et al., 1996). In acute cases, parenteral therapy or general anesthesia may abort the episode, but the EPC will often recur on cessation of treatment (Hughes et al., 1992; Shorvon, 1994). Where possible treatment of the underlying pathology should be commenced, and is likely to contribute to improved outcome (Chalk et al., 1991; Singh & Strobos, 1980; Tran et al., 1999). One small series reported a decrease in seizure frequency, including termination of EPC, with chronic electrical stimulation of the centromedian thalamic nuclei (Velasco et al., 1993). However, this has not been reported elsewhere and probably has at best only a modest benefit. In intractable cases with identifiable focal lesions surgical excision probably produces the best outcome in terms of seizure remission (Legatt et al., 1996; Caraballo et al., 1999), but given the location of the focus often leaves permanent neurological deficit (Desbiens et al., 1993). Multiple subpial transections may be a less destructive option (Molyneaux et al., 1998), but has not gained wide currency. Conclusions EPC is an uncommon condition, but one which has interested movement disorder specialists and epileptologists throughout the last century. Characterized by clonic twitching of a group of muscles lasting from hours to days or longer, EPC is, by definition, cortical in origin and thus represents a form of focal status epilepticus. The cortical origin may be inferred by the coexistence of other seizure types, or be demonstrable by neurophysiological recordings (back-averaging). Physicians in all disciplines may rarely encounter cases, given the broad range of etiological factors, but specialist referral should always be considered as both diagnosis of the underlying condition and treatment of the EPC can be difficult.

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Seizures, myoclonus and cerebellar dysfunction in progressive myoclonus epilepsies Roberto Michelucci1, José M. Serratosa2, Pierre Genton3 and Carlo Alberto Tassinari1 1

Department of Neurology, Bellaria Hospital, Bologna, Italy Departamento de Neurologia, Fundación Jiménez Diaz, Madrid, Spain 3 Centre St Paul, Marseille, France 2

Introduction Progressive myoclonus epilepsies (PMEs) are a heterogeneous group of rare genetic disorders sharing a common clinical picture: myoclonus, epileptic seizures and signs of neurological deterioration, particularly dementia and ataxia (Marseille Consensus Group, 1990). The causes of the PME syndrome are many; most of them, however, can now be accurately diagnosed in life due to recent advances in pathology, biochemistry and molecular genetics (Berkovic et al., 1986; Roger et al., 1992). In particular, molecular genetics has most dramatically increased our knowledge of the basic mechanisms involved in the PMEs (Serratosa et al., 1999a). In order to establish a precise diagnosis, knowledge of the biochemical and molecular genetic bases of the PMEs must now complement experience in identifying the clinical, neuropathological, and neurophysiological characteristics of each PME. Aside from the problems of diagnosis, there are still some unresolved issues concerning the neurophysiology and pathophysiology of some clinical features, like myoclonus, which contribute in different ways to the movement disorder and disability associated with the PME syndrome (Commission on Pediatric Epilepsy of the ILAE, 1997). In this chapter we will outline the main specific disorders causing PME, along with the recent advances of molecular genetics contributing to the nosology and knowledge of these conditions. Finally, we will also address the issues of the clinical and neurophysiological aspects of PMEs, with special reference to three outstanding features of the syndrome: seizures, myoclonus and cerebellar dysfunction. Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Specific disorders causing PME Despite a large number of rare conditions that may present with a PME syndrome, five principal causes are responsible for most cases of PME worldwide: Unverricht–Lundborg disease, Lafora disease, mitochondrial encephalomyopathies, neuronal ceroidlipofuscinoses and sialidosis. Unverricht–Lundborg disease (ULD)

Until recently the nosology of this condition was questioned due to the absence of any biological or pathological marker. Since 1990, however, linkage and molecular genetics studies have demonstrated that ULD is a specific entity (Lehesjoki et al., 1991, 1994; Malafosse et al., 1992), due to mutations of the cystatin B gene (Pennacchio et al., 1996; Virtaneva et al., 1997). It is a recessively inherited disorder with an ubiquitarious distribution, but clusters of the disease are present in Finland, Southern Europe and North Africa (Koskiniemi, 1986; Tassinari et al., 1989; Genton et al., 1990). Clinical onset is with myoclonus or tonic–clonic seizures between the ages of 6 and 18 years (mean: 11 years). Action myoclonus is the hallmark of the disease, causing most disability. Seizures are usually rare and of tonic–clonic, clonic or myoclonic type. Absences may occur. The progression of the disease is variable: after 20 or more years of evolution, about half the patients are still autonomous or nearly autonomous, 30% are severely handicapped in their daytime activities and 20% are bedridden (Tassinari et al., 1998b). There may be considerable intra- and interfamilial variation in the severity of the disease. Cerebellar signs are present in almost all cases, whereas intellectual decline is mild and late. The electroencephalogram (EEG) background activity may be normal or show some diffuse theta activities, with superimposed fast spike wave (SW) discharges (Tassinari et al., 1974; Koskiniemi et al., 1974b). Sporadic focal spikes, particularly in the occipital regions, may be seen (Tassinari et al., 1998b; Berkovic, 1997). Photosensitivity is almost invariably present. At variance with idiopathic generalized epilepsy, the SW activity is diminished during non-REM sleep. Focal spikes in the vertex and central regions appear during REM sleep (Fig. 14.1) (Tassinari et al., 1974). The EEG picture remains unchanged and does not deteriorate even two or more decades after onset. The gene responsible for Unverricht–Lundborg disease was initially mapped to the long arm of chromosome 21, band q22.3 (Lehesjoki et al., 1991). A positional cloning approach was then used to identify the responsible gene. The gene, known as the cystatin B (CSTB) gene is approximately 2.5 kb in length and contains three small exons (Pennacchio et al., 1996). The most common mutation (86%) consists of the expansion of a dodecamer repeat in the promoter region of the CSTB

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gene. Only a minority of EPM1 alleles (14%) harbour mutations within the transcriptional unit of CSTB (Lalioti et al., 1997a, b). No genetic locus heterogeneity has been reported (all EPM1 patients show mutations in the CSTB gene). Cystatin B is a small, 98 amino acid protein and a member of a superfamily of cysteine proteinase inhibitors. It is found in all tissues examined so far and is thought to protect against inappropriate intracellular degradation by proteinases that leak from lysosomes (Järvinen & Rinne, 1982; Turk & Bode, 1991). However, it is not yet understood how loss-of-function mutations in the cystatin B gene cause seizures or the other neurological symptoms of EPM1. The finding that the cystatin B gene is defective in EPM1 patients, provided the basis for constructing a knockout mouse model for the disease (Pennacchio et al., 1998). For a long time, controversy existed regarding the relationship between Unverricht–Lundborg disease, in the past also referred to as Baltic myoclonus (Eldridge et al., 1983; Koskiniemi, 1986), and Mediterranean myoclonus which was formerly reported as a subgroup of the Ramsay Hunt syndrome (Roger et al., 1968; Tassinari et al., 1989; Genton et al., 1990; Marseille Consensus Group, 1990). The differences in the course of the disease between what was known as Baltic and Mediterranean myoclonus, have clearly been associated with the deleterious effects of treatment with phenytoin in the Baltic patients (Eldridge et al., 1983). Molecular genetic testing has now ended this debate, as it has been shown that both Mediterranean and Baltic myoclonus are caused by mutations in the CSTB gene and are thus Unverricht–Lundborg disease. Lafora disease

Lafora disease is an autosomal recessive condition characterized by the presence of typical polyglucosan inclusions (Lafora bodies) in neurons and a variety of other sites, including heart, skeletal muscle, liver and cells of the sweat gland ducts (Lafora & Glueck, 1911). The diagnosis is most simply made by demonstration of the typical inclusions in the eccrine ducts of the sweat glands in a simple skin biopsy specimen (Carpenter & Karpati, 1981). The onset of the disease occurs between the ages of 6 and 19. The symptoms at the onset are generalized tonic–clonic seizures, often associated with partial visual seizures. A severe resting and action myoclonus syndrome then progresses rapidly along with a relentless cognitive decline and cerebellar and pyramidal signs. The prognosis is dismal with death occurring 2 to 10 years after onset . In a few cases, symptoms begin in early adulthood and the course of the disease is milder and protracted, spanning between 10 to 45 years. These cases, also labelled as ‘late onset’ Lafora disease, may represent a genetic subtype of Lafora disease that is separate from the classical form (Kraus-Ruppert et al., 1970; Kaufman et al., 1993; Footitt et al., 1997).

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At onset, the EEG shows normal background activity with isolated SW and poly SW (PSW) discharges, so that the disorder may resemble a typical idiopathic generalized epilepsy. However, SW discharges are not increased during non-REM sleep and are constantly exacerbated by intermittent photic stimulation. Erratic myoclonus is also seen on polygraphic recording with or without EEG correlation. During the next few months or years, the background activity deteriorates, the paroxysmal bursts begin to look like fast SWs and PSWs and focal, particularly occipital spikes appear. The physiological sleep patterns tend to disappear and, in the terminal phase of the illness, the EEG is quite disorganized (Tassinari et al., 1978). By using linkage analysis and homozygosity mapping, a gene responsible for most patients with PME of the Lafora type (EPM2A) was mapped to chromosome 6q23–25 (Serratosa et al., 1995). The responsible gene, subsequently characterized, is a previously unidentified protein tyrosine phosphatase (Serratosa et al., 1999b; Minassian et al., 1998). The EPM2A gene expands 4 exons and the mutations are remarkably variable, making the molecular diagnosis complicated. At the time of this writing, more than 20 different mutations in the EPM2A gene had been identified in Lafora disease patients (Gómez-Garre et al., 2000). Deletions are common but missense and nonsense mutations are also found. How mutations in the Lafora associated protein tyrosine phosphatase produce the storage of Lafora bodies and the disease phenotype is not known. There is evidence supporting the existence of at least one additional yet unidentified gene responsible for a minority of patients with Lafora disease (10–20%) (Minassian et al., 1999). Syndrome of myoclonus epilepsy and ragged red fibres (MERRF)

A PME syndrome associated with mitochondrial encephalomyopathy (or MERRF syndrome) has emerged since 1980 as one of the most common causes of PME, accounting for a number of cases previously labelled as ‘cryptogenic’ or included under different eponyms (Ekbom disease, May–White disease, Ramsay Hunt syndrome), (Marseille Consensus Group, 1990). MERRF may be sporadic or familial. All familial cases are transmitted through the maternal line, in accordance with mitochondrial inheritance (Rosing et al., 1985). In MERRF, unlike the other forms of PME, the age of onset varies substantially from patient to patient, even within families, and ranges from early childhood to late adulthood (Berkovic et al., 1989, 1991). The clinical presentation is also variable because the classic PME syndrome is constantly associated with a constellation of other neurological signs and multisystem abnormalities in various combinations . The most frequently associated signs include dementia, muscle weakness and atrophy, and ocular abnormalities (Berkovic et al., 1989, 1991). The EEG shows abnormal background activity in 80% of cases. Also noted are

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SW and PSW discharges, focal abnormalities, slow bursts and photosensitivity (So et al., 1989). Muscle biopsy may demonstrate the typical ragged red fibres, although these can be absent. Biochemical assays of the mitochondrial respiratory enzymes and magnetic resonance spectroscopy may provide further clues to the diagnosis, along with the detection of specific mutations of mitochondrial DNA (Berkovic et al., 1989). A point mutation at nucleotide position 8344 in the mitochondrial tRNALys coding gene leading to a substitution of adenine for guanine is the major cause of MERRF (Shoffner et al., 1990). This A-to-G mutation at nucleotide 8344 accounts for 80% to 90% of MERRF cases. Other mutations that can produce the MERRF phenotype are the 8356 T-to-C (Silvestri et al., 1992) and the 8363 G-to-A transitions (Ozawa et al., 1997) MERRF may also be considered among the clinical syndromes associated with the A to G transition at nucleotide 3243 of the tRNALeu(UUR), which is usually associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (Fabrizi et al., 1996; Verma et al., 1996; Campos et al., 1996). The tRNALys gene mutation at position 8344 causes a substantial decrease in the tRNALys specific aminoacylation capacity per cell (Enriquez et al., 1995). This limitation produces premature termination of translation and a sharp decrease in the rate of mitochondrial protein synthesis. Mutation of mitochondrial tRNA genes leads to the assembly of bioenergetically incompetent mitochondria. Neuronal Ceroid Lipofuscinoses

The neuronal ceroid lipofuscinoses are characterized by the accumulation of abnormal amounts of lipopigment in lysosomes. Three genetically distinct forms (late infantile of Jansky–Bielschowsky, juvenile of Spielmeyer–Vogt–Sjogren and adult of Kufs) may cause the PME syndrome. These variants occur worldwide, with foci in various parts of the world, especially Scandinavia (Marseille Consensus Group, 1990). The late infantile and juvenile forms, which have a recessive inheritance, are characterized by a PME syndrome with prominent psychomotor regression; a progressive visual failure, with funduscopic evidence of optic atrophy, macular degeneration and attenuated vessels, develops invariably. Photosensitivity is marked and single flashes may evoke giant posterior evoked responses in the late infantile form. The electroretinogram becomes progressively attenuated or flat in both conditions. The EEG shows slowing of the background activity with generalized epileptiform discharges (Pampiglione & Harden, 1977; Westmoreland et al., 1979). The adult form is considerably rarer. This condition, which may occur in families with dominant inheritance, may present with a PME syndrome around the age of 30. Blindness is notably absent and the optic fundi are normal. The EEG shows

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generalized fast SW discharges with marked photosensitivity. The electroretinogram is normal (Berkovic et al., 1988). All the forms of ceroid lipofuscinoses have a bad prognosis, with death occurring a few years after the onset of the disease; the earlier the onset, the shorter is the survival time (ranging from 5 to 12 years). Definitive diagnosis presently requires the demonstration of characteristic inclusions (curvilinear profiles – CVBs, fingerprint profiles – FPPs, and osmiophilic deposits) by electron microscopy. These can be found most simply in eccrine secretory cells. However considerable expertise may be required in the pathologic interpretation of the electron micrographs (Carpenter, 1988). Advances in human molecular genetics have allowed positional cloning strategies to be applied to the identification of some of the defective genes and have led to the definition of ten subtypes of neuronal ceroid lipofuscinoses (CLNs 1 through 8 plus the late infantile and juvenile forms with GRODs) (Bate & Gardiner, 1999). There is considerable phenotypic variation within the category of the late infantile neuronal ceroid lipofuscinoses. At least four subtypes exist including classical late-infantile NCL (classical Jansky–Bielschowsky disease, CLN2), Finnish variant late-infantile NCL (CLN5), variant late-infantile NCL (sometimes called ‘early juvenile’, CLN6), and Turkish variant late-infantile NCL (CLN7). The diagnosis usually depends on the demonstration of CVBs with or without FPPs on ultrastructural studies. These can be identified most easily by the pathological study of skin (punch biopsy) and/or buffy coat. Some cases require a rectal mucosal biopsy in order to study autonomic ganglion cells. Molecular genetic studies can now be very helpful in order to reach the precise diagnosis. The gene responsible for classical late-infantile neuronal ceroid lipofuscinosis (CLN2) was mapped to chromosome 11p15 (Sharp et al., 1997) and subsequently identified by using the mannose-6-phosphate modification of newly synthesized lysosomal enzymes as an affinity marker (Sleat et al., 1997). The CLN2 gene codes for tripeptidyl peptidase-I, a lysosomal pepstatin-insensitive protease that shows significant similarities with bacterial carboxyl peptidases. Rapid diagnosis can be made by using specific polyclonal antibodies against the CLN2 gene product (Kurachi et al., 2000) or by testing the activity of the defective enzyme (Sohar et al., 1999). The variant late infantile NCLs are characterized by a mixed phenotype with both CVBs and FPPs. The responsible gene for Finnish variant late infantile NCL, denoted CLN5, was successfully assigned to chromosome 13q21–q32 by linkage analysis (Sakuvoski et al., 1994) and characterized (Sakuvoski et al., 1998). CLN5 encodes a putative transmembrane protein which shows no homology to previously reported proteins. Other variants of late infantile NCL presenting a clinical course similar to the classical late-infantile NCL have been delineated by means of

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molecular genetic studies. These include a variant late infantile NCL that maps to chromosome 15q21–23 (CLN6) (Sharp et al., 1997) and Turkish variant late infantile NCL of still unknown chromosomal localization (CLN7) (Wheeler et al., 1999). The gene responsible for the juvenile form of neuronal ceroid lipofuscinosis of Spielmeyer–Vogt–Sjogren was initially assigned to chromosome 16 (Eiberg et al., 1989; Gardiner et al., 1990) and then cloned (The International Batten Disease Consortium, 1995). More than 20 different disease-causing mutations have been detected. About 80% of the patients carry the so-called 1.02 kb deletion, which is the common founder mutation. Most patients are homozygous for this mutation. An additional three deletions have been identified and the remaining mutations include 1–2 bp insertions or deletions and single-base changes causing missense, nonsense, or splice-site mutations. Patients with a milder phenotype comprising visual failure but relatively preserved cognitive and motor function have missense mutations in CLN3 on at least one disease chromosome (Lauronen et al., 1999). The CLN3 gene encodes a 438 aminoacid protein of as yet unknown function. It is most probably a lysosomal/endosomal protein that is trafficked through the endoplasmic reticulum (ER) and Golgi (Pearce, 2000). Sialidoses

The sialidoses are autosomal recessive disorders associated with defects of sialidase (also known as neuraminidase) resulting in elevated urinary excretion of sialilated oligosaccharides (O’Brien, 1977, 1978; Lowden & O’Brien, 1979). The diagnosis can be confirmed by chromatographic screening of the urine for sialyloligosaccharides, which are normally cleaved by sialidase. Cultured skin fibroblasts or lymphocytes show deficiency of sialidase. The human lysosomal sialidase cDNA has been recently cloned and sequenced (Bonten et al., 1996; Pshezhetsky et al., 1997). A G-to-T substitution at nucleotide 1258 of the sialidase gene (also known as NEU gene) that introduces a premature TAG termination codon at amino acid 377 has been described in two sibs with type I sialidosis (Bonten et al., 1996). Mutations in the sialidase gene have also been described in type II sialidosis but the mutations differ from those found in sialidosis type I (Bonten et al., 1996; Pshezhetsky et al., 1997). Sialidosis type I (or cherry red spot-myoclonus syndrome), begins in adolescence, with myoclonus, gradual visual failure, tonic-clonic seizures, ataxia and a characteristic cherry red spot in the fundus. Sensations of burning hands and feet, aggravated by exposure to heat and lens opacities are often seen. Myoclonus is severe and predominates around the mouth. Dementia is usually absent (Lowden & O’Brien, 1979; Rapin et al., 1978). In sialidosis type II, at variance with type I, the onset is later and there may be

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additional findings of coarse facies, dysostosis multiplex, corneal clouding, hearing loss and limited intellect (Lowden & O’Brien, 1979; Matsuo et al., 1983). The EEG shows normal to fast, low voltage background activity. Massive myoclonias are associated with generalized SW discharges or with trains of 10 to 20 Hz, small, vertex spikes preceding the EMG artefact (Franceschetti et al., 1980; Engel et al., 1977; Rapin, 1986). Photosensitivity is usually absent. Galactosialidosis, an autosomal recessive lysosomal storage disease, may also present as PME. In addition to PME, the disease involves dysmorphia, mental retardation, angiokeratoma, and short stature. The cause is a defect in a lysosomal enzyme known as protective protein/cathepsin A (PPCA) and mutations in the PPCA gene are present in affected individuals (Zhou et al., 1996). PPCA is an acid carboxypeptidase that normally associates with galactosidase and neuraminidase to create a fully functional and stable enzyme complex. The deficiency of PPCA causes lysosomal storage of syalilated oligosaccharides and glycopeptides, and, thereby, oligosacchariduria. Rare causes of PME and differential diagnosis

Rare causes of PME include dentatorubral–pallidoluysian atrophy, non infantile neuronopathic Gaucher’s disease, atypical inclusion body disease, action myoclonus-renal failure syndrome, neuraxonal dystrophy, coeliac disease, late-infantile or juvenile forms of GM2-gangliosidosis, Hallervorden–Spatz disease, and childhood form of Huntington’s chorea. PMEs should be distinguished from degenerative disorders in which seizures, myoclonus or both can occur but do not represent the main or initial clinical picture, e.g. Alzheimer disease. The PME syndrome should also be separated from progressive myoclonus ataxia (PMA); this is a syndrome, caused by a variety of etiologies (including celiac disease, Whipple’s disease, etc.), in which the onset is in adulthood with myoclonus and ataxia but there is little or no evidence of seizures and dementia (Marseille Consensus Group, 1990). A condition that should be distinguished from the PME syndrome is familial adult myoclonic epilepsy (Uyama et al., 1985; Yasuda, 1991; Terrada et al., 1997). This disorder has been described in Japan, and is an autosomal dominant primary generalized epilepsy characterized by adult onset myoclonic jerks in the upper and lower extremities, tremulous finger movements, and rare generalized tonic–clonic seizures. As with juvenile myoclonic epilepsy, the EEG shows PSW complexes. Photosensitivity is marked. Jerk-locked back-averaged recordings show positive spikes preceding the myoclonus. The course is benign and non-progressive and there is no associated cerebellar ataxia or dementia. This condition has recently been reported outside Japan in European families (Elia et al., 1998). Molecular

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genetic studies helped delineate this syndrome by means of linkage studies that mapped the disease to chromosome 8q (Mikami et al., 1999; Plaster et al., 1999). Seizures PMEs are characterized by a wide range of epileptic seizures. Surprisingly, however, there are only a few reports in the literature devoted to the clinical and neurophysiological description of seizure types in PMEs. It is commonly agreed that most seizure types are ‘generalized’ and the terms tonic–clonic, clonic, myoclonic are usually employed to describe these seizures. Definite partial seizures are also encountered in specific forms of PMEs. Tonic–clonic seizures are usually reported at the onset of Lafora disease in the vast majority of patients (Tassinari et al., 1978); they are also the first symptom in about the half of the patients with ULD (Tassinari et al., 1998b). At an early stage of these conditions, tonic–clonic seizures may suggest the alternative diagnosis of idiopathic generalized epilepsy. They may occur without any warning or after a long build-up of myoclonias. It is not known whether the clinical and neurophysiological features of tonic–clonic seizures in PMEs are somewhat different from those observed in other forms of epilepsy. Typical tonic–clonic seizures have been recorded in Lafora disease by Tassinari et al. (1978). Roger et al. (1967) recorded a generalized ‘convulsive’ seizure in Lafora disease and observed that the tonic phase was followed by a short ‘vibratory’ phase: from the electrophysiological point of view the tonic phase was accompanied by a fast 10 Hz recruiting rhythm and the ‘clonic’ or ‘vibratory phase’ by a short discharge of SWs at 3Hz. ‘Tonic–vibratory’ seizures resembling tonic clonic seizures were also recorded in two patients with cryptogenic forms of PME showing a motor status (Fig. 14.2) (Riguzzi et al., 1997). So-called ‘tonic–clonic seizures’ in PMEs may reveal to be clonic or myoclonic seizures. Tassinari et al. (1974) recorded 11 generalized motor seizures in six patients with so-called Ramsay Hunt syndrome (now better defined as ULD); they observed that the seizures, lasting 50 s. to several minutes, were characterized by massive myoclonic jerks at 8–10 Hz, with some waxing and waning of frequency during the same attack, and were accompanied on the EEG by generalized SW discharge at 4–7 Hz. There was no tonic phase and the seizures were not followed by flattening of the EEG; the consciousness was not completely lost but there was obtundation, particularly evident in the long seizures. It is therefore conceivable that most generalized motor attacks observed in PMEs of whatever etiology are true myoclonic or clonic seizures; these attacks may also account for the relatively frequent ‘falling’ seizures observed in these conditions. Kyllerman et al. (1991), in four siblings with ULD, provided the polygraphic description of occasional nocturnal build-up myoclonias culminating with violent, generalized jerks causing a

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EOG Mylo R.W.Flex. R.W.EXt. R.Tib.A M.P.

41 yrs

male

16-11-94

100 µV 1s

Fig. 14.1

Adult patient with a 25-year history of myoclonus, rare generalized motor seizures and cerebellar disturbance. Molecular genetic analysis led to the diagnosis of ULD. On polygraphic recording during REM sleep, one can observe the occurrence of fast spikes over the vertex, diffusing to the parasagittal regions, and erratic myoclonic jerks, inconstantly related to the vertex spikes. EOG: electro-oculogram. Mylo: mylohyoideus; R.W. Flex:right wrist flexor; R.W. Ext: right wrist extensor; R tib.A.: right tibialis anterior.

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progressive increase in the tone of the trunk with breathing difficulties and laryngeal spasm. These attacks were labelled ‘cascade’ myoclonic seizures. ‘Absence seizures’ have been reported in Lafora disease, but the clinical and EEG semiology seems quite different from that observed in typical absences of idiopathic generalized epilepsy or atypical absences of Lennox–Gastaut syndrome (Tassinari et al., 1978). When recorded, the absences in Lafora disease are described as episodes of increased slowness with an EEG correlate of discrete increase of the polyspike discharges (Tassinari et al., 1978). Typical absences, as observed in idiopathic generalized epilepsy, have been described in a small proportion of patients with ULD in the Bologna series (2 out of 36 cases) (Tassinari et al., 1998b) and Marseille series (5 out of 43 cases) (Roger et al., 1968). Partial seizures can occur in PMEs. Occipital seizures involving visual simple hallucinations or scotomas have been reported in around 50% of patients with Lafora disease in the early stage (Roger et al., 1983; Tinuper et al., 1983). Visual auras are also common in Kufs disease (Berkovic, 1988). Partial seizures of motor type have been reported in Gaucher disease and MERRF syndrome. It is also conceivable that many ‘tonic–clonic’ seizures observed in PMEs may be revealed as secondarily generalized focal seizures (Fig. 14.3). Myoclonus Myoclonus is an essential and constant finding in PMEs. Clinically, it is described as spontaneous or, more often, it is induced or exacerbated by a variety of stimuli (such as light, sound, touch, emotional strain) and movement or posture. Action myoclonus, in which muscular jerking is initiated by movement, attempts at movement and even intention to move, is the most frequent and disabling form of myoclonus, commonly seen in almost all the conditions underlying PME (Fig. 14.4) (Lance, 1986; Shibasaki, 1996; Hallett, 1997). Myoclonus in PME is typically fragmentary and multifocal; it is particularly apparent in the musculature of face and distal limbs. Bilateral massive myoclonic jerks, which tend to involve muscles of the proximal limbs, may also occur, sometimes resulting in the individual falling to the ground. Polygraphically, myoclonus may appear as an abrupt and short muscular contraction (positive myoclonus) or as a sudden interruption of muscle discharge without evidence of an antecedent myoclonia on maintenance of a posture (negative myoclonus) (Shibasaki, 1996; Tassinari et al., 1996, 1998a). A mixture of positive and negative myoclonus is common in the same patients in PMEs. Myoclonus may occur arrythmically at rest in different muscles. Sometimes it may occur in brief bursts of rhythmic activity with a progressive increase of amplitude and spreading to other muscles, both at rest and on voluntary contraction (Engel et al., 1977). It may also appear as a continuous rhythmic activity in so called ‘epileptic

Fig. 14.2

A 21-year-old boy with PME syndrome of unknown etiology. The patient had episodes of ‘motor’ status epilepticus, refractory to benzodiazepines. Clinically, the seizures were characterized by a prolonged tonic contraction followed by a short vibratory component. From the EEG point of view, there is a recruiting rhythm progressively rising from the fronto-central regions and increasing in amplitude (tonic phase of the seizure), with a brief decrease of frequency at the end of the attack (vibratory phase of the seizure). The seizure is followed by slowing of the tracing and persistence of paroxysmal activity over the frontocentral regions.

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cortical tremor’, which is a recently identified epileptic condition to be considered in the differential diagnosis of PMEs (Terrada et al., 1997). As to the sites of the generator of myoclonus, the neurophysiological findings suggest that cortical reflex myoclonus is common to all the conditions included under the heading of PMEs (Tassinari et al., 1998a). These findings include: • a rostro-caudal propagation of myoclonus along the muscles innervated by cranial nerves (Hallett et al., 1979); • the demonstration of a premyoclonic cortical potential that is temporally and consistently correlated with the myoclonic potential and localized on the contralateral sensorimotor regions, as demonstrated by EEG, Magnetoencephalography (MEG) and jerk locked back averaging (Hallett et al., 1979; Shibasaki & Kuroiwa, 1975; Shibasaki et al., 1991; Mima et al., 1998); • the existence of a C-reflex at rest, which is presumed to occur through a cortical mediation (Sutton & Mayer, 1974); • enlarged somatosensory evoked potentials (SEPs), whose giant components are more often P25/N30 and N35. Since the first cortical component (N20) has normal amplitude, an abnormality of intracortical inhibition following arrival of the first volley of thalamo-cortical activity could be the cause of the giant SEPs and of activation of the descending motor outputs leading to C-reflex (Rothwell et al., 1986). In this respect, studies with transcranial magnetic stimulation (TMS) have demonstrated a loss of intracortical inhibition as the putative mechanism of hyperexcitability in PMEs (Valzania et al., 1999). In PMEs cortical reflex myoclonus may be typical (if the reflex jerk has a latency of 50 ms) or atypical (if the reflex jerk has a latency of 40 ms), the differences in latency probably reflecting differences in the processing and relay of sensory information in thalamo-cortical pathways (Thompson et al., 1994). One particular form of cortical reflex myoclonus is that induced by photic stimuli, i.e. photic reflex myoclonus. In PMEs, intermittent photic stimulation may induce bursts of PSW discharges associated with massive myoclonic jerks. If the triggering stimulus is prolonged, the clinical responses may translate into a generalized convulsion. The mechanism of photic reflex myoclonus has been investigated and it involves the participation of both occipital and motor cortices, with bilateral spread – presumably mediated by transcallosal connections – and propagation down the spinal cord via fast-conducting cortico-spinal projections (Rubboli et al., 1999). A subcortical origin for myoclonus in PMEs has also been suggested, on the basis of the discrepancies between the latency of reflex myoclonus and the sum of afferent and efferent times to and from the cortex as evidenced by TMS studies (Cantello et al., 1997). Finally, abnormalities of ipsilateral and transcallosal inhibition could explain the rapid spread of myoclonic activity, leading to bilateral and

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(a)

(b)

(c)

Fig. 14.3

(d )

Apparently generalized motor seizure in a patient with Lafora disease. The seizure begins gradually, merging with the ‘interictal’ background activity (a). The recruiting rhythm mainly involves the posterior regions (b) before diffusing to the whole hemispheres (c). Generalized slow SWs appear during the last stage of the seizure (d).

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Fig. 14.4

Polygraphic recording in a patient with ULD. The patient was asked to keep the hands extended. Muscular contraction in both hands is fragmented by myoclonic potentials, intermixed with brief silent periods. The myoclonic jerks are related or unrelated to the EEG spikes. Rright; Lleft; Deltdeltoid muscle; FDBflexor digiti brevis; EDBextensor digiti brevis.

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diffuse jerks (Brown et al., 1991; 1996). Electrophysiological studies seem to suggest, however, that in individual cases bilateral jerks may be generated in the brainstem–reticular reflex myoclonus (Hallett et al., 1977). Cerebellar dysfunction Signs of cerebellar dysfunction are common in PMEs, as demonstrated by pathological, neuroradiological and clinical data. Postmortem studies have demonstrated that the distribution of the pathological lesions within the various forms of PME are remarkably similar. Cerebellum is constantly involved, with evidence of Purkinje cell loss and dentate nucleus atrophy. Other common pathological lesions involve the olives, the olivo-cerebellar pathways, and the medial nuclei of thalamus. It has been suggested that this uniform pathological pattern reflects a selective vulnerability of these structures in PMEs, whatever the etiology and the underlying abnormality (Lance, 1986; Habib et al., 1985). Neuroradiologic studies performed in different forms of PME usually show either normal findings or ‘cerebellar atrophy’. However detailed studies on this subject are remarkably absent. Preliminary results of a MRI volumetric study in patients with ULD disclosed a decrease of the bulk of the cerebellar vermis and of the medulla oblongata in some cases (Mascalchi et al., personal communication). Clinical signs of cerebellar involvement are present in almost all cases of PME and include hypotonia, dysmetria, intention tremor, scanning speech, disorders of ocular movements and ataxia. In general, there is a wide clinical spectrum of cerebellar involvement, even within the same disease and cerebellar signs may deteriorate with time. In PMEs, however, it is often difficult to clinically assess cerebellar functions, because of the coexistence of severe spontaneous or action myoclonus which can obscure or mask cerebellar signs (Harding, 1989). One of the most intriguing issues in this field concerns the relationships, if any, between cerebellar involvement and action myoclonus. It is generally known that one-third of patients with myoclonus have cerebellar signs and that many cerebellar disorders are associated with myoclonus (Lance, 1986). The most consistent pathological change noted at autopsy in patients with action myoclonus has been degeneration of Purkinje cells or dentate nuclei (Habib et al., 1985; Koskiniemi et al., 1974a). It has been postulated that these pathological abnormalities may be caused by hypoxia during epileptic fits or by antiepileptic medication, but this explanation may account for only a minority of cases. On the contrary, it is now widely accepted that cerebellum may modulate the balance between inhibition and facilitation in the motor cortex and that cerebellar lesions may play a role in the mechanisms of action myoclonus, acting as an adjuvant factor; loss of Purkjnie cells

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might result in a facilitatory effect on the thalamo-cortical loop and/or influence the monoaminergic input in the brainstem (Lance, 1986; Bathia et al., 1995; Tijssen et al., 2000). Postmortem studies showing cerebellar involvement with sparing of cerebral cortex in otherwise typical cases of PMEs with cortical reflex myoclonus (Bathia et al., 1995; Tjissen et al., 2000) or animal models of PME (Pennacchio et al., 1998) seem to support this view.

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Opercular epilepsies with oromotor dysfunction Javier Salas-Puig1, Angeles Pérez-Jiménez1, Pierre Thomas2, Ingrid I.E. Scheffer3, Bernardo Dalla Bernardina4 and Renzo Guerrini5 1

Department of Neurology, Hospital General de Asturias, Oviedo, Spain Department of Neurology, CHU, Nice, France 3 Department of Neurology, Austin and Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria, Australia 4 Neuropediatric Department, Borgo Roma Hospital, Verona, Italy 5 Neurosciences Unit, Institute of Child Health, The Wolfson Centre, London, UK 2

Introduction The term operculum insulae denotes the cortical region that covers the insulae Reili. It is made up of frontal, parietal, and temporal cortical convolutions. A bilateral structural or functional disturbance of the cortical motor areas of the anterior part (frontal) operculum, including the inferior rolandic area, and their corticonuclear projections to the nuclei of the 5th, 7th, 9th, and 10th cranial nerves, causes a unique clinical picture of a supranuclear (pseudobulbar) palsy. It presents with swallowing difficulties, anarthria or severe dysarthria, and loss of the ability to imitate oral gestures, resulting from a central disturbance of volitional control of the facio-linguo-glosso-pharyngo-masticatory muscles, while preserving automatic, involuntary, emotional innervation, and reflex motor activity. Pathological crying and laughing are conspicuously absent. It is also designated Foix–Chavany– Marie Syndrome (FCMS), in honour of the authors who described it in 1926, in two adults with bilateral infarction of the anterior operculum (Foix et al., 1926). Bilateral cortical impairment underlies the symptomatology of FCMS as lower cranial nerve brainstem receive innervation from both hemispheres. The best known form of the syndrome is the classical FCMS due to serial strokes in adults with cerebrovascular disease (Bruyn & Gathier, 1969). FCMS can also occur in infancy and childhood, in relation to diverse etiologies and different clinical evolutions. It can be permanent, secondary to congenital malformation or to acquired structural lesion in early life, or can have an intermittent or reversible expression in the background of certain epileptic disorders involving the Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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perisylvian regions (Christen et al., 2000). In children, structural FCMS is frequently associated with other neurological and neuropsychological deficits and chronic epilepsy, particularly in patients with malformative forms (Kuzniecky et al., 1996). Recently, Scheffer et al. (1995), have described a family with autosomal dominant rolandic epilepsy and speech dyspraxia with anticipation. The first case of pseudobulbar symptoms secondary to seizure activity was reported by Penfield and Jasper (1954), who described a young woman with continuous drooling of ictal origin related to a cortical scar over the region of anterior operculum. Anarthria and drooling may appear in patients with focal motor status epilepticus and epilepsia partialis continua (EPC) of oropharyngeal muscles due to restricted cortical lesions or acute neurological insults (Thomas et al., 1977, 1995, Fusco et al., 1992). In children with idiopathic partial epilepsy with centrotemporal spikes (benign epilepsy with centrotemporal spikes) (BECTS), fluctuating appearance of short or long periods of pseudobulbar dysfunction can be observed in relation to continuous regional epileptiform activity involving both hemispheres (Fejerman & Di Blasi, 1987; Roulet et al., 1989; Boulloche et al., 1990; Colamaria et al., 1991; Septien et al., 1992; Deonna et al., 1993; Shafrir & Prensky, 1995; De Saint-Martin et al., 1999; Fejerman et al., 2000). A similar situation has been observed in patients with focal symptomatic epilepsy and perisylvian structural abnormalities who develop a BECTS-like electroclinical picture (Iannetti et al., 1994; Dalla Bernardina et al., 1997). In this chapter, we review the different situations in which epilepsy and pseudobulbar palsy of cortical origin tend to occur all together in childhood. We describe the epileptic spectrum of the patients affected by these rare conditions, and analyse their electroclinical characteristics, according to features related to distribution and extent of the dysfunctional cortex, age-dependent EEG patterns, and etiology (Table 15.1). We will also report on some personal examples of different opercular syndromes and epilepsy. Irreversible opercular syndrome Acquired bilateral opercular lesions

FCMS can be an unusual complication of bilateral focal cortical damage of vascular or infectious origin during the perinatal period or infancy. The postencephalitic cases of FCMS in infancy have been recently reviewed (Christen et al., 2000). Anterior operculum syndrome, as a presenting and persisting feature, is rather specific for Herpes simple virus encephalitis (Château et al., 1966; Mao et al., 1989; Grattan-Smith et al., 1989; Prats et al., 1992; Van der Poel et al., 1995; Mateos et al., 1995; McGrath et al., 1997). These patients develop acute or subacute pseudobulbar signs associated with focal motor seizures, mainly involving the face bilaterally. EEG

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Table 15.1. Classification of conditions with opercular syndrome and epilepsy

Irreversible opercular syndrome Acquired bilateral opercular lesions: Central nervous system infections (e.g. herpes encephalitis) Stroke Birth anoxia Status epilepticus Congenital bilateral opercular lesions: Cortical perisylvian developmental disorders (congenital bilateral perisylvian syndrome) Familial operculum syndrome and rolandic epilepsy Reversible opercular syndrome Operculum syndrome in focal status and epilepsia partialis continua Functional operculum syndrome in benign epilepsy with centro-temporal spikes (BECTS) Functional operculum syndrome in bects-like epilepsy and unilateral brain lesions

may reveal sharp wave-and-spike activity and periodic regional epileptiform discharges (Prats et al., 1992). Lasting deficits generally include chewing and swallowing difficulties, which frequently tend to improve (Mao et al., 1989; Grattan-Smith et al., 1989; Prats et al., 1992; Van der Poel et al., 1995), and severe dysarthria or anarthria. Prats et al. (1992) considered that the mutism with normal comprehension observed in their case might be attributed to a severe expressive speech disorder affecting phonological programming, in addition to a pure paretic oromotor disturbance. Mild hemiparesis was observed in three of the reported cases (Mateos et al., 1995). MRI usually reveals cortical lesions involving both perisylvian and rolandic areas, such as sharply demarcated hyperintensity during the acute phase (Prats et al., 1992), and focal atrophy and subcortical gliosis in the chronic stage (Mateos et al., 1995). Among the reported cases, only three out of eleven developed chronic epilepsy (Christen et al., 2000; Grattan-Smith et al., 1989; Mateos et al., 1995). Other unusual causes of early acquired FCMS have been occasionally reported, such as vascular occlusive disease of both middle cerebral arteries in a child with tuberculous meningitis (Moodley & Bamber, 1990), induced brain damage secondary to prolonged status epilepticus of unknown etiology in childhood (PascualCastroviejo et al., 1999), and perinatal difficulties with birth anoxia (Koeda et al., 1995; Guerrini et al., 1992). In some of the reported children with early acquired FCMS, selective pseudobulbar signs appear in the context of cerebral palsy, with quadriparesis, mental retardation, and in some of them intractable epilepsy (Christen et al., 2000). A greater susceptibility of perisylvian structures to hypoxia explains the preferential localization of atrophic lesions in these areas in children with early diffuse cerebral damage (Amir et al., 1990).

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Congenital bilateral opercular lesions Cortical perisylvian developmental disorders

In 1953, Woster-Drought (1953, 1974), suspected for the first time a developmental and familial form of suprabulbar paresis, before the advent of modern imaging techniques. Graff-Radford et al. (1986) identified bilateral symmetrical perisylvian dysplasia suggesting polymicrogyria by MRI in two identical twins with congenital FCMS and epilepsy. Kuzniecky et al. (1989) described four children with oromotor incoordination, developmental delay, mild mental retardation and epilepsy. EEG recordings showed secondary generalized or multifocal abnormalities, and MRI disclosed macrogyric-like bilateral opercular changes. Similar cases, with a broader spectrum of clinical expression, were reported by others (Guerrini et al., 1992; Duché et al., 1992). In a Multicenter Study, the clinical and neuroimaging features and the epileptic spectrum of 31 patients with bilateral congenital perisylvian malformations were outlined (Kuzniecky et al., 1993, 1994a,b, 1996). The condition was proposed as a recognizable anatomoclinical entity, defined as the congenital bilateral perisylvian syndrome (CBPS). The major criteria for diagnosis, present in 100% of the cases, included oropharyngoglossal dysfunction, moderate to severe dysarthria, and bilateral perisylvian malformation on neuroimaging. Additional criteria, present in 85% of the cases, included delayed milestones, epilepsy, mental retardation and abnormal EEG. Most of the patients showed mild pyramidal signs and cognitive deficits, some of them had suffered from feeding difficulties and poor sucking during infancy, a minority had moderate quadriparesis, arthrogryposis multiplex or other limb deformities. In children with CBPS, MRI discloses grossly symmetrical bilateral perisylvian and perirolandic macrogyric appearance. Using inversion-recovery sequences and high definition imaging, the abnormal cortex shows an altered sulcal pattern, and increased interdigitations between white and grey matter overlaid by small fused gyri, suggesting polymicrogyria (Kuzniecky et al., 1994; Raybaud et al., 1996). Other frequent features are a failure to complete formation of the opercula, with abnormal vertical orientation and depth of the lateral sulcus and exposure of the insula with increased subarachnoid space and variable extension of the malformation into the parietal and superior temporal regions (Kuzniecky et al., 1994a; Raybaud et al., 1996; Rolland et al., 1995). Neuropathological studies performed in patients with CBPS have revealed unlayered (Becker et al., 1989) or four layered (Kuzniecky et al., 1993) polymicrogyria, or both (Shevell et al., 1992). The disorder may be attributed to a genetically determined selective aberration of neuronal migration (Graff-Radford et al., 1986; Kuzniecky et al., 1994b; Gropman et al., 1997; Anderman & Anderman, 1996; Borgatti et al., 1999), or secondary to fetal brain ischemia or hypoxia (Lenti & Triulzi, 1996). Sporadically this malformation

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has been observed in children with chromosomal dysmorphic syndromes (Binghan et al., 1998). The neurological expression of patients with bilateral opercular malformations is broad, from severe cerebral palsy (Tatum et al., 1989) to normal clinical examination (García-Herrero et al., 1998). The epileptic spectrum ranges from focal epilepsy responsive to drugs, to severe symptomatic generalized epilepsy (Guerrini et al., 1992; Kuzniecky et al., 1994b; García-Herrero et al., 1998). The speech disorder in CBPS ranges from almost complete mutism to mild dysarthria, with normal visual and tactile naming, and normal recognition of non-verbal sounds (Kuzniecky et al., 1993; Anderman et al., 1990). Neuropsychological assessment of language and speech of patients with CBPS have revealed that the disorder is not limited to a speech paretic disorder (anarthria) and oral dyspraxia as in the classic form of FCMS. It rather reflects a more widespread dysfunction of language, in the form of a non-fluent developmental dysphasic syndrome with some degree of comprehension impairment (Sans et al., 1996). The typical neurological picture of CBPS comprises pseudobulbar palsy, moderate mental retardation, mild motor signs, and poorly controlled seizures beginning in childhood, including tonic and atonic seizures with head-drops, drop-attacks and atypical absences. The electroclinical features resemble, on some occasions, the Lennox–Gastaut syndrome. Kuzniecky et al. (1994a,b) found brief tonic/atonic seizures or atypical absences in 80% of their patients. Some of them had also generalized tonic-clonic attacks and partial seizures (primarily somatosensory but also temporal lobe seizures or both). Nocturnal motor seizures, characterized by bilateral tonic contraction or jerking of the mouth and lips, related to fast recruiting rhythms and polyspike discharges, mainly over the centro-parietal regions (Ambrosetto & Tassinari, 1990), are highly characteristic of CBPS (Kuzniecky et al., 1994a). These attacks, which represent the initial epileptic manifestation, can also be observed during wakefulness, may be associated or evolve into other motor seizures, tonic, or atonic attacks. The characteristic interictal epileptiform abnormalities consist of bursts of bilaterally synchronous sharp and slow wave and independent sharp waves involving frontocentral and temporal or centro-parietal regions, and less frequently, multifocal discharges (Kuzniecky et al., 1989, 1993; Ambrosetto & Tassinari, 1990). Kuzniecky et al. (1994b) observed intermittent bilateral theta activity on frontocentrotemporal regions in 25% of their patients. Dysarthria can be exacerbated when epilepsy is aggravated, due to postictal cortical exhaustion (Anderman et al., 1990; Ambrosetto & Tassinari, 1990), or related to frequent interictal or clinically silent ictal EEG activity (Kuzniecky et al., 1993). Tagawa et al. (1999) described recurrent episodes of non-convulsive status epilepticus in a child

Typical presentation of CBPS

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Fig. 15.1

Case report 1. MRI findings in congenital bilateral perisylvian syndrome.

with CBPS, characterized by frequent head drops, excessive drooling, and subtle myoclonus of the face and limbs lasting several days, in the context of a LennoxGastaut syndrome. CASE REPORT 1 A 32-year-old woman, with an unremarkable family history, had poorly characterized seizures in infancy. Feeding difficulties and excessive drooling were reported during childhood. Neurological exam showed pseudobulbar signs with dysarthria, facio-glosso-masticatory dysfunction and mild mental retardation (video). From the age of 13 years, she suffered daily, complex partial seizures with unresponsiveness, bucco-facial jerking and drooling, sometimes with falling. Multiple antiepileptic drugs were ineffective. EEG recordings showed normal background activity, spikes and spike-waves discharges over both centrotemporal regions. MR imaging showed bilateral symmetrical perisylvian polymicrogyria. (Fig. 15.1)

Some patients with disproportionate enlargement of the sylvian fissures and gyral maldevelopment of the frontoparietal cortex in imaging studies have severe developmental delay and trunkal hypotonia in early infancy (Kuzniecky et al., 1993; Shevell et al., 1992; Gropman et al., 1997; Binghan et al., 1998; Tatum et al., 1989). They generally show signs of abnormal prenatal growth, such as microcephaly, dysmorphic traits and congenital deformities (arthrogryposis) (Gropman et al., 1997; Binghan et al., 1998).

Neonatal and infantile presentation of CBPS

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Elements of pseudobulbar palsy are manifested by dystonic orofacial and poorly organized tongue movements, sucking difficulties, and inability to swallow. Eventually, they may require a gastric feeding tube during infancy, although these symptoms tend to improve during childhood. In these patients, absent speech can be attributed to the severe developmental delay. Epilepsy is not a constant feature (Gropman et al., 1997), but children frequently develop early-onset seizures, including neonatal convulsions (Tatum et al., 1989), infantile spasms (Gropman et al., 1997), and febrile seizures (Gropman et al., 1997). The neuroimaging finding of ‘open opercula’ resembles the fetal operculum configuration observed between the 20th and 24th week of pregnancy (Rolland et al., 1995). As an early sign of arrested development, it can be considered a marker of more diffuse brain abnormality (Rolland et al., 1995; Tatum et al., 1989). CASE REPORT 2 This 10 year-old child had severe developmental delay and oromotor incoordination. MRI showed wide open opercula associated with moderate dysmorphic enlargement of the lateral ventricles, and gyral perisylvian maldevelopment. A congenital cytomegalovirus infection was suspected. Early evaluation revealed microcephaly, severe axial hypotonia, and sucking difficulties. Moderate quadriparesis with right predominance, absence of mastication, and mutism were later noted. At the age of 1, he developed infantile spasms. Partial motor seizures (mainly hemiclonic seizures), atypical absences with facial myoclonia or atonic motor phenomena and occasional mild tonic seizures during sleep, related to fast activity recruiting discharges were then documented. Interictal EEG disclosed bilateral centro-parieto-temporal spikes and generalized spike and wave discharges during wakefulness, and continuous spike-and-wave activity during sleep (CSWS). On some occasions, generalized spike and waves became almost continuous during wakefulness, inducing an increase of hypotonia and drooling. Repeated cycles of steroids controlled recurrent status.

CBPS with mild clinical expression Bilateral perisylvian polymicrogyria may rarely be a neuroimaging finding detected around late childhood or adolescence at the time of the first seizure, in patients with mild motor signs or speech difficulties, and low average intelligence or mild mental retardation. In these cases, epilepsy tends to be less severe than in children with typical CBPS and includes focal seizures, predominantly with somatosensory or somatomotor symptoms, accompanied by mildly abnormal or normal interictal EEG. García Herrero et al. (1998) reported a 14-year-old girl, with normal intelligence and normal neurological status, affected by abdominal epilepsy related to a bilateral asymmetrical sylvian malformation. EEG showed interictal sharp and slow waves over both frontotemporal areas. Van Bogaert et al. (1998) reported a 32-yearold woman with clusters of subtle epileptic spasms as the main clinical manifestation. Guerrini et al. (1992) described two patients with rare unilateral clonic

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seizures or temporal lobe seizures beginning after the age of 10 with normal EEG. They had mild to moderate mental retardation, pseudobulbar palsy, and motor deficits (hemiparesis and quadriparesis) respectively. Kuzniecky et al. (1993, 1994b), reported that 30% of their patients were seizure-free or almost seizure-free under medication. Patients with onset of epilepsy after the age of ten tended to have focal epilepsy with somatomotor or temporal-lobe seizures, and less frequent atonic or tonic attacks. The severity of the epilepsy and the degree of oromotor dysfunction were not correlated with the extent of the structural abnormality, but were related to the grade of symmetry. Patients with asymmetrical malformations tended to have milder forms of dysarthria, presumably due to preserved function of the malformed cortex with at least one side innervating brainstem nuclei (Kuzniecky et al., 1994a). These cases represent the mildest end of the clinical spectrum of CBPS. Misdiagnosis of long-lasting sensory symptoms of probable epileptic origin, such as paresthesia restricted to the perioral region or distal part of the upper limb, is possible in patients with developmental malformations involving parietal perisylvian cortex. These symptoms resemble the posterior operculum syndrome (cheriooral syndrome) described in association with posterior parietal operculum infarction (Bogousslavsky et al., 1991). In children with asymmetric perisylvian malformations and absence of clear pseudobulbar signs, specific neuropsychological deficits and phonologic–syntactic language disorders may be the only signs topographically related to the cortical lesions. Operculum syndrome and reflex epilepsy Eating epilepsy has been observed in patients with bilateral opercular lesion and FCMS secondary to developmental (Andermann et al., 1990) or acquired diseases (Mateos et al., 1995). Depthelectrode-recordings suggest that opercular reflex seizures induced by movements of the jaw and mouth originate in the deep central opercular cortex (Biraben et al., 1999). Neville and Boyd (1995) described a girl with normal brain MRI suffering from attacks of drooling and tongue quivering with interictal pseudobulbar signs, whose attempts to speak seemed to provoke tongue jerking. Andermann et al. (1990) described another patient with CBPS and eating epilepsy with major propioceptive and sensory triggerings: biting into a juicy fruit, eating hot soup or ice cream, from a cone, and even kissing her parents. This type of eating epilepsy is considered typical of the involvement of the postcentral gyrus. Familial operculum syndrome and rolandic epilepsy

Scheffer et al. (1995) described a family of 9 affected individuals in three generations with nocturnal oro-facio-brachial partial seizures, secondarily generalized seizures and centro-temporal epileptiform discharges, resembling BECTS, asso-

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ciated with oral and speech dyspraxia and cognitive impairment. Autosomal dominant inheritance with clinical anticipation could indicate that the expansion of an unstable triplet repeat could be the genetic mechanism. Neuroimaging was normal with the exception of high signal in the perivascular spaces on T2 sequences, a finding of uncertain significance. The seizure disorder was characterized by: onset around the sixth year of life in the third generation, and before the third year of life in two out of three members of the fourth generation. Aura with fear and/or perioral vibration or hand tingling were present in three individuals, typical symptoms included grunt and/or speech arrest and drooling. Secondarily generalization occurred in all patients. Interictal EEG studies in all affected children showed frequent centro-temporal epileptiform discharges, similar to BECTS in their morphology and dipole configuration, activation during sleep and reversal of dipole configuration during a seizure. Language studies revealed mainly oral and speech dyspraxia, without evidence of dysarthria with difficulty in organizing and coordinating the highly elaborated movements necessary to produce fluent and/or intelligible speech. Receptive processing was abnormal and more impaired in the children. Expressive language skills of the adults were mainly in the low–normal range except in the area of naming, which was significally impaired, especially in children. Naming, sentence formulation, and sequencing of ideas were below the normal age-matched range. Speech dyspraxia refers to dysfluency at an articulatory level (as distinct from pure word-finding difficulty), so that speech is slow and laborious with variable phonetic errors. With increasing articulatory complexity, more pronounced difficulties are experienced with frequent sequencing and substitution errors. This family differs from the functional operculum syndrome associated with BECTS (see below) as they had persisting oral and speech dyspraxia into adult life, many years after seizures had ceased. Reversible operculum syndrome Operculum syndrome in focal status epilepticus and epilepsia partialis continua

Frequent seizures and epilepsia partialis continua of the opercular region may provoke long-lasting fluctuating palsy similar to that observed in patients with EPC affecting primary motor areas of the limbs. Prolonged isolated drooling of epileptic origin was first described by Penfield and Jasper (1954) in a patient with a focal symptomatic epilepsy. Bilateral clonic involvement of the face and jaw occurring with acquired true FCMS in adulthood was reported by Thomas et al. (1977). Fusco et al. (1992) described a child with mild left hemimegalencephaly who developed reversible operculum syndrome when continuous epileptic discharges spread from the left hemisphere to the contralateral. Thomas et al. (1995) reported three adults with opercular myoclonic status epilepticus, secondary to unilateral focal lesions of

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various origins (vascular or tumour). These patients had fluctuating cortical dysarthria associated with epileptic myoclonus involving the glossopharyngeal muscles bilaterally, and postictal pseudobulbar palsy, attributed to Todd´s palsy. Absence of epileptiform EEG activity in two patients made it difficult to differentiate them from palatal myoclonus of brainstem origin. CASE REPORT 3 This 33-year-old right-handed man experienced a single tonic–clonic seizure, followed by permanent rhythmic lingual movements. At rest, myoclonias were seen over hyodian area. Tongue protusion produced high amplitude lingual movements with a frequency between 0.5 and 1 Hz, associated with bilateral involvement of the soft palate and pharyngeal muscles. There was no involvement of the perioral muscles. Slow and dysarthric speech and buccofacial apraxia were present. Eating and drinking produced gagging. Neurological examination only showed a bilateral facial central palsy with right predominance. Polygraphic study, recorded from the omo-hyoideus muscle, showed that recurrent seizures comprising 2 Hz rhythmic myoclonic jerks were occasionally superimposed on a continuous background of periodic myoclonias with a 4 seconds frequency (Fig. 15.2). On surface EEG, each myoclonic jerk was preceded by a negative biphasic potential over the left fronto-central area. Occasional slow waves of similar morphology occurred randomly without subsequent muscular contraction. Jerk-locked back-averaging showed that there was a 160 ms delay between the negative cerebral component and the myoclonic jerk, this delay being too long to suggest pure cortical myoclonus. Phenytoin infusion slightly decreased the frequency of the myoclonic jerks but not their amplitude. Status ceased spontaneously 3 days after admission. CT and MRI showed a left opercular infarction. Transesophageal echocardiography showed grade 2 mitral insufficiency. The speech disorder gradually improved over a 7-day period. The only sequelae, on warfarin therapy, was a left facial palsy of central origin.

Functional operculum syndrome in BECTS

There are a few reports of functional or intermittent FCMS in children with clinical and EEG features consistent with BECTS (Fejerman & Di Blasi, 1987; Roulet et al., 1989; Boulloche et al., 1990; Colamaria et al., 1991; Septien et al., 1992; Deonna et al., 1993; Shafrir & Prensky, 1995; De Saint-Martin et al., 1999; Fejerman et al., 2000). These children suffered from recurrent episodes of pseudobulbar palsy, lasting from hours to several months, related to seizure activity or frequent epileptiform discharges on the EEG. Clinically, they showed bucco-facial apraxia, drooling, dysarthria or speech arrest, swallowing and eating problems. Occasional low-amplitude facial twitching or subtle perioral myoclonus were observed in most of them. Somatosensory prodromes (Boulloche et al., 1990), sensory agnosia with unawareness of the presence of food in the mouth (Roulet et al., 1989; Shafrir & Prensky, 1995), palatal paresis, and absent gag reflex (Boulloche et al., 1990) were occasion-

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Fig. 15.2

Case report 3.Opercular myoclonic–anarthric status epilepticus at the acute phase of a left opercular infarction. Tongue protraction shows to-and-fro lingual movements with a 3–4 s periodicity. Each movement is produced by a slow clonic jerk involving the superior part of the tongue’s musculature (arrows). On surface EEG, myoclonic jerk was preceded by a biphasic slow wave over F3. Jerk-locked back-averaging showed a 160 ms delay between the onset of slow wave and the myoclonic jerk. Calibration: vertical bar50 uV; horizontal bar1 s.

ally observed. The children had, otherwise, normal comprehension, and were alert, responsive, and able to follow commands. The EEG showed bilateral continuous epileptiform discharges involving the centro-temporal regions while awake, almost continuous spike-and-wave discharges during NREM sleep. Clear focal seizures, frequently occurring in clusters, could precede or accompany the first FCMS episode, but pseudobulbar episodes were the first clinical manifestation in some patients (Deonna et al., 1993; Shafrir & Prensky, 1995). On rare occasions, the symptoms rendered the patient unable to eat, requiring a nasogastric tube. Investigations were frequently initially oriented toward a laryngeal or a gastrointestinal disease (Boulloche et al., 1990; Mao et al., 1989). Some children responded to clobazam and sodium valproate (Colamaria et al., 1991), whereas others were successfully cured with steroids (Fejerman & Di Blasi, 1987; Mao et al., 1989). Worsening of the pseudobulbar signs and of the EEG picture was noticed in some children treated with carbamazepine (Shafrir & Prensky, 1995). In some of the reported cases, the anterior operculum syndrome corresponded to clear-cut episodes of status epilepticus: no pseudobulbar

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symptoms or other neuropsychological deficits were present between the episodes despite persistence of frequent interictal regional epileptiform activity (Boulloche et al., 1990). On some occasions, pseudobulbar attacks were related with a cluster of partial seizures and an increase of the EEG abnormalities, and the neurological signs were attributed to Todd’s palsy (Fejerman & Di Blasi, 1987; Boulloche et al., 1990). In other cases, the neurological abnormalities fluctuated during months or even years, accompanied by prominent epileptiform abnormalities, and were considered an interictal or ‘paraictal’ neurologic disorder (Roulet et al., 1989; Deonna et al., 1993; Shafrir & Prensky, 1995). Authors noticed a correlation between the intensity of the ictal discharges on EEG and the fluctuating course of the symptomatology. Remissions were related to EEG improvement. Relapses were associated with an increase in epileptic activity and appearance of CSWS. Colamaria et al. (1991) observed specific inhibition and blocking of interictal centrotemporal spikes by voluntary movements of mouth and/or tongue. Brief perioral and myoclonic jerks (Boulloche et al., 1990; De Saint-Martin et al., 1999), may be correlated with the interictal spikes. An age-dependent tendency has been observed for worsening of epileptiform activity and the development of CSWS (Fejerman et al., 2000; Dalla Bernardina et al., 1978; Aicardi & Chevrie, 1982; Doose et al., 1996). These patients usually develop absences and positive or negative myoclonus leading to falls, hyperkinetic behaviour and decreased school performance. Children with BECTS, presenting with episodes of pseudobulbar dysfunction may share common features with them (Christen et al., 2000; Fejerman et al., 1987; Deonna et al., 1993; Shafrir & Prensky, 1995). Deonna et al. (1993) observed that epileptiform activity interfered in a variable way with neurological functions, leading to a range of clinical deficits including anterior operculum syndrome, intermittent drooling, oromotor dyspraxia, dysfluency and linguistic deficits involving phonologic production. Some authors suggest a common pathophysiologic mechanism between epileptic anterior operculum syndrome and Landau-Kleffner syndrome (LKS), the first involving suprasylvian opercular structures, the second affecting infrasylvian opercular regions. Although there is some overlap between these conditions, for clinical and prognostic purposes, the pictures of these entities should be differentiated. In a recent review (Fejerman et al., 2000) all five children with CSWS and BECTS were of normal intelligence after a 3-to-14 year follow-up. A smaller percentage of children with LKS make a complete recovery. Functional operculum syndrome in patients with BECTS-like epilepsy and unilateral or asymmetric brain lesions

Some children with unilateral or asymmetric malformations can experience an epilepsy with some features similar to BECTS, including those with unilateral perisyl-

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vian and multilobular or hemispheric polymicrogyria and schizencephaly (Iannetti et al., 1994; Dalla Bernardina et al., 1997; Ambrosetto, 1992; Sheth et al., 1997; Colamaria et al., 1989; Guerrini et al., 1996; Caraballo et al., 1999). Such patients have no clinical deficits, but may frequently show mild or moderate clinical signs, such as astereognosis, pathological left-handeness or hemiparesis, developmental delay, or slight cognitive and language disturbances. Unusual ictal semiology has been described including dysesthesia, tonic deviation of the mouth, or gastralgia and atypical morphology of the rolandic spikes (change in morphology during sleep or increase during hyperventilation). Abnormal background EEG activity is also possible (Dalla Bernardina et al., 1997). There is a strong tendency towards an age-dependent evolution to a CSWS or pseudo-Lennox–Gastaut picture (Iannetti et al., 1994; Dalla Bernardina et al., 1997; Colamaria et al., 1989; Guerrini et al., 1996; Caraballo et al., 1999). Worsening and bilateral synchronization of epileptiform activity is accompanied by recurrent speech and motor disturbances. Other symptoms include reversible or fluctuating dysarthia, transient upper limb neglect, epileptic negative myoclonus, clumsy gait and drooling. CASE REPORT 4 This right-handed 14-year-old girl presented with a history of normal early developmental milestones, poor left hand coordination and slight phonetic difficulties. At the age of 2 years, after a single febrile seizure, she began to suffer from frequent partial seizures involving mouth and lips (paresthesia, tonic deviation of the mouth, drooling, anarthria) or the right arm, sometimes evolving to complex partial seizures with hemiclonic or atonic attacks. Interictal EEG showed right centro-parieto-temporal spikes. At the age of 8 she developed brief tonic seizures with sudden head drops and falling associated with prolonged episodes of dysarthria, drooling, and gait instability. EEG showed almost continuous epileptic activity over both hemispheres. After puberty, she had only brief minor attacks on awakening.

Conclusions Structural and functional abnormalities of bilateral anterior opercular areas in children manifest clinically with oromotor dysfunction and epilepsy. Focal seizures affecting mouth and face bilaterally, drooling, and interictal centro-temporal epileptiform discharges are common. Secondary generalized epilepsy resembling Lennox–Gastaut syndrome is a common presentation of CBPS, although some patients may suffer from some partial seizures which respond to drugs. In CBPS a fluctuating pseudobulbar palsy can be related to epileptic activity. A strong activation with synchronization of bilateral centro-temporal epileptiform discharges is also observed in children with unilateral or bilateral asymmetrical perisylvian malformations without pre-existing pseudobulbar palsy;

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a similar electroclinical picture is rarely observed in children with BECTS. Under these circumstances, almost-continuous bilateral epileptiform activity can underlie subacute oromotor dysfunction. Language areas, and nearby motor and sensory areas for the mouth and one upper limb are frequently involved to a variable degree in children with structural or functional FCMS. The recognition of such rare electroclinical pictures, their differential diagnosis, and the establishment of an appropiate treatment, avoiding drugs that can precipitate secondary bilateral bisynchrony on the EEG (mainly carbamazepine), are crucial to achieve optimal clinical management.

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16

Facial seizures associated with brainstem and cerebellar lesions A. Simon Harvey1, Michael Duchowny2, Alexis Arzimanoglou3 and Jean Aicardi3 1

Department of Neurology, Royal Children’s Hospital, Parkville, Victoria, Australia Department of Neurology, Miami Children’s Hospital, FL, USA 3 Department of Child Neurology, L’Hôpital Robert Debré, Paris, France 2

Hemifacial seizures and cerebellar ganglioglioma In 1996 Harvey et al. reported an infant with a cerebellar ganglioglioma and episodes of hemifacial contraction that were shown conclusively to be epileptic seizures of cerebellar origin. Previous reports in the literature of six infants with cerebellar tumours and ‘hemifacial spasm’ suggested they might have a similar syndrome of cerebellar epilepsy. Since the report by Harvey et al., there have been three further cases reported (Arzimanoglou, 1996; A.S. Harvey et al., unpublished data), with further ictal SPECT evidence in two cases to support an epileptic basis to the attacks of ‘hemifacial spasm’. The clinical seizure characteristics, the location and signal characteristics of the lesions on magnetic resonance imaging (MRI), and the histopathological features of the tumours in these ten patients are so strikingly similar as to conceivably constitute an epilepsy syndrome of infancy characterized by seizures of cerebellar origin. The initial case remains the most well-studied case in the literature, with unequivocal evidence of an epileptic basis and cerebellar origin of seizures (Harvey et al., 1996). Her seizures began on day 1 of life with twitching of the left orbicularis oculi muscle. She was evaluated at the Miami Children’s Hospital at age 6 months when attacks of ‘hemifacial spasm’ were occurring multiple times each day. Immediately prior to each episode she became quiet and fixed her gaze straight ahead. She would then exhibit tonic contraction of the left orbicularis oculi muscle, followed by tonic head and eye deviation to the right, nystagmoid jerks of the eyes to the right, forceful blinks of both eyes and finally, irregular clonic contractions of the left orbicularis oculi and the left angle of the mouth. Tremulous movements of Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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the limbs were occasionally seen and brief elevation of the arms and legs occurred in some episodes. She would often grimace and whimper during attacks and gave the impression of retained consciousness. There was no history of autonomic dysfunction but during video-EEG monitoring she showed ictal apnoea and bradycardia. The episodes lasted 5–30 seconds, occurred during awake and asleep states, were not precipitated by recognizable factors and occurred multiple times each day, often at intervals of less than one minute. Seizures were refractory to a variety of antiepileptic medications used from age 3–6 months. Examination was normal apart from intermittent gaze-evoked nystagmus, slight narrowing of the left palpebral fissure and mild weakness of elevation of the left angle of the mouth. Interictal and ictal scalp electroencephalographic (EEG) recordings were unremarkable. MRI revealed a mass in the left middle and superior cerebellar peduncles which was isointense with grey matter and compressed the fourth ventricle. Single photon emission computed tomography (SPECT) revealed focal hyperperfusion in the region of the cerebellar mass during an attack. Intracranial EEG recording with a depth electrode in the cerebellar mass and a subdural strip electrode over the left cerebellar hemisphere demonstrated focal seizure activity arising from the lesion during typical attacks. Resection of the cerebellar mass resulted in permanent remission of seizures. Histopathology revealed ganglioglioma. She is mildly delayed but otherwise intact neurologically. The case reported in detail by Arzimanoglou et al. (1996, 1999) presented with similar paroxysmal attacks since the age of 3 months. Clinical examination revealed moderate dysmorphic features with left facial asymmetry, a small mandible and an epibulbar cyst of the right corneal limb associated with a pretragus tag and mild atrophy of the inferior part of the left iris. Spine X-rays showed fusion of the pedicles of the second and third thoracic vertebrae. The association of all these abnormalities suggested Goldenhar’s syndrome (Goldenhar, 1952; Gorlin et al., 1990). This syndrome, also described as the ‘oculo-auriculo-vertebral spectrum’, results from an abnormal development of the first and second branchial arches. Involvement may not be limited to facial structures (Gorlin et al., 1990). At the age of 11 years bilateral abnormal eye movements, predominating on the left, were discovered. These may have existed earlier as they were of very small amplitude. They had a regular rhythmical character, were obliquely directed left and upwards with an anticlockwise rotatory component and persisted during sleep. They were synchronous with slight, minimal, palpebral movements of both the superior and inferior eyelids and with mild contractions of the left mentalis muscle. These movements had the characteristic rhythm and regularity of skeletal myorythmias but there was no palatal tremor. Palatal tremor, also known as palatal myoclonus or brainstem myorhythmia (Guillain & Mollaret, 1931), is often associated with myorhythmias of other muscles, especially extraocular and facial muscles in the territory of the first brachial arches (Lapresle, 1979). It is regarded as the prototype of

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a hyperkinetic movement disorder depending on a central pacemaker (Llinas, 1984), the inferior olive, as the rhythmic jerks are time-locked in different muscles (Deuschl et al., 1990). Although in adults most cases are associated with hypertrophic degeneration of the inferior olive, lesions involving at any point the pathway from the contralateral dentate nucleus via the branchium conjunctivum and the ipsilateral central tegmental tract to the inferior olive (triangle of Guillain and Mollaret) can be responsible for palatal myorhythmias. The presence of a dysplastic lesion in association with an abnormal development of the first and second brachial arches is not fortuitous. It was clearly responsible for the episodes of ‘facial spasm’, probably of an epileptic mechanism involving discharges of subcortical grey matter in the cerebellum and/or the facial nucleus. The ocular and skeletal myorhythmias probably resulted from impingement of the tumour on the central tegmental tract on its way from the inferior olive to the oculomotor nuclei. The selective involvement of only some muscles may be related to the somatotopic organization of the inferior olive and of its efferents (Beitz, 1976). This case supports the hypothesis that the same lesion can generate both epileptic seizures and a non-epileptic movement disorder if the same anatomical networks are implicated. However, the possibility of another, undetectable, defect in the brainstem in relation with the regional developmental abnormality cannot be completely excluded (Arzimanoglou et al., 1999). The clinical, imaging and operative findings in the ten reported patients with this syndrome are summarized in Table 16.1 (Flüeler et al., 1990; Jayakar & Seshia, 1987; Bills & Hanieh, 1991; Langston & Tharp, 1976; Al-Shahwan et al., 1994; Arzimanoglou et al., 1999; Harvey et al., in preparation). There is an equal sex distribution of patients and all presented with attacks in the first year of life, with at least four having episodes first noted in the newborn period. All presented with episodes of unilateral tonic spasm or clonic jerking of the face, beginning in the orbicularis oculi and then involving the lower facial muscles, ipsilateral to the side of the cerebellar lesion. Additional ictal motor manifestations included tonic head deviation in four (ipsilateral in three, contralateral in one), tonic deviation or nystagmoid jerks of the eyes in six, and abnormal movement of the ipsilateral arm in six. Autonomic manifestations occurred in only three patients, with facial flushing in one, bradycardia in one and alteration of respiratory rate in three. Consciousness was retained during seizures in all patients. Seizures occurred multiple times per day, often in clusters every few minutes, during awake and asleep states. Duration varied from several seconds to 30 minutes, with seizures in most patients lasting less than 5 minutes. Clinical course was that of relentless attacks occurring over years, resistant to antiepileptic medications in all patients. Abnormal neurological findings were present in seven patients, typically being delay in motor development, weakness or tremor of the limbs ipsilateral to the lesion, ataxia of gait or nystagmus, of mild–moderate degree.

Table 16.1. Clinical, imaging and operative details in ten cases of hemifacial seizures and cerebellar mass lesions

Reference – case #

Sex Onset Assessment

Harvey et al., 1996

Female 1 day 6 months

Tonic and clonic contraction of L orbicularis oculi / angle of mouth, head and eye deviation to R, nystagmoid jerks of eyes to R, / brief tremor and elevation of limbs, / apnea and bradycardia, 5–30 seconds duration, every 2–10 minutes, awake and asleep

Jayakar & Seshia, 1987

Male 1 year 18 months

Bills & Hanieh, 1991

Male 3 weeks 2 years

Clinical features of hemifacial seizure

Surgery (pathology)

Examination

Brain imaging

Course

Mild L face and arm weakness, intermittent gaze-evoked nystagmus

CT and MRI: nonenhancing mass in L superior and middle cerebellar peduncles, effacing 4th ventricle SPECT: interictal hypoperfusion and ictal hyperperfusion in region of mass

Subtotal resection at age 3 months, total resection at age 6 months (ganglioglioma)

no tumour recurrence at age 5 years, seizure free, mild development delay with mild L hemiparesis

Tonic and clonic contraction of Impaired L then both eyelids, clonic parachute contraction L angle of mouth, reflex in L arm, abnormal respirations, / eye mild deviation up and to R, / incoordination head deviation to the R, / involuntary movements of L arm, no alteration of consciousness, 3 seconds – 30 minutes duration, every 15 minutes, awake and asleep

CT: homogeneous mass in L cerebellar hemisphere

Almost total resection at age 18 months (low-grade dense fibrillary astrocytoma)

no tumour recurrence at 5 years, normal development, mild incoordination of L arm, no episodes

Contraction of the L orbicularis oculi / L lower face, eye deviation to L, dystonic L arm, impression of distress, 10–30 seconds duration, every 3–5 minutes, awake and asleep

CT and MRI: mass in the L superior cerebellar peduncle compressing 4th ventricle

Subtotal resection at 2 years (ganglioglioma)

3 months postop no deficits, and no episodes

Flüeler et al., 1990 – case 2

Female 1 week 10 months

Clonic contraction R eyelid and angle of mouth, no alteration of consciousness, 3–5 seconds duration, every few minutes, precipitated by stress, awake and asleep

Normal

CT: normal MRI: mass in R middle and superior cerebellar peduncles compressing 4th ventricle

None

Multiple daily episodes persisted at age 12 years

Flüeler et al., 1990 – case 3

Female 10 months 18 months

Twitching of R eyelid / lower face, no alteration of consciousness, 1–20 seconds duration, almost continuous, precipitated by stress, awake and asleep

Nystagmus, unsteady gait, intention tremor of upper limbs, nasal speech, hypotonia

MRI: mass involving the R medulla, lower pons, middle and inferior cerebellar peduncles, compressing 4th ventricle

None

Brief, repetitive R facial contractions all day at 5 years, no change in tumour

Langston & Tharp, 1976

Male 6 weeks 8 years

Tonic and clonic contractions of the L orbicularis oculi and lower face, head deviation to R, extension of L elbow, no alteration of consciousness, 3 seconds–5 minutes duration, 3–50 per day, precipitated by stress and fatigue, awake and asleep

Narrowing of L palpebral fissure, slightly impaired alternating movements of R arm

PEG and arteriogram: mass bulging into the L superior aspect of the 4th ventricle

Partial resection at 5 years (ganglioglioma)

episodes continue at lower frequency, L facial weakness, clumsy L arm & nystagmus

Al-Shahwan et al., 1994 – patient 1

Female 1 day 3 years

Tonic contraction of R face, / flexion of R arm and extension R leg, every 5–10 minutes, awake and asleep

Globally delayed development

CT: normal MRI: mass in R middle and superior cerebellar peduncle

Partial resection (ganglioglioma)

Episodes continue but are less severe

Table 16.1. (cont.)

Reference – case #

Sex Onset Assessment

Clinical features of hemifacial seizure

Examination

Brain imaging

Surgery (pathology)

Course

Arzimanoglou, Male 1996, 1999 3 months 16 years

Tonic contraction of L orbicularis oculi and face, flushing, / tachypnea, / L shoulder elevation, / nystagmoid eye movements, no alteration of consciousness, 5–60 seconds duration, awake and asleep, >10 per day

Dysmorphic (Goldenhar’s syndrome), mild axial hypotonia, L 6th nerve palsy

CT: normal MRI: mass in L cerebellar peduncle effacing 4th ventricle

None

Multiple daily episodes, normal intellect, single tonic–clonic seizure

Harvey Male & Singh, 5 months in preparation 18 months – patient 1

Clonic jerking of L orbicularis oculi and angle of mouth, no alteration of consciousness, nystagmoid eye movements, / head deviation to L, 1–5 minutes duration, every 5–10 minutes, awake and asleep

Mild L hemiparesis, intention tremor of upper limbs

MRI: mass in L cerebellar peduncle SPECT: interictal hypoperfusion and ictal hyperperfusion in region of mass

Biopsy at 18 months (ganglioglioma)

Multiple daily seizures at 5.5 years, mild clumsiness and slurred speech

Harvey & Female Singh, < 2 months in preparation 3 years – patient 2

Clonic twitching of the L Normal orbicularis oculi, no alteration of consciousness, preceded by hyperactivity and hyperphagia, deviation and nystagmoid jerks of the eyes to L, / L face jerking, rarely L arm and leg jerking, 5–30 seconds duration, multiple per day, awake and asleep

CT: normal. MRI: non-enhancing mass in L middle cerebellar peduncle effacing 4th ventricle SPECT: ictal hyperperfusion in region of mass

None

Multiple daily episodes. Normal development

Notes: Lleft, Rright, CTxray computed tomography, MRImagnetic resonance imaging, PEGpneumoencephalogram, SPECTsingle photon emission computed tomography, EEGelectroencephalogram

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In all cases, neuroimaging revealed a unilateral, non-enlarging mass in the cerebellar peduncle and/or hemisphere, compressing but not occluding the fourth ventricle. MRI signal characteristics were similar to grey matter with all lesions being low signal on T1-weighted images and high signal on T2-weighted images, and none showed contrast enhancement. The lesions were on the left in seven patients and on the right in three. The MRI features were those of a low-grade tumour or hamartoma, consistent with the histopathological findings of ganglioglioma in five of six operated patients. Scalp EEG recordings in all patients revealed no epileptiform abnormalities between or during episodes. However, in all three patients studied with ictal SPECT there was discrete, focal hyperperfusion during seizures in the region of the cerebellar mass, typical of the regional blood flow changes seen in partial seizures of cerebral origin. In our patient studied with intracranial EEG monitoring, there was irrefutable evidence of focal epileptiform discharges and frank seizure activity arising from the cerebellar tumour. In most of these reports, the episodes were described as ‘hemifacial spasms’. However, the episodes in these infants are clinically and etiologically distinct from typical hemifacial spasm of adults and older children (Jannetta, 1990; Jho & Jannetta, 1987; Ronen et al., 1986). Neither head deviation, eye deviation, limb dystonia, nystagmus nor autonomic dysfunction occur in typical hemifacial spasm. Furthermore, tumours are associated with hemifacial spasm in fewer than 1% of patients, and usually consist of meningiomas or neuromas of the cerebellopontine angle or facial canal which compress the facial nerve or facial nucleus, neither of which was apparent from neuroimaging of tumours in these ten patients. Although some typical features of epileptic seizures are lacking in these patients, such as impaired consciousness, epileptiform patterns on scalp EEG and response to antiepileptic medication, the inability to demonstrate a neurocompressive etiology (theory of ‘ephaptic transmission’) and the positive findings from ictal SPECT and intracranial EEG monitoring provide conclusive evidence of an epileptic basis of the ‘hemifacial spasms’ in the patients studied. The absence of epileptiform activity on scalp EEG is not inconsistent with epileptic seizures, as most subcortical structures lack the laminated architecture required to produce extracellular field potentials at the scalp. The retention of consciousness during seizures, the infrequency of autonomic manifestations, and the discrete cerebellar activation on ictal SPECT and intracranial EEG, suggest the clinical symptomatology is likely to be cerebellar, rather than brainstem, in origin. Electrical and mechanical stimulation of the cerebellum is known to elicit ipsilateral facial grimacing, ipsilateral and contralateral head and eye deviation, nystagmus, alterations of limb tone and posture, and autonomic dysfunction, without disturbance of consciousness (Clark, 1939; Cohen et al., 1965;

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Nashold et al., 1969; Pool, 1943; Nashold & Slaughter, 1969; Bradley et al., 1987). Furthermore, somatotopic representation of the body is present in the cerebellum (Carpenter, 1991) and may account for the marching motor manifestations. Classic doctrine dictates that epileptic seizures arise only in the cerebral cortex, that subcortical structures such as the cerebellum and brainstem have only neuromodulatory influences on cerebral epileptic activity (Engel, 1989; Dow et al., 1962; Miller et al., 1993), and that these subcortical structures participate only indirectly in epileptic seizures (Caveness et al., 1980; Collins et al., 1976). However, a collection of inherently epileptogenic neurons anywhere in the central nervous system might produce epileptic seizures if they retain functional connections. Functional neuroimaging and depth electrode recordings in patients with hypothalamic hamartomata (Kuzniecky et al., 1997; Harvey et al., 1998), subcortical heterotopias (Morrell et al., 1992; Henkes et al., 1991; De Volder et al., 1994) and cerebellar vermal lesions (Koo et al., 1998) provide other examples of intrinsic epileptogenicity in subcortical grey matter. Both ‘hemifacial spasm’ and cerebellar ganglioglioma are rare entities in infancy (Humphreys, 1982; Mickle, 1992; Russell & Rubinstein, 1989). Thus, the coexistence of these two rare entities in a strikingly similar fashion in ten reported patients would seem to constitute a unique clinicopathologic syndrome of infancy, in which a unilateral cerebellar ganglioglioma leads to refractory cerebellar seizures manifesting as hemifacial jerking, with or without ocular, autonomic and ispilateral limb manifestations. Although rare, this syndrome has important implications for current nosological and pathogenetic concepts of epilepsy. The natural history would seem to be one of persistent seizures, with associated neurological morbidity in some patients. Although complete or near-complete resection led to seizure remission in three operated patients, the exact place of surgical treatment is uncertain and should probably be determined by the effect of seizures on the patient.

R E F E R E N C ES

Al-Shahwan, S., Singh, B., Riela, A.R. & Roach, E.S. (1994). Hemisomatic spasms in children. Neurology, 44, 1332–3. Arzimanoglou, A.A. (1996). Hemifacial spasm or subcortical (infratentorial) epilepsy: a case report of a child with Goldenhar’s syndrome and a pontomedullary junction lesion. Trends in Child Neurology, ed. A. Arzimanoglou & F. Goutières, pp. 43–51. Paris: John Libbey Eurotext. Arzimanoglou, A., Salefranque, F., Goutières, F. & Aicardi, J. (1999). Hemifacial spasm or subcortical epilepsy. Epileptic Disorders, 1(2), 121–5. Beitz, A.J. (1976). The topographical organization of the olivo-dentate and dentato-olivary pathways in the cat. Brain Research, 115, 311–17.

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Facial seizures associated with brainstem and cerebellar lesions Bills, D.C. & Hanieh, A. (1991). Hemifacial spasm in an infant due to fourth ventricular ganglioglioma. Journal of Neurosurgery, 75, 134–7. Bradley, D.J., Paton, J.F.R. & Spyer, K.M. (1987). Cardiovascular and respiratory responses evoked from the posterior cerebellar cortex and fastigial nucleus in the cat. Journal of Physiology, 393, 107–21. Carpenter, M.B. (1991). Core Text of Neuroanatomy. 4th edn, pp. 224–9. Baltimore: Williams and Wilkins. Caveness, W.F., Kato, M., Malamut, B.L. et al. (1980). Propagation of focal motor seizures in the pubescent monkey. Annals of Neurology, 7, 213–21. Clark, S.L. (1939). Responses following electrical stimulation of the cerebellar cortex in the normal cat. Journal of Neurophysiology, 2, 19–35. Cohen, B., Goto, K., Shanzer, S. & Weiss, A.H. (1965). Eye movements induced by electrical stimulation of the cerebellum in the alert cat. Experimental Neurology, 13, 145–62. Collins, R.C., Kennedy, C., Sokoloff, L. & Plum, F. (1976). Metabolic anatomy of focal motor seizures. Archives of Neurology, 33, 536–42. Deuschl, G., Mischke, G., Schenck, E. et al. (1990). Symptomatic and essential rhythmic palatal myoclonus. Brain, 113, 1645–72. De Volder, A.G., Gadisseux, J-F.A., Michel, C.J. et al. (1994). Brain glucose utilization in band heterotopia: synaptic activity of ‘double cortex’. Pediatric Neurology, 11, 290–4. Dow, R.S., Fernández-Guardiola, A. & Manni, E. (1962). The influence of the cerebellum on experimental epilepsy. Electroencephalography and Clinical Neurophysiology, 14, 383–98. Engel, J. Jr. (1989). Seizures and Epilepsy, pp. 41–70. Philadelphia: F.A. Davis Company. Flüeler, U., Taylor, D., Hing, S. et al. (1990). Hemifacial spasm in infancy. Archives of Ophthalmology, 108, 812–15. Goldenhar, M. (1952). Associations malformatives de l’oeil et de l’oreille, en particulier le syndrome dermoïde epibulbaire-appendices auriculaires-fistula auris congenita et ses relations avec la dysostose mandibulo-faciale Journal Génétic Human, 1, 243–82. Gorlin, R.J., Cohen, M.M. (Jr) & Levin, L.S. (1990). Branchial arch and oro-acral disorders. In Syndromes of the Head and Neck. Oxford Monographs on Medical Genetics No 19, pp. 641–91. Oxford: Oxford University Press. Guillain, G. & Mollaret, P. (1931). Deux cas de myoclonies synchrones et rythmées vélopharyngo-laryngo-oculo-diaphragmatiques. Le problème anatomique et physiopathologique de ce syndrome. Revue Neurologique, 2, 545–66. Harvey, A.S., Jayakar, P., Duchowny, M. et al. (1996). Hemifacial seizures and cerebellar ganglioglioma: an epilepsy syndrome of infancy with seizures of cerebellar origin. Annals of Neurology, 40, 91–8. Harvey, A.S., Rosenfeld, J.V. & Wrennall, J.A. (1998). Hypothalamic hamartoma and intractable epilepsy: ictal SPECT localization and surgical resection of hamartoma in four children [abstract]. Epilepsia, 39 (Suppl. 6), 65. Harvey, A.S., Singh, R., Hopkins, I.J. & Klug, G.L. Hemifacial seizures and cerebellar ganglioglioma: report of two cases with ictal SPECT localization. [in preparation]. Henkes, H., Hosten, N., Cordes, M. et al. (1991). Increased rCBF in gray matter heterotopias detected by SPECT using 99mTc hexamethyl-propylenamine oxime. Neuroradiology, 33, 310–12.

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A.S. Harvey et al. Humphreys, R.P. (1982). Posterior cranial fossa brain tumours in children. In Neurological Surgery, 2nd edn, ed. J.R. Youmans, pp. 273–58. Philadelphia: W.B. Saunders. Jannetta, P.J. (1990). Cranial rhizopathies. In Neurological Surgery, 3rd edn, ed. J.R. Youmans, pp. 4171–3. Philadelphia: W.B. Saunders. Jayakar, P.B. & Seshia, S.S. (1987). Involuntary movements with cerebellar tumour. Canadian Journal of Neurological Science, 14, 306–8. Jho, H.D. & Jannetta, P.J. (1987). Hemifacial spasm in young people treated with microvascular decompression of the facial nerve. Neurosurgery, 20, 767–70. Koo, B.K., Canady, A. & Nigro, M.A. (1998). Seizures of cerebellar origin presenting as movement disorders [abstract]. Neurology, 50, A447–8. Kuzniecky, R., Guthrie, B., Mountz, J. et al. (1997). Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy. Annals of Neurology, 42, 60–7. Langston, J.W. & Tharp, B.R. (1976). Infantile hemifacial spasm. Archives of Neurology, 33, 302–3. Lapresle, J. (1979). Rhythmic palatal myoclonus and the dentato-olivary pathway. Journal of Neurology, 220, 223–30. Llinas, R.R. (1984). Rebound excitation as the physiological basis for tremor: a biophysical study of the oscillatory properties of mammalian central neurones in vitro. In Movement Disorders: Tremor, ed. L.J. Findley & R. Capildeo, pp. 165–82. London: Macmillan. Mickle, J.P. (1992). Ganglioglioma in children. Pediatric Neurosurgery, 18, 310–14. Miller, J.W., Gray, B.C. & Turner, G.M. (1993). Role of the fastigial nucleus in generalized seizures as demonstrated by GABA agonist microinjections. Epilepsia, 34, 973–8. Morrell, F., Whisler, W.W., Hoeppner, T.J. et al. (1992). Electrophysiology of heterotopic gray matter in the ‘double cortex’ syndrome [abstract]. Epilepsia, 33 (Suppl. 3), 76. Nashold, B.S. & Slaughter, D.G. (1969). Effects of stimulating or destroying the deep cerebellar regions in man. Journal of Neurosurgery, 31, 172–86. Nashold, B.S., Slaughter, D.G. & Gills, J.P. (1969). Ocular reactions in man from deep cerebellar stimulation and lesions. Archives of Ophthalmogy, 81, 538–43. Pool, J.L. (1943). Effects of electrical stimulation of the human cerebellar cortex. Journal of Neuropathology and Experimental Neurology, 2, 203–4. Ronen, G.M., Donat, J.R. & Hill, A. (1986). Hemifacial spasm in childhood. Canadian Journal of Neurological Science, 13, 342–3. Russell, D.S. & Rubinstein, L.J. (1989). Pathology of Tumours of the Nervous System, 5th edn, pp. 289–350. Baltimore: Williams & Wilkins.

17

Neonatal movement disorders: epileptic or non-epileptic Cesare T. Lombroso formerly, Seizure Unit and Division of Neurophysiology, Harvard Medical School, Children’s Hospital, Boston, MA, USA

Introduction and nosologies Abnormal motor movements are frequently seen in newborn infants and may present diagnostic dilemmas. This chapter will describe most of the motor events occurring in this epoch and will offer parameters useful in distinguishing those that are seizures from those that are not. This is not always an easy task. It is, however, not only of considerable theoretical interest but also of clinical importance to better guide therapies and delineate prognosis. Over the past few decades, there has been an unfortunate trend in neonatology to consider non-epileptic movement disorders as seizure events. Hence, newborns often receive unwarranted anticonvulsant drugs, which is a trend that has replaced the previous one of underdiagnosing neonatal seizures. This quandary of overdiagnosing and overtreating is compounded by nosological problems peculiar to the age. The first is whether all neonatal seizures should be classified as epileptic events or not. For example, should one diagnose a neonatal seizure after a transient metabolic insult, such as hypocalcemia, hypoglycemia, or withdrawal states because of maternal drug abuse? This issue has been debated extensively, and the interested reader can refer to a few pertinent articles containing different views (Wasterlain & Vert, 1990; Wasterlain & Sharasaka, 1994; Hrachovy et al., 1990; Lombroso, 1993, 1996; Scher & Painter, 1989; Shewman, 1990; Volpe, 1995). A second source for diagnostic confusion is that, in some neonates, there may be, in addition to seizures, some abnormal movements that are not seizures, while these may exhibit quite a diverse phenotypic expression in the same baby. Such a panorama is rather frequently observed in encephalopathic infants and creates dilemmas in therapeutic plans, as one may unnecessarily continue administering anticonvulsant drugs when the seizures have ceased but the abnormal movements persist. Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Another problem derives from the gamut of abnormal motilities displayed in this epoch of life, and such high incidence applies both to seizures and to other movements disorders. One factor pertinent to the unusual susceptibility to manifest paroxysms of motor phenomena is the number and nature of potentially injurious events that can strike before, during and after birth. Of equal importance is the transient overexpression in the density of receptors for the excitatory amino acids (EAAs) during the early stages of brain development. This occurs during a period when the major inhibitory neurotransmitter (gammaaminobutyric acid, GABA) is poorly developed and may even exert, at times, excitatory influences. The ontogenic imbalance between excitatory and inhibitory systems in the newborn infants brain explains its propensity to react with paroxysmal events to factors that, later in life, would not provoke them. This was evidenced during our earliest prospective investigation of neonatal seizures (Rose & Lombroso, 1970) when it was found that seizures were the most frequent neurological event to occur in the nursery. By way of contrast, most neonatal seizures tend to abate early, even when neurological deficits persist, pari passu with the development of more effective inhibitory mechanisms as well as a decrease in excitatory neurotransmission that occurs as a result of the programmed cell death of excitatory neurons during apoptosis. It also became evident that seizures in newborn infants differ substantially from those occurring in infancy, and beyond, in large part due to the immaturities in the neuroanatomical, neurochemical and bioelectric connections within cortical and subcortical systems (Burke, 1954; Dreyfus-Brisac & Monod, 1964; Minkowski et al., 1955; Pritchard, 1964; Ribstein & Walter, 1959). At this age, we do not encounter such phenotypic epileptic expressions as absences, complex partial seizures, Jacksonian marches, and, generalized tonic–clonic convulsions, although some of the rapidly migrating movements that occur in multifocal clonic seizures or in bouts of shudders and tremors may mimic them. Therefore, the seizures of newborn infants require a different classification from those applicable at other ages. One that has been generally accepted was proposed in the mid-1960s, and was based on purely descriptive features (Rose & Lombroso, 1970). During these early investigations, it also became apparent that newborn infants display a variety of transient abnormal motor activities and other signs that might be mistaken for real seizures. Table 17.1 reproduces this early classification scheme. The task of distinguishing ictal from non-ictal phenomenon may at times be difficult, largely because neonatal seizures can be covert, erratic or fragmentary. In addition, newborn infants exhibit a vast repertoire of peculiar behaviours that can mimic the symptomatologies of true seizures. A careful history is required, together with direct observations

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Table 17.1 Classification of neonatal seizures

Subtle or minimal:

Paroxysmal, stereotypic repetitive event, consists of variable combination of: a tonic deviation and/or roving or jerking of eyes, lid flutters, with fragmentary body movements: single, migratory jerks or brief tremors, focal limbs or truncal posturing; oral automatisms, such as sucking, chewing, tongue moving, limbs automatisms; such as bicycling; autonomic manifestations: transient increase in B/P and heart rate, drooling, central apnea. Most occur in NBs with CNS insults.

Comment:

Similar motor behaviours and automatisms that are not seizures may occur in NBs, especially in prematures or encephalopathic babies, some also in normal FT NBs during REM sleep. These movements are not stereotypic, can be stopped by restraint or repositioning and can be triggered by stimulation. Autonomic changes are usually absent in these non-ictal behaviours, though drooling may occur. Apnea alone is rarely ictal, in which case there is tachy instead of the bradycardia that occurs in central apnea. Polygraphic EEGs may be helpful. There may be good or variable ictal clinical/ EEG correlations; interictal background patterns and organization of states are usually abnormal. The absence of EEG ictal discharge may be a confounding problem but does not necessarily rule out seizures.

Clonic Unifocal:

Multifocal:

Easiest to diagnose: consists of rhythmic flexor–extensor muscle contractures of limbs/face with fast and slow phases. They may start and remain focally in one limb or side of face, spreading, at times, slowly and intermittently to opposite side. They may wax and wane, seemingly allowing function to go on unaltered, without apparent LOC. They exhibit good correlation with EEG, with rare exceptions in very preterm babies. Do not necessarily imply focal pathology. The clonic movements, migrating from limb to limb, shifting sides, may be less sustained than unifocal: more often may involve face, lids, tongue. If they shift rapidly they may mimic generalized convulsions. Ictal EEG: usually concordant, with multifocal discharges.

Comment:

As detailed in the text they must be distinguished from jitteriness, tremors, shudders, hipnic jerks, benign myoclonus of sleep, (all seen in non-seizure states); by direct observation, and by using similar manoeuvres as for the subtle patterns.

Hemi-convulsions:

Common in infants but are rare in NBs, and organized Jacksonian marches are not seen.

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Table 17.1 (cont.)

Tonic Focal:

Stereotypic, abrupt or slower brief tonic posturing of a limb, trunk or tonic deviation of the eyes (similar to those occurring in the subtle pattern), often accompanied by apnea, flushing or mild cyanosis, and drooling, occasionally mixed with brief clonic components. They are not affected by restraints or triggered by stimulation, while these manipulations influence similar focal posturing observed in normal preterms or abnormal FT NBs. Often, these seizures are accompanied by abnormal EEG background patterns. Ictal discharges may be of the delta, alpha or beta-like types.

Generalized:

These symmetric tonic postures, with or without arms pronation, are rarely true seizures. Most represent transient decerebrate or decorticate posturing, can be triggered by stimulation and show no ictal EEG correlates, though background patterns are usually abnormal. They often occur at onset of intracerebral hemorrhages or because of increased intracerebral pressure. However, abrupt tonic limb extension/flexion with ab/aduction may represent true seizure spasms. These may exhibit EEG ‘beta’ discharges, some have no obvious ictal EEG concomitant, but background patterns are almost always severely abnormal (low voltage, burst–suppression, invariant patterns) (see text for further differentiation).

Myoclonic:

Erratic, fragmentary or more generalized myoclonic jerks may be associated with tonic spasms or with multifocal clonic or tonic patterns, or with mixed seizure types. They may persist into infancy, with typical infantile spasms. EEGs show ‘burst suppression’ patterns and there may or not be clinical ictal correlates. They occur in severely affected babies (dysgenetic brains, congenital enzymatic defects, and severe asphyctic encephalopathies), but may also be cryptogenic. Distinct syndromes have been proposed (see text). This myoclonia is easily distinguished from shudders, from benign neonatal sleep myoclonus and from myoclonus of degenerative CNS conditions.

Notes: Modified after Lombroso (1965); Rose and Lombroso (1970); Volpe (1977).

of the infant, and the assistance of polygraphic EEGs and familiarity with their interpretation. Table 17.1 mentions briefly some of the behaviours that might be erroneously interpreted as true seizures. It offers a few parameters and describes some manoeuvres that might assist in the differential diagnosis. This early descriptive classification of neonatal seizures has generally been followed. However, it has been criticized in recent years and another classification has

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been proposed. Although there are areas of overlap between the two systems, some aspects of the new classification raise new concerns. By using careful video–EEG monitoring, several studies have appropriately emphasized how various behaviours displayed by newborn infants are often ‘not ictal events’ even though they exhibit similarities with true seizures (Hrachovy et al., 1990; Kellaway & Mizrahi, 1987, 1990; Mizrahi & Kellaway, 1987). Neonatal seizures were parcellated on the basis of whether the paroxysmal behaviours showed consistent, inconsistent or no correlation with a simultaneous EEG ictal discharge. As shown in Table 17.2, this new classification is composed of four groups. The first consists of seizures that closely correlate with EEG seizure discharges, and includes all focal ones, some focal or generalized myoclonic seizures, focal tonic and apneic seizures. In the second group are those events that have ‘an inconsistent or no relationship to EEG seizure discharges’, and in this group are included ‘all seizures with motor automatisms, generalized tonic seizures, the generalized focal or fragmentary myoclonic seizures’. The third group includes ‘infantile spasms’ and the fourth one consists of electrical evidence of seizure activity with no apparent clinical phenomenon. This electrical–clinical approach led to the proposed classification of ‘epileptic as well as non-epileptic neonatal seizures’ (Hrachovy et al., 1990; Mizrahi & Kellaway, 1987; Kellaway & Mizrahi, 1990). The non-epileptic seizures would be those due to ‘reflex’ or ‘brainstem release phenomena’ secondary to ‘forebrain depression’. While there is no disputing that several behaviours displayed by newborn infants are not seizures, this new classification introduces elements of some confusion. The first is that behaviours considered to represent ‘primitive brainstem and spinal cord motor patterns released from the tonic inhibition normally exerted by forebrain structures’ (Hrachovy et al., 1990; Kellaway & Mizrahi, 1990) would be unlikely to exhibit concomitant EEG discharges. It may also appear confusing to include in a classification of neonatal seizures phenomena that are ascribed to brainstem and spinal cord reflexes. Several of these phenomena will be discussed later when I shall discuss various motor paroxysms not considered to be seizures. Another issue that may arise from a clinical–electrical classification of neonatal seizures consists of depending solely upon a consistent ictal EEG discharge as the only and necessary condition for diagnosing paroxysmal events as being epileptic seizures. A consistent clinical–electrical presence is very helpful, but welldocumented clinical seizures occur at all ages without a concomitant scalp derived EEG ictal discharge. This is even more likely to occur when dealing with newborn infants whose brains may have been gravely injured, and whose EEG background activities may be quite abnormal or diffusely depressed. A corollary of this electrical–clinical classification would also exclude the myoclonia and tonic spasms occurring in the syndromes of early myoclonic and early infantile epileptic encephalopathies in which there is often no EEG discharge concomitant with the clinical events.

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Table 17.2. Classification of clinical seizures and relationship to EEG seizure discharges

I. Seizures with a close correlation to EEG seizure discharges A. Focal clonic 1. Unifocal 2. Multifocal a. Alternating b. Migrating 3. Hemiconvulsive 4. Axial B. Myoclonic 1. Generalized 2. Focal C. Focal tonic 1. Asymmetrical truncal 2. Eye deviation D. Apnea II. Seizures with an inconsistent relationship (or no relationship) to EEG seizure discharges A. Motor automatisms 1. Oral-buccal-lingual movements 2. Ocular signs 3. Progression movements a. Pedalling b. Stepping c. Rotary arm movements 4. Complex purposeless movements B. Generalized tonic 1. Extensor 2. Flexor 3. Mixed extensor/flexor C. Myoclonic 1. Generalized 2. Focal 3. Fragmentary III. Infantile spasms IV. EEG seizures without clinical seizures Source: Reproduced with permission from Hrachovy et al. (1990).

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F7-T3 T2-T5 T6-01 Fp1-F3 F3-C3 C3-F3 P3-01 Fp2-F4 F4-C4 C4-F4 F4-02 F8-T4 T4--T6 T4-02 ECG FZ-CZ EOG

Fig. 17.1

Example of a subtle seizure in a full-term neonate. The electrical seizure with a multifocal pattern, began 5 seconds before the clinical signs, occurring during a period of NREM sleep. At the upper arrow, during the low voltage beta discharge, his eyes opened with roving slow movements, tongue darting in and out with some foam, his trunk posturing tonically for a few seconds. At the lower arrow, during the independent discharge, the infant made rhythmic ‘bicycling’ leg movements, persisting for about 10 seconds, his breathing irregular but without apnea. Note also the excessively discontinuous background pattern, in the right hemisphere, while it was bilateral before and after the ictus.

The issue of clinical–electrical disassociation has long been recognized and has been thought to be due to immaturities in the development of cortico-subcortical and cortico-cortical connections (Rose & Lombroso, 1970; Monod et al., 1972; Watanabe et al., 1977; Dennis, 1978; Clancy et al., 1988). The new classification excludes as being epileptic seizures all behaviours that occur in minimal or subtle seizures in spite of the fact that several of these are well documented in the literature (Lombroso, 1978, 1993; Monod et al., 1972; Watanabe et al., 1977; Dennis, 1978; Clancy et al., 1988; Weiner et al., 1991; Scher, 1998), showing concomitant and consistent ictal EEG discharges (Figs. 17.1, 17.2). The same applies to some generalized tonic seizures (Fig. 17.3). The inclusion of ‘apneas’ in a classification of clinical seizures (Table 17.2) is open to question. Although a few instances of apnea with simultaneous ictal

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FP1-T3 T3-O1 FP2-T4 T4-O2 FP3-C3 C3-O1 FP2-C4 C1-O2 T3-C3 C3-C2 C2-C4 C4-T4 F2-C2 C2-P2 T3-C2 T4-C2 EMG LOC A1 LOC A2 RESP. EKG.

Fig. 17.2

Another example of a subtle seizure. At onset of the electrical discharge in the right central region, this 40 week baby turned the head tonically to the left, exhibiting lingual and eye lateral eye movements, (note eyes channel) and later chewing motions. (Reproduced with permission from Scher, 1998).

discharges have been reported (Deuel, 1973; Willis & Gould, 1980; Fenichel et al., 1980), apneic events as the only ictal manifestation are quite rare. Apneic components accompany some seizures, but most apneas are due to obstructive causes and those that are central in origin are secondary to immaturity of respiratory centres. One distinctive feature is the tachycardia that is present in the ictal apneas while bradycardia occurs in the obstructive and central apneas (Scher, 1998; Fenichel et al., 1980). Usually agitated asynchronous limb movements accompany the central apneas, while mainly oral automatisms, nystagmus, or eye deviations accompany the apneas that are ictal. Some apneas may be iatrogenic in origin. Infantile spasms (Table 17.2), in their full phenotypic expression, occur mainly in infancy, although tonic spasms are exhibited in some severely encephalopathic newborn infants (Watanabe, 1982; Dulac et al., 1985; Ohtahara et al., 1976) (cf. section on Early infantile epileptic encephalopathy). The previous section has dealt with some of the problems still facing the formulation of a generally acceptable classification of neonatal seizures. To some extent,

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FB-T4 T4-T6 T6-02 Fp2-F4 F4-C4 C4-P4 P4-02 Fp1-F3 F3-C3 C3-P3 P3-01 F7-T3 T3-T5 TONIC

POSTURING

T5-01 EOG RESP.

Fig. 17.3

An example of a generalized tonic seizure in a full-term neonate, obtained at 10 postnatal days. The seizures had begun at 3 postnatal days persisting in spite of therapies. The ictal discharge of repetitive high voltage delta waves had started some seconds before the infant exhibited tonic extensions of both legs and tonic flexion of both arms, which persisted throughout the ictus. As soon as the electrical seizure stopped, the baby resumed sleep. (Note the change of paper speed.)

these problems also apply to those abnormal motor behaviours of the newborn that are not seizures, and these will be discussed later. Efforts to reach more definite nosological places for all neonatal paroxysmal motor phenomena have been hampered by several difficulties. Paramount among these is the lack of knowledge about their pathophysiological mechanisms. As already mentioned, the prevalence of excitatory systems at this early developmental period predisposes the neonate to display seizures or other paroxysmal motor activities. The latter may be either an exaggeration of normal behaviours (Prechtl, 1974; Saint-Anne Dargassies, 1979) or a consequence of neurological or systemic disorders. It is also difficult during this period to clearly assess the state of consciousness in newborn infants. Since the majority of neonatal seizures are symptomatic in nature, it has been

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easier to classify them according to etiological factors, or by simple descriptive features, a strategy that has proved useful for instituting appropriate therapies and for delineation of prognostic indices (Lombroso, 1985; Dennis, 1978; Scher, 1998; Watanabe, 1982). More recently, it has been possible to identify clusters of clinical, demographic and laboratory parameters that are considered sufficiently homogenous to be recognized as syndromatic entities, and these will now be reviewed. Proposed syndromes of neonatal seizures Four such syndromes have been included within the International Classification of the Epilepsies and Epileptic Syndromes (1989). Early myoclonic encephalopathy (EME) was proposed by Aicardi and Goutières (1978) as a syndrome characterized by erratic, fragmentary myoclonus and a burst–suppression EEG pattern presented by full-term babies exhibiting severe neurological impairments. At first, newborn infants with pre-, para- or postnatal complications were excluded; hence the condition was presumed cryptogenic in origin (Aicardi, 1986). Later, it was found that other ictal expressions occurred, such as partial motor seizures, generalized myoclonus, and tonic spasms. It was also recognized that, besides cryptogenic cases, others were due to brain dysplasia or to inborn enzymatic defects (Aicardi, 1986; Lombroso, 1990). Among the latter, the most frequently found is non-ketotic hyperglycenemia; although some cases with -glyceric, methylmalonic or propionic acidemias have also been described. The presence of congenital metabolic defects may explain the occasional familial occurrence of EME (Dalla Bernardina et al., 1983). A similar clinical–electrographic picture may also occur following severe hypoxia–ischemia, but these babies have features inconsistent with those of EME (Lombroso, 1990). Approximately half of the reported cases of EME still fall into the cryptogenic group. All therapeutic measures have failed to change the sinister prognosis for these babies, even when seizures may be partially controlled. At least 60% of newborn infants with EME die early, while the survivors exhibit severe developmental deficits, and their seizures may evolve into atypical tonic spasms with hypsarrhythmic EEGs. The multiplicity of presumptive etiologies suggests that diverse pathophysiological mechanisms are involved in the genesis of this syndrome. In some, undetected disorders of migrational or cortical organizations may be the culprits, while others may harbour yet undiscovered enzymatic defects. The finding of elevated glycine levels in blood and in spinal fluid suggests that disorders in neurotransmitters systems may play a role in other cases (Aicardi, 1986, 1990). Early infantile epileptic encephalopathy (EIEE)

Some years before the EME syndrome was proposed, Ohtahara and coworkers had delineated another (Ohtahara et al., 1976). Its main features consist of a difficulty to control tonic spasms associated with an invariant burst–suppression EEG

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pattern, occurring within the neonatal epoch, or a few months later, in infants with severe developmental delays. Several babies were found to have brain malformations and all had poor outcomes, about half evolving into a West syndrome. It was later found that several infants exhibited partial seizures, myoclonic jerks or generalized convulsions (Ohtahara et al., 1987). To my knowledge, only one baby with the EIEE syndrome has been found to harbour a congenital metabolic disorder, consisting of a glycine-induced encephalopathy (Clarke et al., 1987). Some controversy persists regarding whether EME and EIEE constitute separate distinct syndromes (Dulac et al., 1985; Aicardi, 1985, 1986, 1990; Dalla Bernardina et al., 1983; Ohtahara et al., 1985, 1987, 1997; Clarke et al., 1987). The parameters that more clearly separate EME from EIEE are the predominance of erratic myoclonus in the former and of tonic spasms in the latter. Etiological factors also tend to be different, although with some overlap: inborn errors of metabolism are found more often in EME than in EIEE, while dysgenetic defects are more common in EIEE (Lombroso, 1990). To my knowledge, familial occurrence has not been reported in infants with EIEE, which is in contrast to what is known with EME. Finally, the pathophysiology remains unknown for both of these disorders. The burst–suppression patterns so characteristic for both syndromes suggests that, whatever the etiologies may be, they cause a disconnection between the cortex and the subcortical structures. Benign idiopathic neonatal convulsions (BINC)

This syndrome originally called ‘fifth-day convulsions’, is also included in the International Classification of the Epilepsies and Epileptic Syndromes (1989). However, it does not appear to have a sufficiently distinct constellation of parameters to justify its inclusion as a distinct syndromatic entity (Dehan et al., 1977, 1982; North et al., 1989; Plouin, 1985, 1990; Holmes, 1987). The proposed parameters can be found both in newborn infants with symptomatic seizures who may have as good an outcome as newborn infants in the so-called ‘idiopathic’ (cryptogenic) group, while only about one-third of these are free of sequelae. Several of the criteria proposed for BINC have been modified or contradicted. Thus, the required ‘onset of convulsions at the 4th or 5th day of life’ was later modified to an onset that ‘may occur at any time’. The statement that BINC are defined by their good prognosis has been challenged in some reports that indicate half of the babies at followup showed to have a variety of neurodevelopmental deficits, while some even died early (Navalet et al., 1981). Another proposed distinctive feature for BINC is the alternating sharp theta bursts that are present in the EEG. This has also been challenged in other papers stating that this EEG feature occurs in newborn infants with all kinds of pathology, including intracranial hemorrhages (Navalet et al., 1981; Lombroso & Holmes, 1993). It is therefore, not surprising that the incidence of BINC, as reported in the

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literature, has varied from a low of 1.5% to as high as 33% of all newborn infants with seizures (Plouin, 1985, 1990). The statement that ‘BINC remains a diagnosis of exclusion’, and that ‘BINC are defined by their good prognosis’(Plouin, 1985, 1990) appear to be a rather fragile basis to propose a distinct syndrome. Benign familial neonatal convulsions (BFNC)

The syndrome of BFNC was first described by Rett and Teubel (1964). It is relatively rare: 0.9 to 2.1% in a series of 430 consecutive newborn infants with seizures occurring in otherwise healthy appearing babies (Lombroso, 1985; Lombroso & Holmes, 1993; Tibbles, 1980; Ferrari et al., 1991). The seizures usually abate within a few weeks. Their ictal expression is mainly of a clonic pattern, often alternating in sides, occasionally with brief apneas and the EEG patterns have no characteristic features. The existence of the syndrome finds its main justification in its genetics as it has a significant familial incidence. Several siblings may be affected and there is often a family history of generalized epilepsies or of febrile convulsions. Transmission appears to be autosomal dominant with regular penetration but variable expression (Leppert et al., 1989; Ryan & Winitzer, 1990). While a single gene has been localized to the long arm of chromosome 20 (Ryan & Winitzer, 1990), more recent reports suggest that the syndrome may be genetically heterogeneous (Lewis et al., 1993). The neurodevelopmental outcomes for these infants are favourable except that 11% to 14% of these babies later develop epileptic syndromes, mainly generalized convulsions (Holmes, 1987; Plouin, 1997). Abnormal motor behaviours that are not seizure disorders The group of newborn infants seizures are characterized by several patterns of paroxysmal and recurrent motor behaviours that are the peripheral expression of sustained cerebral electrical discharges usually detectable with scalp-derived EEG. Other patterns of abnormal motor behaviours occur in newborn infants. Some of these may mimic those of seizures but often present with distinct clinical characteristics and pathophysiologies. There is a vast array of these events: at one end of the spectrum are abnormal movements that are symptomatic of brain injuries or of severe systemic conditions. At the other end are movements that may be just an exaggeration of behaviours, which are otherwise normal in newborn infants, or that are caused by transient and benign systemic disorders. In the following sections several of these events are described and discussed, with some emphasis on issues of differential diagnosis. Benign neonatal sleep myoclonus (BNSM)

Clusters of jerk-like movements were described to occur in some normal newborn infants during quiet sleep (NREM) and were not considered to be seizures (Prechtl,

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1974; Saint-Anne Dargassies, 1979; Dittrichóva, 1969; Aserinsky & Kleitman, 1955; Parmelee & Stern, 1972). The term BNSM was coined for this phenomenon by Coulter and Allen, who described it in some detail (Coulter & Allen, 1982). Recently, it has been further analysed by using video–EEG monitoring (Tardiev et al., 1986; Dicapra et al., 1993). In BNSM, the jerks affect mainly the arms and hands, they may be present bilaterally, and often appear in short clusters, shifting in sides. The pathognomonic feature is that they occur only in sleep. They almost always are present during NREM stages and do not cause awakening. When in fact the infant is awake, the myoclonus-like activity abates. Rocking the bassinet or crib may induce it (Alfonso et al., 1995). These migrating jerks can occur in term newborn infants who are usually neurologically and metabolically intact; however, they are more common in preterm newborn infants. The polygraphic EEGs show normal staging, without discharges between or during the jerking. A fairly frequent diagnostic error is to consider BNSM as a seizure event and to then start these babies on an anticonvulsant regimen (Table 17.1). The occurrence of BNSM in NREM distinguishes it from the jerky movements observable during REM sleep. Those seen in drug withdrawal states are associated with tremulousness, happen only in waking, and are stimulus sensitive (Holmes & Lombroso, 1993). The self-limited, often partial myoclonus of benign infantile myoclonus (Lombroso & Fejerman, 1977; Pachatz et al., 1999) also occurs only in wakefulness and is rarely seen in newborn infants. The above parameters, taken together with a normal EEG and neurological status, ought to establish the correct diagnosis, and offers a benign prognosis without anticonvulsant medication. The natural course of BNSM is to recede in 2 to 5 months. BNSM does not evolve into other movement disorders and practically never into epileptic syndromes. The report of one baby with BNSM later developing myoclonic astatic epilepsy is unusual (Nolte, 1989). Genetic factors have been suggested (Dooley, 1984; Resnick et al., 1986), but the pathophysiology of this benign neonatal movement disorder remains obscure. It has been postulated that BNSM is associated with a transient immaturity of the serotoninergic system (Resnick et al., 1989). However, this is not supported by the observation that a potent serotonin agonist like clonazepam aggravates BNSM (Tardiev et al., 1986). Other benzodiazepines also have been found to exacerbate the condition (Reggin & Johnson, 1989). Hence, its mechanism appears to differ from that causing the nocturnal myoclonus in the adult, which is abolished by clonazepam. Shuddering attacks

These can be seen in newborn infants, although they appear more frequently in early infancy. They consist of abrupt bouts of tremors (8–10/s) involving primarily flexed and abducted arms; the head may shake sideways. The legs are sometimes

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involved, and the trunk may flex forwards. There is no loss of consciousness and the shuddering does not occur in sleep. Unlike the tremors, elicited by voluntary movements, common triggers for the shudders are stress and excitement (Vanasse et al., 1976; Holmes & Russman, 1986). They can be viewed as being an exaggerated form of normal shivering from which they differ because of their longer duration, their frequency rate and the posturing of arms and trunk. These babies are, in general, neurologically normal, but shudders may also appear in encephalopathic newborn infants. Video–EEG monitoring shows no concomitant electrical discharge but the quasiclonic movements and the posturing may be mistaken for seizures. Some authors suggest that they are the expression, in an immature brain, of the essential tremor that occurs later in the adult (Vanasse et al., 1976). However, in one series of shuddering attacks there was no family history of essential tremor (Holmes & Russman, 1986). Tremulousness or jitteriness

These movements have similarities with shuddering attacks. They occur, in general, in neurologically intact newborn infants while fully alert. However, the tremors are faster than the shudders, may be induced by stimulation and decreased or extinguished by flexing, extending or repositioning the limbs. The latter manoeuvres do not affect shudder attacks (Table 17.1). Tremors consist of to and fro movements of equal duration, in contrast to the clonus of seizures that have fast and slow movement phases. Other conditions in which transient jitteriness may be observed include newborn infants of mothers with a history of substance abuse, infants born from diabetic mothers, small for gestational age infants, or sometimes in newborns with intracranial bleedings (Holmes & Lombroso, 1993). The tremors subside by 6–10 weeks postnatally and rarely require treatment, unless other morbid factors are present such as marked prematurity, being small for date, or fetal distress with some degree of hypoxia. If any of these factors are present, the babies may also have low Apgar scores, display hypotonicity, have midriatic or poorly reactive pupils, disturbed sleep cycles and autonomic dysfunctions (see section on iatrogenically and metabolically induced paroxysmal movement disorders). Because of these comorbid factors, some newborn infants, in addition to tremors, may also suffer from seizures, often triggered by an early-onset hypocalcemia (Lombroso, 1992). Startle disorders

The startle reflex is a polysynaptic event causing involuntary motor and vegetative reactions to unexpected stimuli, and is a normal physiological event. It is present at birth, being a component of the Moro reflex. While the latter tends to disappear with maturation, a startle response persists in minor degrees at all ages. However,

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it may assume a pathological dimension and this is characteristic of so-called startle disorders. Traditionally, the latter are divided into two categories: the syndrome of startle disease and that of startle epilepsy. Although the two share common symptomatology, they also differ in several aspects. It is this author’s opinion that startle epilepsy would be better classified within the group of epilepsy with reflex seizures and, as it mostly affects older subjects, it will not be discussed here. Startle Disease (S.D.) or Hyperekplexia1

This disorder can be considered a syndrome with clinical, genetic and neurophysiological distinct features (Kurstein & Silverskiol, 1958; Suhren et al., 1966; Gastaut & Villeneuve, 1967; Anderman et al., 1980). Although not frequent in its full expression, it presents a number of features that often lead to diagnostic errors. It will therefore, be discussed in some detail. Its most dramatic symptom is the violent startle response to various stimuli, fully developed in infancy, but already present in the neonatal period. At this time, besides the exaggerated startle, the most striking sign is that of severe hypertonicity, with overactive tendon reflexes, but with normal plantar responses. This neonatal condition has been compared to the ‘stiff man’ syndrome in a detailed investigation of three generations of a family (Klein et al., 1972). The diffuse spasticity characteristically abates during all stages of sleep. It is easily induced or exaggerated by handling or by loud noises, leading to tonic spasms which can be severe enough to cause feeding problems and, at times, the development of hernias (Suhren et al., 1966). With the tonic spasms there may be apneas due to interference with respiratory excursions and perhaps aggravated by a central component. The latter causes other vegetative symptoms, such as hyperhydrosis or tachycardia, instead of the bradycardia that accompanies apneas (Fenichel et al., 1980; Lombroso, 1992; Suhren et al., 1966; Gastaut & Villeneuve, 1967; Andermann et al., 1980). These apneas may be so severe as to precipitate respiratory arrest (DeGroen & Kamphuisen, 1978; Kurczynski, 1983). This potential fatal outcome may be avoided by forcibly flexing head and trunk (Vigevano et al., 1989). During quiet sleep, the neonates often exhibit exaggerated hypnic jerks, akin to what happens in BNSM. Motor development of these infants may be delayed and when walking is achieved, gait continues to be unsteady, and there are often periods of limb tremulousness. Some patients display other developmental deficits including language acquisition and attentional disturbances (Suhren et al., 1966; Gastaut & Villeneuve, 1967; Andermann et al., 1980; Klein et al., 1972). In infancy, the main event consists of the startle which first triggers a tonic reaction in all muscles, followed immediately by what appears a loss of muscle tone causing the child to fall. 1

Excessive jumping, from the greek:  : above measure; - : jerk, jump.

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The child is unable to perform protective manoeuvres, although there is no loss of consciousness. Others believe that the fall is due to a myoclonic event instead of an atonic or akinetic one (Kurstein & Silverskiol, 1958; Gastaut & Villeneuve, 1967; Bernasconi et al., 1996). One of the effective stimuli to trigger such spells, both in neonates and in infants, is a tap on the glabellar region or on the nose. The metabolic and neuroimaging investigations are normal, while the literature contains contradictory reports regarding the interictal electroencephalogram. Generalized spike waves discharges, paroxysms of high voltage delta waves with sharp components at the frontocentral derivations, ‘excessive slow waves’, or ‘epileptic’ abnormalities and ‘focal spikes’ have all been mentioned (Karstein & Silverskiol, 1958; Suhren et al., 1966; Gastaut & Villeneuve, 1967; Andermann et al., 1980; Gordon, 1993). Normal interictal EEGs are reported in other papers (Bernasconi et al., 1996; Markland et al., 1984). In our own investigations, seven of eight subjects had normal interictal EEGs, while one exhibited mild degrees of diffuse slow activities. There is general agreement about the main EEG features that occur during the event. There is an initial high voltage sharp wave, mainly over the rolandic areas, followed by some diffuse theta waves and then several seconds of ‘desynchronized activity’ (Kurstein & Silverskiol, 1958; Suhren et al., 1966; Gastaut & Villeneuve, 1967; Andermann et al., 1980; Klein et al., 1972; Bernasconi et al., 1996; Markland et al., 1984). My patients have exhibited this same EEG sequence during major startle episodes. The initial rolandic sharp wave may represent an exaggerated somatosensory potential as we could elicit it by just tapping the glabella without an ensuing spasmic event. This would then be akin to the giant somatosensory potential described previously (DeMarco & Negrin, 1973). Startle disease is usually familial (Kurstein & Silverskiol, 1958; Suhren et al., 1966; Andermann et al., 1980; Klein et al., 1972) and the mode of transmission appears to be by autosomal dominant inheritance. Linkage analysis of several affected families suggest that the disease is due to mutations in a subunit of the glycine receptor, located at chromosome 5q (Ryan et al., 1992). Reevaluations of these families suggested that there may be at least two mutations, one occurring in subjects with more benign symptomatology, while a second mutation occurring in patients with more severe symptoms (Bernasconi et al., 1996; Ryan et al., 1992; Shiang et al., 1993). It has also been argued that different phenotypic expressions may be tied to the same autosomal dominant gene, the major and minor forms representing a single genetically determined disorder (Andermann et al., 1980; Bernasconi et al., 1996; Tussen & Shiang, 1995). Well-described sporadic cases have been reported, and some have separated these sporadic cases into their own group, although it remains unclear whether there are distinctive clinical characteristics other than genetic ones (Gastaut & Villeneuve, 1967; Andermann et al., 1980; Saenz Lope et al., 1984).

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The pathophysiology of startle disease remains unsolved, both for the peculiar spasticity during the neonatal epoch and for the startle-induced tonic–atonic spells. Suhren and colleagues suggested that the disorder may occur because of a poor control over nociceptive reflexes due to a delayed maturation of the rhombomesencephalic reticular formation, one of the important inhibitory centres in the neuroaxis (Suhren et al., 1966). Instead, Wilkins et al. (1986) concluded that startle disease results from a summation of a reticular reflex myoclonus and of a cortical myoclonus, as described by Hallet et al. (1974). This would place startle disease within the group of sensory-induced myoclonic disorders, in essence a distinct phenotypic expression of an epileptic disorder. Hence, startle disease and startle epilepsy would overlap. More recent data from molecular studies have begun to characterize mutations within the gene encoding subunits of the glycine receptors, and these have reinforced the concept of a disordered inhibitory influence (Shiang et al., 1993; Rees et al., 1994; Koch et al., 1996; Baxter et al., 1996). Since the glycine receptors, located mainly in brainstem and spinal cord, exert a potent inhibitory function, it can be posited that a lack of inhibition within brainstem might underlie the dominant symptomatology of startle disease, both in the neonatal and infancy periods. Other neurotransmitters may be implicated, as suggested by the good control obtained with clonazepam, a potent serotonin agonist, an effect cited as circumstantial evidence for a serotonergic participation in the disease (Ryan et al., 1992; Andermann & Andermann, 1997). The delays in motor and language development, together with the attentional difficulties and the exaggerated somatosensory potentials raise the probability of some degree of cortical involvement. Hence, it appears that, in startle disease, there may be dysfunctions at many levels of the neuroaxis. The diagnosis of startle disease may present problems during the neonatal epoch because of the diffuse hypertonus that may be mistaken for a spastic quadriplegia. At the onset of the startle-induced major phenomenology, the abrupt tonic spasms may at first suggest an atypical West syndrome, while the sudden fall raises the question of tonic, atonic or myoclonic epileptic phenomena. The clinical data, often including a positive family history, direct observation of the episodes and of their triggers, together with the EEG parameters should assist in reaching the diagnosis. The long-term evolution of startle disease differs considerably among subjects, probably according to the variable degree of CNS involvement. The spasticity, the abnormal gait, the tremors and the major motor components of the startle episode may resolve in time, or be significantly ameliorated, although an excessive startle response may persist indefinitely. The symptomatologies pointing to some degree of cortical dysfunction in some subjects may become more evident in later infancy, requiring appropriate therapies.

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Episodic dystonic posturing and tonic events

Opisthotonic posturings, often with pronation of the arms, occur more often in babies with spastic encephalopathies, but occasionally occur in normal infants as well. A delayed dystonia may appear after neonatal encephalopathy (Deonna, 1993). The dystonic-like movements happen only in wakefulness, often when the baby is stimulated or crying, and generally are short in duration (Angelini et al., 1988). Prolonged events raise the suspicion of increased intracranial pressure with transient downward herniation. The clinical history and the examination should prove sufficient to rule out this alarming condition. Some colics, and the kaleidoscopic expressions of gastroesophageal reflux, should also be considered. The distinction from the rare generalized tonic seizures can be made by the clinical history, the presence usually of other seizure phenotypes occurring in babies with abnormal neurological examinations and EEGs background patterns, also often with altered states organizations (Table 17.1). Some have concomitant electrical discharges (Fig. 17.2). Tonic components, even with opisthotonic postures, may be triggered by anoxia which, in neonates, is generally induced because of cardiacpulmonary pathologies (Volpe, 1995; Scher, 1998; Lombroso, 1978). With obstructive apneas or in association with gastroesophageal reflux, there are also at times tonic spells. Some drugs given to improve gastroesophageal reflux may themselves cause tonic or dystonic reactions (Shafir et al., 1986). Gastroesophageal reflux

This condition may present with a gamut of symptoms and signs, several mimicking movement disorders, including seizures. It may occur in newborn infants and it is sometimes called Sandifer syndrome, the name of the doctor who cared for the child first described by Kinsbourne (1964). It may cause abrupt or slow flexions–extensions of the arms and trunk hyperextension (Sutcliffe, 1969). Head contortions may be severe. There may be jerks or tremors of the arms, accompanied by choking with cyanosis and laryngospasm, and it is not uncommon for these babies to be treated because of suspected epilepsy. Both obstructive and central apneas can be associated with gastroesophageal reflux obviously aggravating the cyanosis (Walsh et al., 1981). The newborn infants with reflux may also develop recurrent pneumonitis. The movements and other symptoms appear often in the context of feedings and may be exaggerated if the baby lies in the supine position. Clinically, the neonates may be neurologically intact, and their polygraphic EEG normal but gastroesophageal reflux occurs also in cerebropathic babies (Lombroso, 1992; Pedley, 1983). Diagnosis is reached by barium swallow X-ray, by probe-measuring of gastric pH, and occasionally by a biopsy.

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Iatrogenic, infectious and metabolic factors inducing paroxysmal movement disorders In a previous section, jitteriness and tremors secondary to withdrawal syndromes were described. In a few instances, neonatal withdrawals from heroin or other narcotic–analgesic and hypnotic–sedative drugs abused during pregnancy can induce episodes of sustained clonus and symptoms of autonomic dysfunction (Holmes & Lombroso, 1993). Supportive measures or small doses of Benadryl, chlorpromazine or paregoric offer rapid control. Prognosis is excellent, unless other complicating factors are present, such as small-for-date size, eclampsia, or obstetrical trauma. The EEGs in such cases may exhibit transiently abnormal backgrounds but they show no ictal discharges. However, transient seizures, multifocal clonic in pattern, with EEG ictal discharge may follow either transplacental intoxication or accidental injection of local anesthetics into the fetus brain (Lombroso, 1992). These newborn infants, in addition to the seizures, appear distressed, hypotonic and poorly reactive to stimulation. Diagnosis is made by a toxic screen and the discovery of needle marks on the scalp. The seizures are transient and prognosis is excellent, unless there are other acquired injuries. Newborn infants of ethanol-addicted mothers may also suffer brain and systemic malformations but, to my knowledge, rarely develop neonatal seizures. A vast array of metabolic disorders, both congenital or acquired can induce seizures or abnormal motor behaviours. These have been amply reviewed, and will not be discussed here (Ogier & Aicardi, 1992; Adams & Lyon, 1986). However, there are some congenital aminoacidurias that cause dystonic posturing or characteristic, repetitive athetoid movements. These may be mistaken for convulsive episodes. Seizures from congenital enzymatic disorders tend to have their onset in early infancy. Exceptions occur, the most relevant being the syndrome of early myoclonic encephalopathy (EME), discussed earlier, and that can be caused by various congenital enzymatic defects. Another familial syndrome causing intractable neonatal seizures is the rare condition of pyridoxine dependency (Rose & Lombroso, 1970; Aicardi, 1986). Urea cycle disorders, or primary hepatic dysfunction, may induce seizure-like events generally attributed to the hyperammonemia present in these babies. The role of hyperammonemia in causing seizures or dystonic postures is unclear, since high levels of serum ammonia may be present, especially in preterm babies, without causing them. Blood osmolarity disorders, such as hyper or hyponatremia may induce multifocal clonic seizures, especially if other morbid factors are present, such as intracerebral hemorrhages or severe sepsis (Lombroso, 1978). But in some newborn infants instead of seizures there may be only hypotonia, dystonic

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posturing including opisthotonic crisis and tremors. These will all disappear once fluids intake and blood osmolarity are corrected. The most common expression of biotinidase deficiency occurs in early infancy with massive myoclonia, but seizure-like events may at times have their onset in newborn infants, though often without EEG ictal discharge and their abnormal movements are not controlled by anticonvulsants, while they are promptly improved by biotin. The most common finding is hyperlactatemia (Wastell et al., 1988). These newborn infants are hypotonic, apathetic, and later exhibit characteristic rashes and alopecia. The ever-growing group of peroxysomal inherited disorders may cause a variety of neurological disorders, including seizures or abnormal movements. These tend to appear in early infancy (Moser, 1989). However, in Zellweger syndrome, the prototype of this group of disorders, seizures may start soon after birth. Likewise, babies with acquired HIV infection display early disparate neurological signs, including seizures, but these tend to be rare in newborn infants and the EEGs are usually non-specific (Mintz, 1993). Abnormal movement disorders induced by the administration of drugs are not often encountered in newborn infants. Among such few events, perhaps the most dramatic is the quite rare but severe dystonia with choreoathetosis and even ballismus following the administration of phenytoin (PHT). This condition, often misdiagnosed, occurs usually in older infants, generally in those with some degree of encephalopathy, but I did observe this dramatic syndrome in full-term newborn infants. Two of these babies received PHT to control what were diagnosed as ‘convulsions’ while, in fact, they probably were suffering from benign sleep myoclonus or from early infantile myoclonus. After stopping PHT and with an injection of Piperidine, the dramatic dyskinesia promptly abated. It is generally stated that this PHT-induced dyskinesia can develop even when blood levels are in normal range. It should be stressed that, while total PHT blood level is within normal range, the free fraction, which reaches the brain, is usually significantly elevated. Barbiturates may also cause mild dyskinesia, tremulousness, hyper- or hypoactivity, and decreased periods of REM sleep, but these side effects pose no diagnostic dilemmas. To my knowledge, there have been no reports in the literature of movement disorders similar to those encountered later in life, due to the administration to newborn infants of other antiepileptic agents, or secondary to psychotropic agents such as stimulants or analeptics. Comment

From the previous sections it should have become apparent that a number of abnormal, paroxysmal motor phenomena may pose diagnostic problems to the clinician. This is especially true when dealing with neonates and young infants in whom

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abnormal movements may masquerade as epileptic events, and vice versa. At this early stage of ontogenesis, the preponderance of the excitatory pathways over the inhibitory ones all along the neuraxis, is one reason why paroxysmal motor phenomena occur more frequently, even from factors that would not provoke them in later life. This developmental physiological state can induce both epileptic and nonepileptic manifestations that, in fact, can be present in the same neonate, adding, at times, to the diagnostic and therapeutic difficulties that confront the clinician. There are many laboratory tests that can be helpful, and these are becoming ever more sophisticated. However, none can become a substitute for the careful historytaking that the physician ought to do, at times repeatedly, including detailed inquiries into the family and genetic history. Often, the available descriptions obtained from the parent or from previous medical reports are inadequate or misleading. Direct observation of the paroxysmal event is the most helpful way to note its various features and to perform those simple manoeuvres, which can influence them (see Table 17.1). In practice, this is not always possible, since the episodes may be infrequent. A video, obtained by the parents at home, becomes an important substitute and can be sufficient to avoid the expense of a hospital admission for long-term EEG video polygraphies. Moreover, within the plethora of laboratory investigations some may be both necessary and helpful to reach a diagnosis. However, it is the careful history-taking, again, that will help in avoiding the routine ordering of a vast number of expensive tests and can also indicate their most appropriate timing. When dealing with a paroxysmal event, whose nature is unclear, the importance of timing is exemplified by the benefit of obtaining an EEG–polygraphic test before embarking on a specific therapeutic plan while considering alternative etiological causes that may not require the use of antiseizure medications. As mentioned in the introduction, there are some taxonomic problems in deciding which seizure events can be defined as ‘epilepsy’ in the neonate. This is largely due to the heightened excitability in the neonatal brain. A transient hypocalcemia, for example, may induce a period of sustained electrical discharge accompanied by concomitant clonus. Other conditions cause neonatal seizures that are transient and these may disappear spontaneously once the etiological factor is corrected, even when the underlying condition leaves enduring neurological deficits. Most prospective studies of neonates with seizures report that only about 11 to 16% will later suffer from epileptic conditions (Rose & Lombroso, 1970; Watanabe et al., 1977; Dennis, 1978; Scher, 1998; Watanabe, 1982). It is legitimate then to raise the question whether most neonatal events are true ‘epilepsy’? It is perhaps not by chance that, in all the literature dealing with neonates, the authors generally use the term of ‘seizures’ rather than that of ‘epilepsy’. Similar dilemmas exist beyond the neonatal period. For example, one may mention the convulsions occurring only with high fevers or those many seizure-like phenomena

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provoked by a transient hypoxia, as aptly discussed by Stephenson (1990). A resolution of these questions is likely to occur only when the pathophysiology and molecular biology of these events are clarified. We shall then deal with disease entities rather than descriptive or syndromatic nosologies.

R E F E R E N C ES

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Epileptic and non-epileptic periodic motor phenomena in children with encephalopathy Giuseppe Gobbi1, Antonella Pini1 and Lucia Fusco2 1 2

Infancy and Childhood Neuropsychiatry Service, Maggiore C.A. Pizzard Hospital, Bologna, Italy Section of Neurophysiology, Bambino Gesù Children’s Hospital, Rome, Italy

Introduction Paroxysmal epileptic motor phenomena occurring in the first year of life in symptomatic encephalopathies (hypoxic–ischemic, metabolic or malformative) are frequently constituted by spasms. Apart from the West syndrome, epileptic spasms are characteristic of some specific infantile epileptic syndromes such as Ohtahara syndrome (Ohtahara, 1978), early myoclonic epileptic encephalopathy (Aicardi & Goutières, 1978), tuberous sclerosis complex and Aicardi disease. They may also occur in neurofibromatosis and in other symptomatic encephalopathies of different origin (Commission on Pediatric Epilepsy of the ILAE, 1992; Roger & Dulac, 1994). In these syndromes epileptic spasms tend to recur in clusters. Recently it has been established that epileptic spasms may be present beyond infancy (Gobbi et al., 1987; Commission on Paediatric Epilepsy of the ILAE, 1992; Roger & Dulac, 1994; Talwar et al., 1995). Among these ‘non-age-related’ epileptic spasms, a particular type named periodic spasms has been described and their electroclinical characteristics have been detailed (Gobbi et al., 1987; Bednarek et al., 1998). The term ‘periodic spasms’ has been chosen to emphasize one of the most striking characteristics of these spasms: their repetition into the cluster in an almost periodic sequence at rather regular intervals. The most important aspect of periodic spasms is that the whole cluster of spasms has to be considered as a single, complicated partial seizure, with a particular type of secondary generalization, and not simply as the result of a long-lasting series of seizures (the spasms), which repeat in a periodic sequence (Gobbi et al., 1987). Finally, periodic spasms may be very polymorphous and their clinical expression may be very subtle or suggestive of a movement disorder. As a consequence they may be missed or misdiagnosed. Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Besides periodic epileptic motor phenomena, neurologically impaired patients may present non-epileptic periodic motor phenomena during the transition between wake and sleep. Sleep starts, also called hypnagogic or hypnic jerks usually occurring in isolation with sleep onset, may in fact repeat in clusters, in neurologically impaired children. These repetitive sleep starts should be recognized and clearly differentiated from epileptic seizures, especially while they appear in children with epilepsy (Fusco et al., 1999). In this chapter the clinical semeiology of periodic spasms and of repetitive sleep starts is described in detail through some case reports studied by video-EEG recording with the aim of emphasizing their polymorphous clinical characteristics and redefining their clinical–EEG criteria for a correct diagnostic recognition and to define correct differential diagnosis criteria among other types of periodic movement disorders. From our personal series of 27 patients (Gobbi et al., 1987; Pini et al., 1996; Fusco et al., 1999), with repetitive motor phenomena, we selected for analysis in this chapter 11 patients who had video-EEG recording of their periodic events. Twentyfour patients had periodic spasms and 3 had periodic sleep starts. Among the 11 patients selected, 8 had periodic spasms and 3 periodic sleep starts. The term ‘periodic’ has been only reserved for those motor phenomena which repeated at rather regular intervals in the cluster. Specific epileptic syndromes with more or less periodic seizures in cluster such as West syndrome, Ohtahara syndrome, early myoclonic epileptic encephalopathy and Lennox–Gastaut syndrome have been excluded. Non-epileptic sleep periodic limb movements were also excluded. Consequently, periodic spasms and repetitive sleep starts are the periodic motor phenomena types selected for this study. In 24 patients with periodic spasms, the aetiology was constituted by clastic brain lesions (8 patients), brain malformations (7 patients), metabolic encephalopathy (1 case affected by a mitochondrial disorder) and tuberous sclerosis complex (1 case). In 7 cases the aetiology remained unknown. Patients with repetitive sleep starts showed acquired encephalopathies due to feto-neonatal asphyxia. Age at time of video-EEG recordings ranged from 7 months to 23 years. Clinical and EEG semeiology of periodic motor phenomena have been analysed and the following have been selected for didactic purpose. These 11 patients were selected because they had been studied with prolonged video/EEG recordings, allowing careful analysis of clinical semeiology.

C A S E R E P O R TS Patient 1: Cluster of periodic spasms as a single seizure This is a 7-year-old boy with slight mental retardation and normal brain magnetic resonance (MRI). Since the age of 2 years he presented clusters of periodic spasms which stopped at

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Epileptic and non-epileptic periodic motor phenomena the age of 4 after VGB treatment. Periodic spasms were characterized by a progressive intensification of clinical semeiology and by an increase of spasms repetition rate during the cluster. At the beginning of the cluster, the spasms were only constituted by mild head flexion, then asymmetrical spasms with head flexion, right arm abduction and right leg extension developed. During the cluster, the muscular contractions became more tonic. Since the onset of the cluster the child’s behaviour changed, as if he were aware of something strange. Towards the end of the cluster, the spasms became less intense again and the child gradually came back to his preictal behaviour. Patient 2 This child, aged 7 months, had suffered severe neonatal asphyxia. Since the first month of life he showed tonic seizures and partial motor seizures with secondary generalization. Periodic spasms started at the age of 2 months and their clinical semeiology was characterized by an asymmetrical clinical pattern. Hypsarrhythmia never developed. Ictal EEG showed prolonged focal discharges intermixed by periodic spasms (Figs. 18.1 and 18.2). Patient 3: Periodic spasms with mild clinical expression at the onset of the cluster: at risk to be missed This girl, aged 5 years, showed mild developmental retardation of unknown origin. Brain MRI was normal. Clusters of periodic spasms started at the age of 3 years and stopped following hydrocortisone treatment. Since the clinical semeiology of spasms at the onset of the cluster was very mild, seizure onset was difficult to distinguish. Her mother immediately realized that the seizure was starting because she was aware of her daughter’s behaviour alteration. In this case each spasm showed clinical focal signs (mouth deviation to the right) and became more intense and complicated during the cluster. When a very intense and complicated spasm occurred, with jerks of the mouth on the right, head deviation to the right, left shoulder raising and minimal left leg extension, the little girl started to cry. On EEG recording, the cluster of periodic spasms was preceded by a focal discharge followed by a diffuse slow wave with superimposed fast rhythm. Patient 4: Periodic spasms with asymmetric clinical semeiology This boy, aged 5 years, presented partial agenesis of corpus callosum, hydrocephalus and subcortical atrophy due to perinatal asphyxia. He showed severe mental impairment and spastic quadriparesis with axial hypotonia. Epileptic seizures started from the first months of life as partial motor tonic, and right hemiclonic seizures, other than periodic spasms. Ictal semeiology of spasms was particularly complicated because of their relevant asymmetry and because of intercalated focal motor seizures. Figs. 18.3 and 18.4 show an example of this type of periodic spasms. Patient 5: Periodic spasms mixed with postural reflex This girl, aged 4 years, presented postmeningoencephalitis cortical atrophy and Chiari I malformation, left hemiparesis with dystonia and moderate mental retardation. Periodic spasms occurred at the age of 14 months and were difficult to recognize because they looked like postural reflex and were sometimes combined with it.

Fig. 18.1

on the right side.

Case n. 2 Seizure starts with a sudden change of background activity followed by a first spasm and then by repetitive occipital spikes

SEIZURE ONSET

Fig. 18.2

Case n. 2 Two minutes and 20 seconds later, repetitive right occipital spikes persist periodically intermixed with a diffused slow wave with superimposed fast rhythms. Each complex is concomitant with deltoid contraction and with change in breathing rhythm.

Fig. 18.3

Case n. 4 Seizure starts with a diffused polyphasic slow wave followed by repetitive spike and wave discharges on the right.

Fig. 18.4

Case n. 4 Ten seconds later a series of biphasic or triphasic slow waves predominant on the right appear,which are repeated in periodic sequence.

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G. Gobbi et al. Patient 6: Periodic spasms mixed with tics This boy, aged 9 years, presented facial dysmorphisms, mental retardation and hypoplasia of cerebellar vermis on brain MRI. He showed a movement disorder consisting of a kind of dystonic tic with blefarospasm and oculogiric deviation. Moreover, he presented epilepsy with periodic spasms which were, however, difficult to recognize because the spasms were similar to the tics and mixed with them. Sometimes one spasm followed a tic giving the impression that it was induced by the tic, or that the patient self induced his spasm by tic. Patient 7: Spontaneous and acoustic-induced repetitive sleep starts This girl aged 2 years 6 months old at time of video-EEG recording, showed severe psychomotor retardation and spastic tetraparesis more prominent on the left side resulting from perinatal asphyxia. At 7 months of age, she developed West syndrome, which responded well to ACTH. At 18 months, clusters of repetitive spasms appeared while she was falling asleep. Video-EEG recording revealed that each cluster lasted about 5 minutes and was followed by awakening. Startle events were both spontaneous and induced by acoustic stimulation. Clinical characteristics were similar in both instances: sudden brief massive contractions, involving axial and limb muscles. Spasms repeated in a rather ‘random’ manner. EEG–polygraphic recordings showed repetitive massive tonic contractions, resembling true startles, which often induced an EEG pattern similar to arousal, ultimately producing complete awakening. The EEG counterpart of each repetitive event was represented by a diffuse artefact. Patient 8: Repetitive sleep starts mimicking tonic seizures This girl, aged 10 months at time of video-EEG recording, showed fetal distress and neonatal asphyxia. Psychomotor retardation and spastic quadriparesis with axial hypotonia were present. Brain MRI showed widespread white matter reduction. Partial motor seizures appeared at the age of 9 months. At the same time, the parents reported ‘spasms’ at the beginning of sleep. We observed and recorded a cluster of spasms lasting almost 12 minutes when the child was falling asleep. During the cluster, contractions were massive and sudden, sometimes acoustically induced. During the longer motor events, there was a persistent increase in muscle tone resembling true startles. Each spasm followed one to another at rather irregular intervals. An arousal was often induced by a spasm. Their EEG counterpart was unremarkable.

Semiology and differential diagnosis

Periodic motor phenomena may be epileptic or non-epileptic and occur in neurologically impaired patients with or without epilepsy. Since it could be often difficult to establish the correct nature of paroxysmal motor phenomena in patients with potentially epileptogenic encephalopathies, it is important to know these types of paroxysmal motor manifestations and their

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clinical–electrophysiological characteristics because of the relevant therapeutic implications. Periodic spasms repeat at rather regular brief (few seconds) intervals grouped in long-lasting clusters. The term ‘spasm’ for these motor phenomena has been chosen with an extensive signification. The polygraphic aspect of these ‘spasms’ is a contraction involving the axial muscles with a duration ranging between 0.8 and 3.3 seconds. The surface-EMG conformation of the muscular contraction corresponds to the so-called ‘true spasm’, typical of the West Syndrome (Fusco & Vigevano, 1993). According to these authors the true spasm reaches a peak more slowly than a myoclonic jerk, but more rapidly than a tonic seizure. Then, it quickly decreases and appears polygraphically as a kind of rhombus. However, this relatively homogeneous polygraphic aspect of periodic spasms does not correspond to as much homogeneous clinical presentation. In fact, clinically these ‘spasms’ may look like a myoclonic jerk or a short tonic contraction (Gobbi et al., 1987). Moreover, the muscle contraction during the cluster may be very subtle, as in patient 3, or it may evoke a movement disorder like a tic as in patient 6 or it may mimic awakening myoclonus, or it may be mixed with postural reflex or with tics and be confused with them. The risk of misdiagnosis is therefore high. Another interesting feature of periodic spasms is the progressive intensification of the clinical expression of spasms and their repetition rate increase during the cluster. The clinical semeiology of each spasm may change along the cluster, becoming more intense, sometimes more prolonged and complicated involving asymmetrically more body segments. Then, after a variable period of stabilization, an attenuation of both spasms and their frequency at the end of the cluster occurs. This incremental–decremental course along the cluster is probably the result of a gradual development of the seizure and supports the concept of periodic spasms as a single epileptic event. The entire series of spasms could represent a single partial ictal event where the spasms themselves represent the secondary generalization. As suggested by the fact that the cluster may be opened by or intercalated with focal ictal EEG changes. Moreover, the series of periodic spasms is associated with a sudden change in the child’s behaviour concomitant with a progressive slow focal or hemispheric EEG activity. The hypothesis suggested by Yamamoto et al. (1988) and by Chugani et al. (1992) on a focal cortical origin of epileptic activity with a spreading to subcortical centroencephalic structures (including basal ganglia), may be assumed to explain the semeiology of spasms. According to this hypothesis, spasms may depend on an abnormal interaction between the injured cortical and subcortical structures. The repeated coincidence with awakening might suggest an abnormal participation of subcortical structures controlling the sleep–waking cycle (Gobbi et al., 1987).

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Table 18.1. Clinical and EEG characteristics of periodic spasms

Long-lasting cluster (2–20 minutes) of epileptic spasms repeated at rather regular short (few seconds) intervals Focal epileptic ictal event (either electroclinical or only electric) opening the cluster or intercalated with it Sudden change in the child’s behaviour with cluster onset and rapid recovery at the end Spasms with asymmetric pattern or focal signs Slow wave with fast rhythm or polyspike as spasm’s EEG correlate Progressive slow focal or hemispheric activity, or spikes between one spasm and another Incremental–decremental or decremental–incremental course of spasms along the cluster Non-age-relation

Many clinical and EEG characteristics are probably determined by type and topography of the underlying pathology. It is well accepted that asymmetrical spasms suggest a symptomatic encephalopathy or a focal cortical lesion (Commission on Pediatric Epilepsy of the ILAE, 1992; Fusco & Vigevano, 1993; Dulac et al., 1993; Chugani et al., 1992). Moreover, clinical semeiology of motor phenomena appears to depend on a child’s resting position when the spasm supervenes, on the type and distribution of neuromotor impairment and on the time of seizure occurrence with respect to brain plasticity and maturational phase (with development or persistence of pathological motor patterns). Finally, periodic spasms may be self-induced by proprioceptive stimuli. Clusters of spasms induced by self stimulation have already been reported (Guerrini et al., 1992). Since periodic spasms are usually drug-resistant, an exceedingly aggressive therapeutic approach is not recommended in that they do not represent a dangerous event. In our experience, periodic spasms may be temporarily controlled by benzodiazepines, occasionally by pyridoxine, or vigabatrin treatment in two others. Table 18.1 shows a set of diagnostic criteria which may be considered for a correct identification of periodic spasms among epileptic spasms occurring in infancy and childhood. Video-EEG recording of any type of repetitive spasms or motor phenomena and their careful examination are mandatory for a correct diagnosis. Repetitive sleep starts (Fusco et al., 1999), should be correctly recognized because they can be confused with epileptic seizures and unnecessarily treated. The events we described recurred repetitively in a rather random manner during the period of falling asleep. The clinical characteristics of each motor phenomena are very similar to those of sleep starts (Broughton, 1988), which however, usually

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recur in isolation. As for sleep starts, muscle contraction suddenly involves trunk and limbs and is usually spontaneous, but it can be induced by acoustic and tactile stimulation. The duration of muscle contraction may be short or prolonged, looking like myoclonic or tonic seizures, respectively. In neurologically impaired patients, repetitive sleep starts may persist for a longer time compared to simple sleep starts. This enhancement of the physiological oscillation between sleep and wake during the period of falling asleep, could be caused by the lack of pyramidal tract physiological inhibition, due to pyramidal lesion (Fusco et al., 1999). Differential diagnosis of repetitive sleep starts is with every repetitive motor manifestation during sleep, such as periodic limb movements and epileptic seizures. Periodic limb movements do not have startle characteristics, are not a massive movement, and are not elicited by acoustic stimulation. Sleep tonic seizures of Lennox–Gastaut syndrome are easily diagnosed by the typical ictal EEG pattern. On the contrary, motor partial seizures of frontal lobe origin, which usually occur during sleep (Kellaway, 1985) and may repeat at subperiodic intervals (Scheffer et al., 1995), do not have a clear EEG counterpart. However, the characteristic clinical semeiology of seizures originating from the frontal lobe permits a sufficient degree of agreement on diagnosis (Vigevano & Fusco, 1993). Therapy should be proposed only if periodic starts produce a sleep disturbance with subsequent daily drowsiness and if the event is not limited to the wake–sleep transition. Benzodiazepines appear to be the drug of choice. The prone position could reduce repetitive sleep starts, as suggested by some parents. This position represents in fact, a limitation of movements, thus limiting movement related arousal. Acknowledgement The authors thank Professor Renzo Guerrini for his kind permission to include some patients attending the Division of Child Neuropsychiatry, Stella Maris Foundation, University of Pisa.

R E F E R E N C ES

Aicardi, J. & Goutières, F. (1978). Encéphalopathie myoclonique néonatale. Revue Electroencephalogie et Neurophysiologie Clinique, 8, 99–101. Bednarek, N., Motte, J., Soufflet, C., Plouin, P. & Dulac, O. (1998). Evidence of late-onset infantile spasms. Epilepsia, 39 (1), 55–60. Broughton, R.J. (1988). Pathological fragmentary myoclonus, intensified hypnic jerks and hypnagogic foot tremors; three unusual sleep-related movement disorders. In Sleep 86, ed W. P. Koella, F. Obal, H. Schulz et al., pp. 240–2. Stuttgart: Gustav Fisher.

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G. Gobbi et al. Chugani, H.T., Shewmon, D.A., Sankar, R., Chen, B.C. & Phelps, M.E. (1992). Infantile spasms: II. Lenticular nuclei and brain stem activation on positron emission tomography. Annals of Neurology, 31, 212–9. Commission on Pediatric Epilepsy of the International League Against Epilepsy (1992).Workshop on Infantile Spasms. Epilepsia, 33(1), 195. Dulac, O., Chugani, H.T. & Dalla Bernardina, B. (1993). Royaumont Workshop on West Syndrome. Epilepsia, 34(4), 670. Fusco, L. & Vigevano, F. (1993). Ictal clinical electroencephalographic findings of spasms in West Syndrome. Epilepsia, 34(4), 671–8. Fusco, L., Pachatz, C., Cusmai, R. & Vigevano, F. (1999). Repetitive sleep starts in neurologically impaired children: an unusual non-epileptic manifestation in otherwise epileptic subjects. Epilpetic Disorders, 1(1), 63–7. Gobbi, G., Bruno, L., Pini, A., Giovanardi Rossi, P. & Tassinari, C.A. (1987). Periodic spasms: an unclassified type of epileptic seizure in childhood. Developmental Medicine and Child Neurology, 29, 766–5. Guerrini, R., Genton, P., Dravet, C. et al. (1992). Compulsive somatosensory self-stimulation inducing epileptic seizures. Epilepsia, 33(3), 509–16. Kellaway, P. (1985). Sleep epilepsy. Epilepsia, 26 (1), S15–S30. Ohtahara, S. (1978). Clinico-electrical delineation of epileptic encephalopathies in childhood. Asian Medical Journal, 21, 7–17. Pini, A., Merlini, L., Tomé, F.M.S., Chevallay, M. & Gobbi, G. (1996). Merosin-negative congenital muscular dystrophy, occipital epilepsy with periodic spasms and focal cortical dysplasia. Report of three Italian cases in two families. Brain and Development, 18, 316–22. Roger, J. & Dulac, O. (1994). West syndrome: history and nosology. In Infantile Spasms and West syndrome. ed. O. Dulac, H.T. Chugani & B. Dalla Bernardina, Chapter 1, pp 6–11. London, Philadelphia, Toronto, Sydney, Tokyo: W.B. Saunders. Talwar, D., Baldwin, A., Hutzler, R. & Griesemer, D. (1995). Epileptic spasms in older children: persistence beyond infancy. Epilepsia, 36(2), 151–5. Scheffer, I.E., Bhatia, K.P., Lopes-Cendes, I. et al. (1995). Autosomal dominant nocturnal frontal lobe epilepsy. Brain, 118, 61–73. Vigevano, F. & Fusco, L. (1993). Hypnic tonic postural seizures in healthy children provide evidence for a partial epileptic syndrome of frontal lobe origin. Epilepsia, 39, 110–19. Yamamoto, N., Watanabe, K., Negoro, T. et al. (1988). Partial seizures evolving to infantile spasms. Epilepsia, 29, 31–40.

19

Epileptic stereotypies in children Thierry Deonna1, Martine Fohlen2, Claude Jalin2, Olivier Delalande3, Anne-Lise Ziegler4 and Eliane Roulet4 1

Department of Neuropediatrics, CHUV Cautonal Hospital, University of Lausanne, Switzerland Service de Neurochirurgie, Fondation Rothschild, Paris, France 3 Department of Pediatric Neurosurgery, Fondation Rothschild, Paris, France 4 Paediatric Department, CHUV, Lausanne, Switzerland 2

Introduction Abnormal, seemingly purposeless, repetitive motor behaviours are typical manifestations of seizures of temporal or frontal origin and are referred to as automatisms. In adults, these ‘epileptic automatisms’ or ‘epileptic stereotypies’ (Penfield & Jasper, 1954), are usually recognized as clearly different from the normal patient’s behaviour and also because there are usually other simultaneous manifestations of temporal or frontal seizures. However, in very young children and especially when stereotypies are the only epileptic symptoms, the situation is more complicated, because stereotypies can be seen in a variety of circumstances and have very different causes. Before further discussion of ‘epileptic stereotypies’, the use of the term ‘stereotypy’ needs first to be clarified (Ridley, 1994; Mason, 1991). Stereotypies are defined as repetitive, similar, non-goal-directed (purposeless) movements. This definition is wide and can apply to many types of abnormal movements, for example tremors and tics. It leaves many open questions: repetitive implies a certain frequency and regularity of successive occurrence, but this can be quite variable. Similar means that the movement is always the same, but variations in intensity, rapidity and complexity are frequently observed from one episode of stereotypy to the next. The movement itself can be simple and without apparent significance, or complex and in this case appears as an organized deliberate gesture which is part of the person’s repertoire. Finally, non-goal directed implies that it is involuntary and automatic and beyond the person’s control. However, stereotypies can appear goal directed even if they are not made with a deliberate intention (for instance, chasing an insect on one’s face). The dichotomy automatic/voluntary is not so straightforward as one might think (Jeannerod, 1983). These difficulties should be acknowledged when using the term clinically. Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Table 19.1. Epileptic stereotypies: clinical characteristics and differential diagnosis

Motor stereotypies (habitual, typical)

Epileptic stereotypies

Complex tics

Paroxysmal dyskinesias

Boredom excitement

Variable (may be triggered by external or internal stimuli: frontal)

Variable

Movement exercise stress

• suppressed by external stimuli

Yes

Yes (possible)

No

No

• temporary voluntary control

Yes

No

Yes

No

Simple to complex May be highly movement organized

May be highly organized

Dystonic choreoathetotic

None

Other epileptic phenomena (vegetative, consciousness, motor seizures)

Simple tics

None or permanent underlying dyskinesia

Autism mental retardation

Symptomatic partial epilepsy other seizures (not always ?!)

Tic disorder

Basal ganglia diseases

• uncomfort preceding mvmt

No

?

Yes

No

• associated pleasure

Yes

?

No

No

No

No

No

A. Circumstances of occurrence

B. Nature of movement C. Associated motor or other neurol. event

D. Underlying conditions

E. Significance for individual:

• easily suppressed Yes without discomfort

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It is important first to realize that stereotypies can occur as a normal developmental phenomenon in children (Tröster, 1994; Tan et al., 1997). Table 19.1 shows differentiating clinical features between these so-called ‘habitual’ (typical) motor stereotypies from other more complex situations: epileptic stereotypies, complex tics and other dyskinesias which are important in the context of this presentation. It can be seen that the circumstances of occurrence, the associated neurological signs and symptoms and the underlying pathological conditions can be more useful clinical indices than the characteristics of the movements themselves. Stereotypies in the case of young developing children present some special problems. They can occur sometimes transitorily in otherwise early normal development or as a result of sensory or/and affective deprivation or serve as compensatory phenomenon in some special ocular or central pathologies. Stereotypies are typically seen in children with mental retardation and particularly in autism. However, these children frequently also have epilepsy whose manifestations can be quite difficult to diagnose when they consist of subtle changes in awareness, vigilance or in cognitive capacity. This is even more problematic to recognize that some of their stereotypies might be epileptic in origin. Gedye (1991) has discussed in detail the hypothesis that some of the repetitive abnormal motor behaviours seen in autism could be frontal lobe seizure manifestations. Another critical point is that early symptomatic epilepsies can have devastating effects on cognitive and emotional development, specially those of frontal or temporal origin, which are precisely those in which ‘epileptic stereotypies’ can be observed. For these reasons, clinical recognition of this symptomatology in young children is very important. The final proof of the epileptic origin of stereotypies is the direct video-EEG recording, which is difficult to perform in young retarded children. Also, routine EEGs may not reveal spike discharges when they arise from regions far from the brain surface such as the mediofrontal, orbitofrontal or cingular regions. The present chapter is a combined presentation of (i) a purely clinical-routine EEG observation of seven children in whom the diagnosis of ‘epileptic stereotypies’ was suspected on the basis of indirect evidence (Deonna and collaborators), and (ii) that of a young child in whom this could be documented by electrocorticography prior to epilepsy surgery (Fohlen, Delalande and collaborators). The data suggest that ‘epileptic stereotypies’ in young children with developmental disorders can be easily overlooked, are probably more frequent than presently recognized, and that they can be the first or the only visible manifestation of epilepsy. Clinical study of epileptic stereotypies We have studied seven young (1 to 3 years) children who were admitted to the Neuropediatric Unit of the CHUV, either for diagnosis of abnormal paroxysmal

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movements, possibly epilepsy, or for work-up of a developmental disorder and in whom we also found abnormal movements which we suspected in both situations to be ‘epileptic stereotypies’. All children were studied longitudinally for several years and underwent several waking and sleep EEGs, cerebral imaging (MRI), and detailed developmental testing. All cases were subsequently treated with antiepileptic drugs. We paid attention to the dynamics of development (retardation, stagnation or developmental regression and its characteristics: autistic type or other) and if this course had any time correlation with the onset of the stereotypies and if this was modified with antiepileptic treatment. Method of analysis of abnormal paroxysmal stereotypic motor behaviour

Our analysis was based on the video documentation of suspected abnormal movements–posture obtained either at home by the parents themselves, during outpatient consultations or recognized, sometimes a posteriori, during videotaped neuropsychological testing. The movements were analysed on the video (using slow motion, stills and photographs) sometimes with ‘montages’ of several periods with stereotypies to see if they were always identical or contained only fragments of the prototypical ones or different variations. We looked if they contained also more typical and simple motor epileptic phenomena (tonic, clonic, posturing) before, during or just after the stereotypies or independently. Several EEGs were obtained in the seven children but because of their difficult behaviour, we could not, with one exception (case TdG.) use ambulatory EEG monitoring to try to obtain a clinical EEG correlation of these stereotypies. In most EEGs we had to use sedation and sleep EEGs were obtained. Simple myoclonic seizures and ‘spasms’ were recorded with EEG correlation but we could document in only one case (case AB) a clinical–EEG stereotypy identical to that we had seen clinically. We also asked the parents and attendants what they thought of these abnormal movements and how they interpreted them, i.e if they gave it a special meaning or what they thought was the child’s ‘purpose’ in doing it. Results Characteristics of stereotypies, associated seizures, EEG and MRI findings in seven children

Table 19.2 summarizes the major clinical findings in the seven children. It should be noted that three of the children were referred for evaluation of a developmental problem and not primarily for suspicion of epilepsy. The detailed developmental course of Case 2 has been previously published (Deonna et al., 1995). The only child who had epileptic stereotypies without other epileptic manifesta-

Table 19.2. Cinical data on seven children with epileptic stereotypies

case 1 AB

case 2 TdeG

case 3 AD

case 4 BP

case 5 QG

case 6 YdiP

case 7 JvH

age at onset

7 mo

22 mo

3y

2 mo

10 mo

<3y

2y

reason for referrala

parox.

parox.

dev.

dev.

parox.

dev.

parox.

retardation











regressionb







main stereotypy

hand gazing plugs one’s ear

‘fencing’

‘catching flies’

‘looking at ceiling’

head tilting and turning

‘praying’

arm elevation above head

other epileptic seizures





-







probablec

effect of AED on –development –stereotypies –other seizures –EEG

improve improve improve improve

improve improve improve improve

improve improve partial

no effect ? no effect improve

no effect no effect no effect no effect

no effect no effect no effect no effect

improve improve improve partial

EEG

a

a

b

a

a

a

c

MRI

nl (2x)

nl

nl

nl

abnl

nl (2x)

nl

videoEEG: recorded electro-clinic. ‘spasms’ stereotypies

 

 

 

 

 

 

 

Notes: a parox: paroxysmal motor phenomena dev: retardation, stagnation, regression b more pronounced in domain of communication (autistic-like) c suspect loss of awareness with eye deviation a: periods of diffuse intermittent spike-waves (mainly in sleep) and unilateral or bilateral multiple spike foci (mainly anterior) b: paroxysmal frontal slow waves c: asymmetrical slow fronto-central (sleep) nl: normal abnl: abnormal

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Table 19.3. Significance given to abnormal paroxysmal movement–posture

Description

Interpretation from care takers

Head or eye deviation

Avoids or attracted to situation

Arm in front of chest

Defensive posture, fright

Hand gazing

Preoccupation with self

Eye rubbing, thumb suck

Fatigue, discomfort

Body twist

Dance-like, funny movement

tions (case 3, AD) had several bizarre abnormal motor behaviours (‘catching flies’, shrugging of shoulders). Six out of seven were found to have other associated seizures. Five of these had ‘epileptic spasms’, mainly with documented clinical-EEG diffuse paroxysmal dysrhythmia during sleep (cases 1, 2, 4, 5, 6). All had, at one time or another, focal spikes on the EEG in frontal or fronto-temporal areas. In case 1 (AB), we could on one occasion record an episode of ‘hand gazing’ concomitant with contralateral and diffuse EEG discharges. MRI was normal in six out of seven children. One child (case 5, QG) had an abnormally thick cortex in the left inferior temporal region compatible with dysplasia. None of the children had a family history of epilepsy or an abnormal phenotype and except for case 5, no evident cause for their seizure disorder. Attributed significance of abnormal paroxysmal behaviours

Initially, the stereotypies were not considered as a possible epileptic manifestation by the parents. Laughing and crying were considered as emotional outbursts. Table 19.3 lists some of the abnormal motor behaviours observed and the interpretation given to them by the parents or attendants. Evolution of stereotypies, development and behaviour

In four out of seven children there was a cessation or marked decrease of the epileptic stereotypies with antiepileptic drugs along with a clinical improvement, mainly in communicative behaviour. Three of these had shown a regression in development concomitant with the onset of stereotypies. Child AB born 12.6.93. Hand gazing episodes

AB was the first child of healthy parents with no history of pre, peri or postnatal problems. There was no concern from his parents or his paediatrician about his early development. At 12 months, we saw him for acute onset of brisk head flexion

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and arm extension. On examination, we saw and videotaped intermittent episodes of altered vigilance with eye blinking followed by fatigue, which in retrospect had been present from the age of 7 months. The EEG showed focal and diffuse paroxysmal EEG abnormalities. He was treated with valproate with immediate disappearence of the spasms and other episodes and normalization of the EEG. At 13 months his DQ on the Brunet–Lézine was 83. He progressed until 22 months with some delay more obvious in play and verbal language. A gradual concern about his behaviour and communication was present from his second birthday. At 27 months he had a rapid autistic-like regression with worsening of his EEG and epileptic spasms during sleep. At around this period he developed episodes of ‘hand gazing’. These consisted of extension of the left arm with dorsal flexion of the hand and abducted fingers with the child’s gaze directed at the hand (see Fig. 19.1). In this case, we had the opportunity to observe and videotape during a home visit a sequence of three consecutive episodes of ‘hand gazing’ (‘cluster’) which showed the following sequence: (i) Hand gazing immediately followed by brisk eye and head rotation to right and elevation of the shoulders. (ii) Hand gazing followed by subtle identical sequence. (iii) Isolated hand gazing episode. On another occasion we could videotape a hand gazing episode during an outpatient visit with alteration of awareness and followed by fatigue. The mother who initially interpreted the ‘hand gazing’ as a bad habit clearly recognized it later as an epileptic manifestation. They disappeared on steroid treatment along with the other epileptic manifestations which had been uncontrolled with valproate, clonazepam, carbamazepine and vigabatrine. They occasionally reappeared in the next 3 years, each time with a temporary regression in behaviour and altered mood, sometimes at the time of an intercurrent febrile illness and without other more typical epileptic manifestation. Intracranial videoEEG monitoring of epileptic stereotypies AS is a caucasian boy born in November 1993. He is the second child of healthy unrelated parents. Pregnancy, birth, and first three months of life were uneventful. Epilepsy started at 3 months with partial seizures characterized by staring, and followed by head and eye deviation to the left. Ictal EEG showed a flattening of background activity followed by slow rhythmic spike and waves localized on FPZ, FP2, F4, C4, F8, FT10. Interictal EEG showed on prefrontal and fronto-orbital areas showed either flattening, or slow spikes and slow waves. MRI showed a lesion in right internal fronto-orbital lobe characterized by a thickened gyrus and hypersignal of white matter on T2 sequences. Antiepileptic drugs were effective for 10 months but the epilepsy relapsed and became medically intractable. At the same time, the child started to show impairment of psychomotor development. Because

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(b)

Fig. 19.1

Photographs of case 1 (AB). (a) Hand gazing. (b) Eye and head rotation to right and elevation of the shoulders.

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Right hemisphere Seizure onset Seizure spread I Seizure spread II Surgical resection

Fig. 19.2

Schema of electrocortical recording in case AS.

of pharmacoresistance, cognitive impairment and convergence of electroclinical and radiologic features toward the prefrontal lobe, epilepsy surgery was considered. The child was referred to our neurosurgical department at 2 years of age. On admission the patient continued to suffer more than 40 seizures each month. Neurological examination at 2 years of age did not show any motor deficit. Developmental Quotient (Brunet–Lezine test) was 60. He produced only monosyllabic language. The child’s behaviour showed psychotic features such as repetitive movements (noisy slapping and hiding one’s eyes with hands) poor visual contact, and limited social interaction. Seizures recorded on the scalp video-EEG were similar to those previously reported. Intracranial video–EEG was performed. Electrode grids were implanted by craniotomy: 64 plots covered the right fronto orbital, frontopolar, prefrontal mesial and frontal convexity area, while 2 deep electrodes (16 plots) were positioned inside the lesion (Fig. 19.2). Seizures were recorded on a BMSI computer (128 channels)

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connected to a system allowing automatic detection of paroxysmal electrical events. The identification of the seizures was made by medical staff, parents’ and by means of computer detection. The intracranial video-EEG was performed over 5 days and nights. More than 110 seizures were recorded. Analysis of seizures

Two types of seizures were registered: the usual partial motor seizure and a sort of ‘behavioural seizure’. The usual seizures were clinically similar to those previously recorded on the scalp video-EEG tape. They all had a motor component (blinking of eyelids, deviation of the eyes and head toward the left, vibratory hypertonia of left limbs), preceded by a staring. They started on the EEG with a flattening of background activity due to rapid rhythms (16c/s) on plots OE1–2, OI1–3, and FA1–2. They continued with rhythmic 2 Hz spike-waves spreading to fronto-polar and anterior part of frontal intermedialis dorso lateralis area (plots OE 1 to 8, OI 1 to 8, FA 1 to 8, MA 1 to 8, FE 8, FI 8, deeper plots of PA and PP). The seizure’s end was marked by sudden spike-waves interruption followed by a depression of background activity especially over fronto-orbital area. The second type of seizures (‘behavioural seizures’) consisted of motor stereotypies. They consisted in slow rhythmic clapping (‘applause’) associated with vocalizations. The boy did not appear to be in contact with his surroundings, sometimes looking at his hands. Actually, when analysed on video tape, those manifestations were preceded by a staring similar to that preceeding the motor partial seizures. On EEG (Fig. 19.3) the staring corresponds to a flattening with rapid rhythms over orbito-frontal plots while the stereotypies correspond to an involvement of frontal pole with rhythmic spikes and waves. Both, hand clapping and spikes stopped simultaneously. The child suddenly appeared more alert. This kind of clinical manifestation was always associated with ictal EEG abnormalities. The surgical procedure consisted of removing fronto-orbital, fronto-mesial and fronto-polar part of right frontal lobe. Neuropathological examination showed a typical dysplasia according to the description of Taylor et al. (1971). Three years after surgery the patient is still seizure free (Engel class 1A), and antiepileptic drugs have been withdrawn since 2 years. At 5 years of age, his QD was 75; the child did not have any repetitive stereotypic movements and the relationship with the parents was dramatically improved. Discussion Unusual paroxysmal repetitive motor behaviour in young children can sometimes be epileptic manifestations. The intracranial recording of stereotypies of

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Fig. 19.3

EEG during epileptic stereotypy with ‘applause’ in case AS.

‘applauses’ in child A.S. with right frontal cortical dysplasia is a direct demonstration of this special epileptic behaviour. Several data are in favour of the epileptic origin of the abnormal paroxysmal motor behaviour observed in the other seven cases presenting with epileptic stereotypies. With one exception, we could not obtain a direct clinical–EEG correlation which would prove beyond doubt that the stereotypies are epileptic manifestations, but there are good arguments which support that interpretation. They must be precisely discussed because direct EEG recording in these young children is very difficult and in many cases the only available evidence will be purely clinical. The fact that these stereotypies are sometimes preceded or followed occasionally by typical seizure movement or other epileptic signs, the concurrent change in usual behaviour (fatigue, somnolence, etc.) are the most important points. The improvement of EEG and disappearance of stereotypies with antiepileptic drug treatment also suggest that these motor phenomena are closely related to epilepsy. Finally, the occurrence at other times of clear epileptic manifestations (myoclonic, clonic, tonic, loss of awareness) and autonomic signs (colour, respiration) are other circumstantial arguments. In addition to the epileptic stereotypies, five out of the seven children also had brief myoclonic seizures with EEG correlation (diffuse high voltage spike-waves followed by flattening). They occurred mainly in sleep and often in clusters with unilateral single or multiple spikes foci in the anterior regions. In the absence of clearcut clinical–EEG correlation of these stereotypies in the first seven children,

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the exact locus of origin of the discharges responsible for the stereotypies remains speculative. The anterior location of the EEG foci in these seven cases and the direct electroclinical recording in case AS in the frontoorbital area, as well as data in adults with epileptic stereotypies suggest primarily a frontal origin. The generalized seizures and their EEG correlate resemble what is now recognized as ‘late onset infantile spasms’ which can coexist with more complex epileptic phenomena. Children reported with late onset infantile spasms often have anterior (frontal) EEG foci and severe developmental delays associated with a regression of the autistic type (Deonna et al., 1995; Bednarek et al., 1998; Deonna, 1999). The detailed description of such abnormal repetitive movements is found exclusively in electroclinical recordings of adults with epileptic automatisms, To our knowledge it has not been specifically studied in children. Penfield and Jasper (1954) reported ‘stereotypic behaviour’ after stimulation of the cingular gyrus. It consisted of an integrated behaviour of the upper limbs of which the patient was conscious and which he could reproduce voluntarily. In a paper entitled ‘Automatisms during frontal lobe epileptic seizures’ Geier et al. (1976) reported three patients with deep EEG recordings with automatisms of mimicry, fear, laughter or crying and complex movements. Examples are tapping a piece of bread with fork, sticking fork rythmically into the bread, rubbing, clutching and arrangement of clothes, and hitting out with right hand. They described the nature of the movement as ‘eupractic behaviour’, ‘forced nature’ of movement, ‘semipurposeful’, ‘pseudointentional’, and ‘adapted to environment’ (to concrete objects but not to humans). Deviation of head and eyes either before or after the automatisms was often seen. Bancaud and Talairach (1992) stated that they observed ‘complex gestural behaviour’ as seizure manifestations arising from the frontopolar area and ‘simple gestures’ from the medial intermediate frontal area, but they did not give further details. In one study, Riggio and Harner (1995) noted that the motor activity occurred in the preferred visual field (‘attracted’), i.e. on the side where the patient actually directed his attention when the seizure occurred. These complex movements with apparent intentionality are probably dependent on the inner emotional or cognitive state of the person at seizure onset and on the environmental situation. The movements involved in the ‘automatisms’ can be a continuation of the person’s activity at that time. Fenwick (1992) noted that ‘because seizure discharges activate structures that are already involved in ongoing behaviour, the latter phases of the automatisms contain certain activity that is relevant to the patient. Thus, patients who have complex seizures on the pavement seldom walk into the street’. Epileptic ‘automatisms’ of frontal origin can be differentiated from those of temporal origin. The motor automatisms are shorter in duration and better adapted than the motor activity seen in partial temporal lobe seizures and recollection is sometimes pos-

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sible. The automatisms of mimicry, fear, laughter or crying are not as intense and constant as in temporal seizures, there is a slow sequence of ‘eupractic’ movement of ‘forced nature’. Do these stereotypies result from the direct effect of cortical epileptic discharges or from the release of control of lower motor programs induced by the discharges? In the chapter entitled ‘Neurobiological substrates of ictal behavioural changes’ Gloor (1991) gives a remarkable description of the possible mechanisms of epileptic automatisms: When, in the course of a seizure, complex behavioural manifestations such as experiential phenomena or automatic behavior appear which on first impression seem to indicate that some brain mechanism has become activated by the ictal discharge, it is assumed that these manifestations nevertheless must reflect negative effects of that discharge. It may be argued that their apparently positive nature can be attributed to a release phenomenon which becomes manifest, because a mechanism which normally restrains these behavioural mechanisms has become inactivated by the seizure discharge . . .’

In very young children one can anticipate that the characteristics of epileptic ‘stereotypies’ or ‘automatisms’ will be different from those in adults with a later acquired epilepsy in the same locations (frontal? cingular? mesial–frontal?). The level of motor experience and repertoire of a young child will probably also determine the nature and complexity of the automatisms. Importantly, epileptic stereotypies can be the first or the only visible part of a seizure disorder which can be at the origin or contribute to some unexplained developmental retardation–regression after the early infancy period (1 to 3 years mainly). Their onset may coincide with a developmental regression probably because they originate or spread to cortical areas important for cognition and behaviour and at a time when possibly no other recognized epileptic manifestations have yet occurred. The possible striking improvement (clinical and EEG) with antiepileptic therapy is sometimes the best clue as to the epileptic origin of these phenomena. Epileptic stereotypies in young children are particularly difficult to diagnose; they are not what most people imagine epileptic seizures to be, specially when the movement appears intentional or can be interpreted as such. In young children, with retarded development or autistic behaviour, like the children of this study, the stereotypies, which were very disturbing to parents, were interpreted mainly as a sign of mental disturbance or misbehaviour. In case 8 (AS) they were initially not recognized because during the initial videoEEG recordings, only typical partial seizures notified by the parents were reviewed. Mesial frontal and orbitofrontal paroxysms do not always appear over scalp electrodes because of their deep location. Prefrontal paroxysms must be searched over electrooculogram electrodes.

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The awareness of these unusual epileptic manifestations and the increasing use of video–EEG recording and at times invasive recordings will probably bring further useful data. When surgery is considered, intracranial EEG monitoring associated with seizure detection equipment can provide unique data to document a probably under-recognized epileptic phenomenology in children.

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Bancaud, J. & Talairach, J. (1992). Clinical semiology of frontal lobe seizures. In Advances in Neurology, vol. 57 pp. 3–33 New York: Raven Press Ltd. Bednarek, N., Motte, J., Soufflet, C., Plouin, P. & Dulac, O. (1998). Evidence for late infantile spasms. Epilepsia, 39, 55. Deonna, T., Ziegler, A.L., Maeder, M.I., Ansermet, F. & Roulet, E. (1995). Reversible behavioural autistic-like regression: a manifestation of a special (new?) epileptic syndrome in a 28-monthold child. A 2-year longitudinal study. Neurocase, 1, 91–9. Deonna, T. (1999). Developmental consequences of epilepsies in infancy. In Childhood Epilepsies and Brain Development, ed. A. Nehling, J. Motte, S.L. Moshé & P. Plouin, pp. 113–22. Paris: John Libbey & Co. Fenwick, P.B.C. (1992). The relationship between mind, brain and seizures. Epilepsia, 33 (Suppl. 6). S1–S6. Gedye, A. (1991). Frontal lobe seizures in autism. Medical Hypotheses, 34, 174–82. Geier, S., Bancaud, J. Talairach, J. Bonis, A. Enjelvin, M. & Hossard-Bouchaud, H. (1976). Automatisms during frontal lobe epileptic seizures. Brain, 99, 447–58. Gloor, P. (1991). Neurobiological substrates of ictal behavioral changes. In Advances in Neurology, ed. D. Smith, D. Treiman & M. Trimble, vol. 55, pp. 1–34. New York: Raven Press Ltd. Jeannerod, M. (1983). Le Cerveau-Machine. Physiologie de la Volonté. Paris: Fayard Ed. Mason, G.J. (1991). Stereotypies: a critical review. Animal Behavior, 41, 1015–37. Penfield, W. & Jasper, H. (1954). Epilepsy and the Functional Anatomy of the Human Brain, pp. 515–20. Boston: Little Brown and Co. Ridley, R.M. (1994). The psychology of pervasive and stereotyped behaviors. Progress in Neurobiology, 14, 221–31. Riggio, S. & Harner, R.N. (1995). Repetitive motor activity in frontal lobe epilepsy. In Epilepsy and the Functional Anatomy of the Frontal Lobe, ed. H.H. Jasper, S. Riggio & P.S. GoldmanRakic, pp. 153–66. NewYork: Raven Press Ltd. Taylor, D.C. & Falconer, M.A. (1971). Focal dysplasia of the cerebral cortex in epilepsy. Journal of Neurology, Neurosurgery and Psychiatry, 34, 369–87. Tan, A. Salgado, M. & Fahn, S. (1997). The characterization and outcome of stereotypic movements in nonautistic children. Movement Disorders, 12, 47–52. Tröster, H. (1994). Prevalence and functions of stereotyped behaviors in nonhandicapped children in residential care. Journal of Abnormal Child Psychology, 22, 79–97.

20

Non-epileptic paroxysmal eye movements Emilio Fernández-Alvarez Servicio de Neuropediatria, Hospital de San Juan de Dios, Esplugues Barcelona, Spain

Introduction Paroxysmal eye movements are most frequently observed in epileptic seizures. A tonic ocular deviation may be the first sign of an epileptic seizure, but usually the eye movements are associated or followed by other extraocular movements and alteration of consciousness. However, non-epileptic paroxysmal eye movements can be observed in several other neurological disorders of childhood (Table 20.1) and this chapter will deal with some of them. Ocular tics Tics are the abnormal movement most frequently observed in children. Their frequency and their association with fascinating disturbances of human behaviour such as compulsion and obsessions, grants them a prominent place amongst paroxysmal movement disorders in children. Tics are repetitive movements of skeletal (motor tics) or respiratory/nasopharyngo-laryngeal muscles (phonatory tics). They are considered as stereotyped, involuntary, sudden, inopportune, non-propositional, absurd, irresistible movements, of variable intensity. The term tic designates both a symptom and a disease. As a symptom it has a wide variety of clinical manifestations. Tic diseases are even more polymorphous. They may be limited to simple, transient tics present for less than a year, or as in Tourette disease, patients may present with several types of chronic motor and phonatory tics, which are often associated with compulsive–obsessive disorder, attention deficit, non-appropriate behaviour or sleep disturbances. Although tics per se are generally easy to identify even for the lay person, they may sometimes be difficult to distinguish from other abnormal movements. Simple tics should be differentiated from myoclonus and complex tics from choreic Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Table 20.1. Disorders with non-epileptic paroxysmal eye movements in children

Aromatic -amino acid decarboxylase deficiency Benign paroxysmal tonic upgaze of childhood Encephalitis Neuronal intranuclear inclusions disease Opsoclonus–myoclonus syndrome Paroxysmal downgaze Tics Tyrosine hydroxylase deficiency

movements, dystonia and stereotypies. The capability of patients to temporally control their tics is a useful diagnostic feature. Abnormal eye ball movements usually consist of brief, rapid, conjugating upward and/or side-to-side ocular movements, sometimes presenting as eye rolling. They can be associated with head movements. Although considered an uncommon tic, eye-rolling, forced staring or ocular deviations were found in 19 cases out of 29 Tourette syndrome patients (Frankel & Cummings, 1984). In my series of 280 children in whom it was possible to determine which was the first tic noticed as such by the parents, 19 patients (6%) recognized eyeball tics as the onset symptom. Moreover, 38 other cases had ocular tics as one of their various motor tics, through the natural curse of their disease. Therefore, 20% of these patients had ocular tics at the onset or in the course of their disease. In a case reported by Binyon and Prendergast (1991), rapid, brief, conjugate upward and lateral eye movements was the only tic for years. An ocular tic per se can be difficult to differentiate from other abnormal movements such as opsoclonus and even from non-propositive movements that are part of the behavioural repertoire of every individual. The diagnosis becomes easy after a child has presented different tics with fluctuating intensity for a period of time, or if he/she explains their compulsive character. It may be a greater diagnostic challenge if a single tic is the first manifestation of the disease. To reach a correct diagnosis, it is necessary to obtain a comprehensive view of the evolution of the process and of the psychic context. Reinterpretation of phenomena that had appeared normal (e.g. throat clearing mistaken for a cough), may help to make the diagnosis, as well as searching for other tic disorders, obsessive disorders in the family and the presence of obsessive-compulsive features or ADHD in the patient himself. The description of a ‘premonitory urge’ to perform the movement is another useful

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diagnostic tool. We found that the ability of children to reproduce the tic a useful clue in that it is not found in any other movement disorder. In summary, tics of the eyeballs are generally associated with other tics, but may occur as an isolated feature and bear a resemblance to nystagmus or opsoclonus. When isolated, they should not be mistaken for epileptic seizures with an oculogyric expression. The ability to reproduce the movement, preserved consciousness and a normal EEG differentiate these types of tics from epileptic phenomena. Paroxysmal tonic upgaze deviation of infants (PTUD) The essential manifestations of this complex disorder include prolonged episodes of sustained or intermittent upward gaze deviation with down-beating nystagmus on attempts to look downward and preserved horizontal eye movements. The episodes last hours but rarely days (Deonna et al., 1990; Gieron & Korthals, 1993). They frequently worsen with fatigue or infections and disappear or are reduced by sleep. A single patient with more severe symptoms following sleep has, however, been reported (Apak & Topçu, 1999). The episodes spontaneously remit in 1 month to 6 years, but in a single case they lasted only 2 days (Hayman et al., 1998). PTUD was first reported in 1988 by Ouvrier and Billson. More than 30 cases (Ahn et al., 1989; Deonna et al., 1990; Echenne & Rivier, 1992; Gieron & Korthals, 1993; Campistol et al., 1993; Sugie et al., 1995; Ruggieri et al., 1998; Guerrini et al., 1998; Spalice et al., 2000) including a large series (Hayman et al., 1998) have been reported. Initially considered as a benign, transient disorder, it has sometimes proved to be associated with severe, permanent neurological sequelae on long-term follow-up. The onset is in the first months of life (usually within 10 months) (see Fig. 20.1). Some patients (Ouvrier & Billson, 1988; Deonna et al., 1990), may in addition present with ataxia that persists during the episodes (Echenne & Rivier, 1992; Campistol et al., 1993; Apak & Topçu, 1999). Recurrence in a modified form has been reported (Hayman et al., 1998). In up to 60–70% of children, developmental or language delays have been reported (Hayman et al., 1998). Both autosomal dominant (Campistol et al., 1993; Guerrini et al., 1998) and recessive inheritance (Hayman et al., 1998) has been suggested. Some children can present with tonic upgaze without additional neurological deficits for a few months after birth (Mets, 1990). Laboratory tests, neurophysiological and neuroimaging studies are normal. Only one child (Sugie et al., 1995), has been reported with possible periventricular leukomalacia on MRI in spite of a normal perinatal history. In two out of the 16 cases (Hayman et al., 1998), MRI was possibly suggestive of mild delay in myelination which, however, was not confirmed in subsequent examinations. Neuropathological study of one patient was normal (Ouvrier & Billson, 1988).

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5

Cases

4 3 2

32

26

20

14

9

11

NB

7

3

0

5

1

Months Fig. 20.1

Age of onset of 32 reported cases of paroxysmal tonic upgaze deviation of infants (Campistol et al., 1993; Deonna et al., 1990; Echenne & Rivier, 1992; Guerrini et al., 1998; Hayman et al., 1998; Ouvrier & Billson, 1988; Ruggieri et al., 1998; Spalice et al., 2000).

In a few cases, -dopa treatment (150 mg/day) (Ouvrier & Billson, 1988, Campistol et al., 1993), resulted in the disappearance of episodes (within 15 days and 3 months, respectively, in the two patients reported by Campistol et al., 1993) but it was ineffective in others (Ruggieri et al., 1998; Hayman et al., 1998). Because of the frequently associated neurological signs and the variable outcome, PTUD could be an age-related heterogeneous disorder. This hypothesis is supported by reports of symptomatic cases (vein of Galen malformation (Hayman et al., 1998), pinealoma of the mesencephalic region (Spalice et al., 2000). Tonic epileptic seizures, mesencephalic tumours and opsoclonus–myoclonus syndrome can be easily ruled out, based on clinical history, normality of EEG and neuroimaging studies. PUTD shares some clinical features with alternating hemiplegia of childhood, in particular worsening of symptoms with fatigue and relief with sleep. However, the core of the clinical syndrome is different. Pathophysiology of PUTD is unknown. However, considering the frequent presence of tonic upgaze in patients with lesions in the mesencephalic region, it seems likely that PUTD results from an age-related dysfunction, mainly affecting the supranuclear pathways that control vertical eye movements. Benefit of sleep and normality in pathological and neuroimaging exams are in favour of this hypothesis. It remains difficult, however, to explain the paroxysmal nature of the disorder.

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A transient failure of cortical compensation provoked by fatigue or intercurrent infection has been suggested (Hayman et al., 1998), but neurotransmission and/or ion channel function are the most likely impaired mechanisms. Paroxysmal downgaze A few infants have been reported in whom paroxysmal self-limited downgaze (‘setting sun sign’) was the only neurological abnormality (Cernerud, 1945; Biglan, 1984). The eyes return to primary gaze shortly after assuming the downward position. Oculocephalic response is normal. These movements can be provoked by raising and lowering the infant’s head in the vertical plane. Associated downward nystagmus has been occasionally reported (Biglan, 1984). Usually, the sign is observed shortly after birth and resolves before the age of 6 months (Miller & Packard, 1998). Development and neuroimaging studies are normal. This phenomenon is quite common in newborn babies. It was observed in 5 out of 242 prospectively examined healthy newborns (Hoyt et al., 1980) and it was also reported in preterm infants (Kleiman et al., 1994). Paroxysmal downgaze has been reported in infants with spastic quadriplegia or diplegia and mental retardation (Yokochi, 1991), but in these patients it persisted beyond the first 6 months of life. Opsoclonus-myoclonus syndrome (OMS) The syndrome was identified by Sandifer and reported by Kinsbourne (1962) as ‘myoclonic encephalopathy of infants’. Kinsbourne described six cases with onset between 9 and 20 months of age of uncoordinated, irregular movements of the trunk and limbs, myoclonus and chaotic ocular movements. Four of these patients were improved by ACTH treatment. Some similar cases, usually attributed to encephalitis or poliomyelitis infection, had previously been reported (Walsh, 1947; Keller & Karelitz, 1948; Cogan, 1954; Cottom, 1957; Kaplan et al., 1959; Arthuis et al., 1960; Kennedy & Tucket, 1962). Attention to the frequent association between OMS and neural tumours was mainly drawn by two independent reports by Solomon and Chutorian and by Dyken and Kolar (1968), although isolated observations (Cushing & Wolbach, 1927; Kligman & Hodges, 1944) and subsequent reports have amply confirmed this association. OMS is a disorder of infants and young children. The average age at onset is 17–19 months (Fernández-Alvarez et al., 1978; Bolthauser et al., 1979; Hammer et al., 1995) ranging between 4 months and 6 years. Ocular dyskinesia allied with irritability, tremor and, incoordination constitute

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the four main symptoms of OMS. Initial symptoms usually appear within 1 or 2 weeks after a viral infection or immunization and the clinical picture is completed in a few more days. A change in behaviour (irritability, aggressivity) without decrease of the level of consciousness and some instability, are rapidly followed by severe incoordination and generalized tremor. The infants are unable to stand or sit without help. Walking with support is disorganized, with excessive flinging of the legs. Simultaneously or a few days later, ocular dyskinesia becomes obvious. The most characteristic ocular abnormalities in OMS consist of chaotic, rapid, irregular bursts of movements occurring generally in the horizontal plane but ‘sudden jerks’ may ‘occur in other directions’ (Orzechowski, 1927, quoted by Smith & Walsh, 1960). Opsoclonus is often intermittent and may be associated with fast palpebral movements reminiscent of the wing motion of insects. Opsoclonus is an important sign of opsoclonus–myoclonus syndrome. Other abnormal ocular movements may include vertical or horizontal lightning eye movements (Atkin & Bender, 1964). These are sometimes the only ocular abnormalities. Although eye movements appear to be conjugate, electrophysiologic analysis has shown that they are not (Vignaendra & Lim, 1977). The eye movements persist during sleep and may be perceived under closed eyelids. Treatment with ACTH (10–40 UI/d) usually produces a quick disappearance of the clinical manifestations. Prednisone is also used but may be less effective than ACTH (Hammer et al., 1995). Duration and the minimum effective dose of maintenance treatment should be adjusted to the individual patient’s response. Treatment usually needs to be prolonged for months or even years (Christoff, 1969; Papini et al., 1992; Fernández-Alvarez, 1989). Increased doses may be necessary at the time of intercurrent infections. The necessity of continuing treatment has to be determined by periodically trying to decrease and eventually discontinue drugs. Relapses occur, even after months or years, and necessitate resumption of treatment. Without treatment the disorder persists and leads to severe motor and cognitive handicap (Despres et al., 1968; Christoff, 1969; Chiba et al., 1970; Martinez-Lage et al., 1976). Even with treatment OMS has a propensity for relapsing very often in relation with viral infections. Non-relapsing forms have been reported in association with immunization (Tuchman et al., 1989), or viral infections such as Coxsackie B3 virus (isolated in CSF, feces or serologically demonstrated), mumps (Ichiba et al., 1988), togavirus (Estrin, 1977; Baringer et al., 1968; Kuban et al., 1983; Herve et al., 1988), Epstein–Barr virus (Sheth et al., 1995) and poliomyelitis (Arthuis et al., 1960). In such cases onset is usually after 3 years of age. Except the possible presence of neuroblastoma, the ancillary investigations are usually normal.

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Neuroblastoma must be carefully searched for in patients with opsoclonus, as detection of the tumour can be difficult. Catecholamine determination in urine is of limited value as it is within normal limits in 40% of patients (Senelick et al., 1973). Standard radiological studies can be negative (Koh et al., 1994), but CT or MRI scans usually detect neuroblastoma in more than 90% of cases (Telander et al., 1989; Mitchell & Snodgrass, 1990; Koh et al., 1994). Scintigraphic visualization of neuroblastoma is possible, using MIBG (metaiodobenzylguanidine), a radioisotopic, structural analogue of noradrenaline, selectively uptaken and stored by tumours derived from the neural crest and has proved very useful (Kimming et al., 1984, Gelfand et al., 1993; Parisi et al., 1993). Octreotide (a long acting analogue of somastostatin) seems to be even more sensitive in localizing the neuroblastoma, and yields images of better quality (Posada & Tardo 1998). Several clinical variants of OMS can occur. In some cases incomplete manifestations may be present for up to several months before the fully fledged syndrome (Moe & Nellhaus, 1970; Roberts & Freeman, 1975; Fernández-Alvarez, 1989). Three-quarters of patients with the classical form (or presenting with neuroblastoma) have long term sequelae such as mental retardation, learning difficulties, delayed language development, persistent ataxia or marked clumsiness (Marshall et al., 1978; Koh et al., 1994). Improvement over time of cognitive abilities and of social–adaptive skills is common (Papero et al., 1995).

R E F E R E N C ES

Ahn, J.C., Hoyt, W.F. & Hoyt, C.S. (1989). Tonic upgaze in infancy. Archives of Ophthalmology, 107, 57–8. Apak, R.A. & Topçu, M. (1999). A case of paroxysmal tonic upgaze of childhood with ataxia. European Journal of Paediatric Neurology, 3, 129–31. Arthuis, M., Lyon, G. & Thieffry, S. (1960). La forme ataxique de la maladie de Heine-Medin. Revue Neurologie, 103, 329–40. Atkin, A. & Bender, M.B. (1964). Lighting eye movements (ocular myoclonus). Journal of Neurological Science, 1, 2–12. Baringer, J.R., Sweeney, V.P. & Winkler, G.F. (1968). An acute syndrome of ocular oscillations and truncal myoclonus. Brain, 91, 473–80. Biglan, A.W. (1984). Setting sun sign in infants. American Orthoptic Journal, 34, 114–16. Binyon, S. & Prendergast, M. (1991). Eye-movement tics in children. Developmental Medicine and Child Neurology, 33, 352–5. Boltshauser, E., Deonna, Th. & Hirt, H.R. (1979). Myoclonic encephalopathy of infants or ‘dancing eyes syndrome’. Report of 7 cases with long-term follow-up and review of the literature. Helvetica Paediatrica Acta, 34, 119–33.

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E. Fernandez-Alvarez Campistol, J., Prats, J.M. & Garaizar, C (1993). Benign paroxysmal tonic upgaze of childhood with ataxia. A neuroophtalmological syndrome of familial origin? Developmental Medicine and Child Neurology, 35, 436–9. Cernerud, L. (1945). The setting sun sign eye phenomenon in infancy. Developmental Medicine and Child Neurology, 17, 447–55. Chiba, S., Motoya, H., Shinoda, M. & Nakao, T. (1970). Myoclonic encephalopathy of infants: a report of two cases of ‘dancing eyes’ syndrome. Developmental Medicine and Child Neurology, 12, 767–71. Christoff, N. (1969). Myoclonic encephalopathy of infants. A report of two cases and observations on related disorders. Archives of Neurology, 21, 229–34. Cogan, D.G. (1954). Ocular dysmetria, flutter-like oscillations of the eyes and opsoclonus. Archives of Ophthalmology, 51, 318–35. Cottom, D.G. (1957). Acute cerebellar ataxia. Archives of Diseases of Childhood, 32, 181–8. Cushing, H. & Wolbach, S.B. (1927). The transformation of a malignant paravertebral sympathicoblastoma into a benign ganglioneuroma. American Journal of Pathology, 3, 203–15. Deonna, T.H., Roulet, E. & Meyer, H.U. (1990). Benign paroxysmal tonic upgaze of childhood. A new syndrome. Neuropediatrics, 21, 213–14. Despres, P., Herouin, C. & Seringe, Ph. (1968). Encephalopathie myoclonique avec opsoclonies. A propos de deux observations Annales de Pediatrics, 44, 185. Dyken, P. & Kolar, O. (1968). Dancing eyes, dancing feet: infantile polymyoclonia. Brain, 91, 305–20. Echenne, B. & Rivier, F. (1992). Benign paroxysmal tonic upward gaze. Pediatric Neurology, 8, 154–5. Estrin, W.J. (1977). The serological diagnosis of St Louis encephalitis in a patient with the syndrome of opsoclonus, body tremulousness and benign encephalitis. Annals of Neurology, 1, 596–8. Fernández-Alvarez, E (1989). Encefalopatía mioclónica del lactante (Síndrome de Kinsbourne) International Pediatrics, 4 (Suppl. 2), 44–6. Fernández-Alvarez, E., Camino, A., Pineda, M. & Bidegain, I. (1978). Enfermedad de Kinsbourne. Estudio de cuatro casos. An Esp Pediatria, 11, 461. Frankel, M. & Cummings, J.L. (1984). Neuro-ophthalmic abnormalities in Tourette’s syndrome: functional and anatomic implications. Neurology, 34, 359–61. Gelfand, M.J. (1993). Metaiodobenzylguanidine in children. Seminars in Nuclear Medicine, 23, 231–42. Gieron, M.A. & Korthals, J.K. (1993). Benign paroxysmal tonic upward gaze. Pediatric Neurology, 9, 159. Guerrini, R., Belmante, A. & Carrozzo, R. (1998). Paroxysmal tonic upgaze of childhood with ataxia: a benign transient dystonia with autosomal dominant inheritance. Brain and Development, 20, 116–18. Hammer, M.S., Larsen, M.B. & Stack, C.V. (1995). Outcome of children with opsoclonusmyoclonus regardless of etiology. Pediatric Neurology, 13, 21–4. Hayman, M., Harvey, A.S., Hopkins, I.J. et al. (1998). Paroxysmal tonic upgaze: a reappraisal of outcome. Annals of Neurology, 43, 514–20.

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Non-epileptic paroxysmal eye movements Herve, F., Soulier, J. & Berger, J.P. (1988). Syndrome opso-myoclonique et Coxackie B3. Archiv Français Pediatric, 45, 597–9. Hoyt, C.S., Mousel, D.K. & Weber, A.A. (1980). Transient supranuclear disturbances of gaze in healthy neonates. American Journal of Ophthalmology, 89, 708–13. Ichiba, N., Miyake, Y., Sato, K. et al. (1988). Mumps-induced opsoclonus-myoclonus and ataxia. Pediatric Neurology, 4, 224–7. Kaplan, M., Salet, J., Pean, G. et al. (1959). Sur une variete d’ ataxie cerebelleuse acquise de l’enfance avec tremblement ocullaire. Archiv Français Pediatric, 16, 1124–9. Keller, M.J. & Karelitz, S. (1948). Acute ataxia in a twenty-month-old female. Pediatrics, 1, 754–7. Kennedy, C. & Tucket, S.A. (1962). Ocular myoclonus: a clinical and pathological study. Neurology, 12, 297–8. Kimming, B., Brandeis, W.E., Eisenhut, M. et al. (1984). Scintigraphy of a neuroblastoma with 131-I-Metaiodobenzylguanidine. Journal of Nuclear Medicine, 25, 773–5. Kinsbourne, M. (1962). Myoclonic encephalopathy of infants. Journal of Neurology, Neurosurgery and Psychiatry, 25, 271–6. Kleiman, Md., DiMario, F.J., Leconche, D.A. & Zalneraitis, E.I. (1994). Benign transient downward gaze in preterm infants. Pediatric Neurology, 10, 313–16. Kligman, W.O. & Hodges, R.G. (1944). Acute ataxia of unknown origin in children. Journal of Pediatrics, 24, 536–43. Koh, Ps., Raffensperger, J.G., Berry, S. et al. (1994). Long-term outcome in children with opsoclonus-myoclonus and ataxia and coincident neuroblastoma. Journal of Pediatrics, 125, 712–16. Kuban, K.C., Ephros, M.A., Freeman, R.L. et al. (1983). Syndrome of Opsoclonus–Myoclonus caused by Coxsackie B3 infection. Annals of Neurology, 13, 69–71. Marshall, P.C., Brett, E.M. & Wilson, J. (1978). Myoclonic encephalopathy of childhood (the dancing eye syndrome): a long term follow-up study. Neurology, 28, 348. Martinez-Lage, M., Delgado, B.G., Delgado, R.A. et al. (1976). Encefalopatía mioclónica infantil con opsoclonus (S. de Kinsbourne) aparentemente primitiva. A proposito de tres observaciones. Revue Espanol Pediatrics, 32, 365–76. Mets, M. (1990). Tonic upgaze in infancy. Archives of Ophthalmology, 108, 482–3. Miller, V.S. & Packard, A.M. (1998). Paroxysmal downgaze in term newborn infants. Journal of Child Neurology, 13, 294–5. Mitchell, W.G. & Snodgrass, S.R. (1990). Opsoclonus–ataxia due to childhood neural crest tumours: a chronic neurologic syndrome. Journal of Child Neurology, 5, 153–8. Moe, P.G. & Nellhaus, G. (1970). Infantile polymyoclonia-opsoclonus syndrome and neural crest tumours. Neurology, 20, 756–64. Orzechowski, K. (1927). De l’ataxie dysmétrique des yeux: remarques sur l’ataxie des yeux dite myoclonique (opsoclonie, opsochorie). Journal of Psychological Neurology, 35, 1–18. Ouvrier, R.A. & Billson, F. (1988). Benign paroxysmal tonic upgaze of childhood. Journal of Child Neurology, 3, 177–80. Papini, M., Pasquinelli, A. & Filippini, A. (1992). Steroid-dependent form of Kinsbourne syndrome: successful treatment with trazodone. Journal of Neurological Science, 13, 369–72. Papero, Ph., Pranzatelli, Mr., Margolis, L.J. et al. (1995). Neurobehavioral and psychosocial func-

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E. Fernandez-Alvarez tioning of children with opsoclonus–myoclonus syndrome. Developmental Medicine and Child Neurology, 37, 915–32. Parisi, M., Hattner, R.S., Matthay, K.K. et al. (1993). Optimized diagnostic strategy for neuroblastoma in opsoclonus–myoclonus. Journal of Nuclear Medicine, 34, 1922–6. Posada, J.C. & Tardo, C. (1998). Neuroblastoma detected by somatostatin receptor scintigraphy in a case of opsoclonus–myoclonus syndrome. Journal of Child Neurology, 13, 345–6. Roberts, K.B. & Freeman, J.M. (1975). Cerebellar ataxia and ‘ocult neuroblastoma’ without opsoclonus. Pediatrics, 56, 464–5. Ruggieri, V.I., Yepez, L.I. & Fejerman, N. (1998). Síndrome de desviación paroxística benigna de la mirada hacia arriba. Revue Neurologie (Barcelona), 27, 88–91. Senelick, R.C., Bray, P.F., Lahey, M.E. et al. (1973). Neuroblastoma and myoclonic encephalopathy: two cases and a review of the literature. Journal of Pediatric Surgery, 8, 623–31. Sheth, R.D., Horwitz, S.J., Aronoff, S. et al. (1995). Opsoclonus myoclonus syndrome secondary to Epstein-Barr virus infection. Journal of Child Neurology, 10, 297–9. Smith, J.L. & Walsh, F.B. (1960). Opsoclonus–Ataxic conjugate movements of the eyes. Archives of Ophthalmology, 64, 108–14. Solomon, G.E. & Chutorian, A.M. (1968). Opsoclonus and occult neuroblastoma. New England Journal of Medicine, 279, 475–7. Spalice, A., Parisi, P. & Ianetti, P. (2000). Paroxysmal tonic upgaze: physiopathological considerations in three additional cases. Journal of Child Neurology, 15, 15–18. Sugie, H., Sugie, Y., Ito, M. et al. (1995). A case of paroxysmal tonic upward gaze associated with psychomotor retardation. Developmental Medicine and Child Neurology, 37, 362–9. Telander, R.L., Smithson, W.A. & Groover, R.V. (1989). Clinical outcome in children with acute cerebellar encephalopathy and neuroblastoma. Journal of Pediatric Surgery, 24, 11–14. Tuchman, R.F., Alvarez, L.A., Kantrowitz, A.B. et al. (1989). Opsoclonus–myoclonus syndrome: correlation of radiographic and pathological observations. Neuroradiology, 31, 250–2. Vignaendra, V. & Lim, C.L. (1977). Electro-oculographic analysis of opsoclonus: its relationship to saccadic and nonsaccadic eye movement. Neurology, 27, 1129–33. Walsh, F.B. (1947). Clinical Neuro-ophthalmology, 1st edn., pp. 310–12. Baltimore: Williams & Wilkins. Yokochi, K. (1991). Paroxysmal ocular downward deviation in neurologically impaired infants. Pediatric Neurology, 7, 426–8.

21

Shuddering and benign myoclonus of early infancy Christa Pachatz, Lucia Fusco and Federico Vigevano Section of Neurophysiology, Bambino Gesù Children’s Hospital, Rome, Italy

Introduction Benign myoclonus of early infancy is a paroxysmal phenomenon in neurologically healthy infants with onset in the first year of life and a benign self-limited course. It was first described by Lombroso and Fejerman (1977) with the presentation of 16 cases based mainly on anamnestic features. The first polygraphic study on BM was reported by Dravet et al. (1986), who decided to call the phenomenon benign non-epileptic infantile spasms because of the close relationship with the clinical picture of epileptic spasms of West syndrome. We illustrated the clinical and neurophysiological study of 5 patients with BM (Pachatz et al., 1999) and showed that the so-called myoclonus is not a myoclonus in neurophysiological terms, and that it is also clearly distinguishable from epileptic spasms at electromyography and even from a clinical point of view. Since that report, we obtained additional clinical and neurophysiological data in another three children, confirming that BM in its most typical form is characterized by a brief shudder-type axial motor manifestation, which can superimpose a series of other paroxysmal motor phenomena. Clinical and video-polygraphic findings from a recent series Between the years 1994 and 1999 we studied eight children, three girls and five boys, at the Division of Neurology, Bambino Gesú Children’s Hospital, Rome, Italy, using video-EEG recording in all eight patients and polygraphic recording in four of eight cases. Scalp electrodes were placed according to the International 10–20 System. Polygraphic recordings included surface electromyographic (EMG) recording from the two deltoid muscles, channels for respirogram and electrocardiogram. In all patients we studied, family or personal history was negative for neurological pathologies. All children showed normal psychomotor development, as well as a normal neurological–physical examination. Age at onset was 7 to 11 months. The Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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paroxysmal motor manifestations persisted 1 to 13 months and occurred mostly with gradually increasing frequency at the beginning, and spontaneous decrease after a variable duration of daily events. The occurrence of daily episodes in a clustered pattern was the typical finding in all children. The motor manifestations occurred only in wakefulness and were constantly related to excitement or agitation in five cases, to situations of frustration such as anger or irritation in two. Just one child did not show any evident trigger mechanism. When excitement persisted, a cluster of motor paroxysms could be maintained with minimal intervals of a few seconds between the single attacks. Based on anamnestic information, the phenomena were never evident during sleep and two patients showed manifestations prevalently upon awakening. Age at disappearance was 9 to 23 months; only isolated episodes were observed beyond the first year of life. Follow-up continued until ages 16 months to 5 years 7 months, with a mean duration of 2 years 4 months. Follow-up consisted mostly of anamnestic information obtained from parents. Further neurological examinations or EEGs after diagnosis were not considered essential (See Table 21.1). Our video and polygraphic recordings showed that semiological features could vary widely and the intensity of the phenomenon could range from single, barely noticeable episodes to a series of variable motor paroxysms even in a single situation (Table 21.2). Five of eight patients presented with brief tonic contractions of the upper limbs, with lower limb involvement in three. Electromyographic traces, performed in four of these five patients, evidenced brief, moderate hypertonia of the upper limbs (deltoids) lasting 0.5 to 3 seconds, often followed or preceded by a series of voluntary rhythmic or arrhythmic contractions. Video recordings showed tonic limb contractions varying in intensity from hardly noticeable to more sustained, mostly expressed by jerky abductions of the arms and brusque elevations of the shoulders, in one patient accompanied at times by closure of the fists. A characteristic motor manifestation consisted of a brief axial shudder, present in five children, involving mainly the trunk and sometimes the head and neck, but no segmental or more localized motor areas. The axial shudder could occur as an isolated finding with minimal clinical expression and often only recognized by the attentive mother as typical event. In its most typical form the axial shudder superimposed or accompanied the other clinical motor manifestations. A brief nodding of the head, occurring mostly in a clustered pattern, could be observed in five patients, two of which had no other motor manifestations. The head nodding consisted of a forward or sideward movement. Facial grimacing could be seen in two patients as an accompanying finding. Two patients showed only minimal, hardly noticeable clinical expressions, such as a minimal axial shudder or slight abduction of the arms.

Table 21.1. Course of the disorder

Patient 1, f Patient 2, m Patient 3, m Patient 4, m Patient 5, m Patient 6, f Patient 7,f Patient 8, m

Age at onset

Presence of triggering mechanisms

Clustered pattern

Occurrence mostly upon awakening

Age at disappearance

Duration of the disorder

Age at follow-up

10 mths 17 mths 18 mths 18 mths 11 mths 18 mths 17 mths 19 mths

excitement excitement excitement frustration frustration no excitement excitement

yes yes yes yes yes yes yes yes

no no no no yes yes no no

15 mths 12 mths 21 mths 16 mths 23 mths 19 mths 19 mths 12 mths

15 mths 15 mths 13 mths 18 mths 12 mths 11 mths 12 mths 13 mths

3 yrs 2 mths 20 mths 22 mths 5yrs 7mths 2yrs 19 mths 16 mths 17 mths

Table 21.2. Clinical semiology

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8

Tonic, more sustained contractions of arms

Jerky abductions of arms

Elevation of shoulders

       

       

       

Closure of fists

Involvement of lower limbs

Nodding of the head

Facial grimacing

Axial shudder

Minimal clinical expression

       

       

       

       

       

       

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No patient showed focal signs, such as eye deviations or unilateral limb movements. The EEG counterpart never showed modifications, except of muscle artefacts. Differential diagnosis The diagnosis of benign myoclonus of early infancy is based on the following criteria: (i) onset of paroxysmal motor manifestations within the first year of life, with a peak between 7 and 11 months; (ii) a self-limited course and variable duration with disappearance of the motor phenomena before the age of 2 years; (iii) normal psychomotor development; (iv) no concomitance of epileptic seizures; (v) consistently normal EEG recordings during wakefulness and sleep and no pathologic EEG modifications during recordings of the paroxystic phenomena; (vi) occurrence during wakefulness prevalently in relation to emotional stimuli. The clinical course cannot be modified by antiepileptic drug treatment (Lombroso & Fejerman, 1977). The motor phenomena are characterized by a series of paroxysms on a basis of tonic limb contractions or flexions of the head, varying in intensity from hardly recognizable to more sustained, at times expressed by initial jerky myoclonic-like limb movements. As shown by EMG traces (Pachatz et al., 1999), the term myoclonus is not correct from a neurophysiological point of view, as the tonic limb contractions last longer than 200 ms, which is the neurophysiological definition of myoclonus. Affected children never show focalizing signs such as consistently unilateral limb movements or eye-deviations. In our series, the paroxysmal motor phenomenon was represented in its most typical form by a shudder-type motor manifestation characterized by an irregular, arrhythmic brief shivering movement, involving mainly the trunk and sometimes the neck and head, but never focal or segmental muscle areas. This axial shudder could at times appear as an isolated finding, but it typically superimposed the tonic limb movements. Shuddering attacks or shuddering spells described by other authors as a benign movement disorder (Holmes & Russman, 1986) and probable early manifestation of essential tremor (Vanasse et al., 1976) seem to differ from shudder-type manifestations within the clinical entity of BM, as they are strongly associated to posturing and usually appear in isolation, persist in the first decade of life and occur in children with highly positive family history for essential tremor. The most important differential diagnosis should be with respect to epileptic infantile spasms of West syndrome, which differ from BM of early infancy in the characteristic EEG pattern and arrest or regression of psychomotor development. Indeed, some motor components of BM, such as head nodding and jerky or sustained tonic contractions of limbs and shoulders especially when occurring in

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clusters, closely resemble the flexor spasms of West syndrome. The latter can also vary considerably in intensity, being limited at times just to brief jerks or slight shrugs of the shoulders (Kellaway et al., 1979). The most important differentiating criteria of epileptic infantile spasms are (i) repetitive nature with stereotyped clinical expression in a single cluster; (ii) the occurrence in clusters including several dozen spasms and (iii) the elective relation of occurrence to awakening, drowsiness or the end of sleep. In contrast, BM never shows a periodic recurrence or stereotypy within a single situation, where various paroxysms can be observed; the occurence of more than a dozen phenomena within a single cluster is the exception and not the rule; there is no close relation to awakening and drowsiness. The EMG traces of BM never show a rhombus, the typical EMG correlate of epileptic spasms (Fusco & Vigevano, 1993). On the basis of clinical features, epileptic infantile spasms can be clearly distinguished from motor phenomena of BM and the term benign non-epileptic infantile spasms suggested by Dravet et al. (1986) to describe BM of early infancy does not reflect the real clinical situation. Another differential diagnosis should be made with respect to non-epileptic reflex tonic seizures, described by Vigevano et al. (1996). This syndrome can be distinguished by (i) earlier age of onset within the first 3 months of life; (ii) occurrence in strict relation to postural stimuli and (iii) greater tonic component of the motor manifestation, which last up to 5 seconds.

R E F E R E N C ES Dravet, C., Giraud, N., Bureau, M., Roger, J., Gobbi, G. & Dalla Bernardina B. (1986). Benign myoclonus of early infancy or benign non-epileptic infantile spasms. Neuropediatrics, 17(1), 33–8. Fusco, L. & Vigevano, F. (1993). Ictal clinical electroencephalographic findings of spasms in West syndrome. Epilepsia, 34(4), 671–8. Holmes, G.L. & Russman, B.S. (1986). Shuddering attacks. Evaluation using electroencephalographic frequency modulation radiotelemetry and videotape monitoring. American Journal of Diseases in Children, 140, 72–3. Kellaway, P., Hrachovy, R.A., Frost, J.D. & Zion, T. (1979). Precise characterization and quantification of infantile spasms. Annals of Neurology, 6, 214–18. Lombroso, C.T. & Fejerman, N. (1977). Benign myoclonus of early infancy. Annals of Neurology, 1(2), 138–43. Pachatz, C., Fusco, L. & Vigevano, F. (1999). Benign myoclonus of early infancy. Epileptic Disorders, 1, 67–7. Vanasse, M., Bedard, P. & Andermann, F. (1976). Shuddering attacks in children: an early clinical manifestation of essential tremor. Neurology, 26, 1027–30. Vigevano, F., Fusco, L., Cusmai, R. et al. (1996). Tonic reflex seizures of early infancy: an undescribed nonepileptic paroxysmal disorder. Epilepsia, 37 (Suppl. 4), 87.

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Shuddering and benign myoclonus of early infancy Table 21.3. B M E I (41 Cases): Localization and types of attack

Types of Contractions

No of Cases

Myoclonic or brief tonic with flexion of the head

13

Myoclonic or brief tonic with rotation of the head

18

Myoclonic or brief tonic with extension of the head

12

Shuddering of head, neck and shoulders

20

Shuddering extended to upper limbs

14

Myoclonic or brief tonic leading to symmetric or asymmetric extension with abduction of upper limbs

14

Shuddering of upper limbs only

13

Appendix Natalio Fejerman and Roberto Caraballo

In 1976 Fejerman presented as benign myoclonus of early infancy (BMEI) ten infants with fits somehow resembling infantile spasms but with clinical, EEG and evolutive features allowing clear differential diagnoses from West Syndrome (Fejerman, 1977; Lombroso & Fejerman, 1977; Fejerman & Medina, 1986). These cases were later included in another report (Lombroso & Fejerman, 1977), and by 1980, eight new personal cases were added (Fejerman 1980, 1984). We have now followed, during 2 to 27 years, a total of 41 patients comprising this series. Twentysix of them were males and 15 were females. The first three cases had been diagnosed as West syndrome even lacking EEG abnormalities (Sorel, 1978) and their correct diagnosis was reached retrospectively. All cases came to our attention because of repeated jerks of the neck or upper limb muscles leading to abrupt flexion or rotation of the head and extension with abduction of limbs. In 20 patients the movements were described as shuddering of head and shoulders, in four it was extended to upper limbs and in three it was only seen in upper limbs. In several cases shuddering attacks alternated with definite myoclonic jerks. In many others, clear myoclonic or brief tonic contractions led to flexion with or without rotation of the head and flexion or extension with abduction of upper limbs. In four cases the only feature was symmetric or asymmetric extension with abduction of upper limbs (Table 21.3). Isolated cases presented with head rotation and extension of one upper limb or with head drops. In one case, upper limb myoclonus was repeated during 30 minutes. In 14 patients jerks repeated in series, but whether in series or isolated, they were seen several times per day in 40 of the cases. Consciousness was not affected during fits, even in a baby who had repeated myoclonus during 30 minutes. In our series, no case was detected during sleep, but a couple of patients with BMEI having jerks while asleep were reported (Dravet et al.,

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1986). We did see that meal times favoured the appearance of attacks in 11 of our patients, but that is not reason enough to include BMEI in a classification of ‘Benign infantile myoclonus with feeding’, as has been proposed (Fahn et al., 1986). The babies had more jerks when they were more alert: while going to eat, playing with parents, or else, but not as a reaction to feeling uneasy or frustrated. Age at onset ranged between 1 and 12 months, but 90% of children were 3 to 9 months old. This indicates a marked coincidence with ages of onset in cryptogenic or idiopathic cases of West syndrome. Neurologic examination was normal in all cases and repeated EEGs, during waking and sleep, showed no abnormalities. Ictal EEGs were of course also normal. Extensive laboratory work-up disclosed no metabolic abnormalities, and imaging studies were always negative. Most of the children had neuropsychic maturation even advanced for age. Some data concerning family and personal history are not conclusive. For instance, delivery was through caesarean section in 12 cases and with forceps in 9. Only two babies were born prematurely and four suffered some degree of perinatal distress. It is curious that one of our cases had neonatal benign sleep myoclonus and after a free interval, started with BMEI. Thirty-three of 41 families were of middle or upper socioeconomic level, and these figures may have something to do either with etiology or with alertness to the signs of BMEI. Among the cases primarily seen by us, only the first three patients received ACTH according to the initial diagnosis of West syndrome. Six others came for a second opinion after being also treated as West syndrome and five more were treated with antiepileptic drugs after receiving diagnosis of epileptic seizures. Once diagnosed as BMEI, most of the cases received no medication. Frequency of fits tended to increase in the weeks following onset, but was considerably reduced after several months. Most of the children were free of attacks in the course of the second year of life and in only four cases were sporadic myoclonic jerks seen in the third year. Concerning incidence of epilepsy in this group, one patient developed benign myoclonic epilepsy at 19 months of age and another presented cryptogenic partial epilepsy at 6 years of age. Language and cognitive development were normal in all cases, and 11 children showed hyperkinetic behaviour with no specific learning disorders. Differential diagnosis with other non-epileptic paroxysmal neurologic disorders and with West syndrome and other epileptic syndromes occurring during the first 2 years of life have been extensively dealt with in other publications (Fejeman 1991, 1994, 1998). We were not able to perform polygraphic recordings of the episodes in our patients. Therefore we cannot discuss at that level the exact type of contractions, although we did clinically see a long time ago that 65% of the patients had shuddering type of fits (Fejerman et al., 1997), and we also saw that in some of the patients

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with BMEI the contractions were more ‘brief tonic’ than myoclonic (Table 21.3). An important question remains concerning triggering factors: we agree about the relation to ‘states of excitement’ but not with frustration (Pachatz et al., 1999). We did not include in our series cases of elder infants who present a peculiar tonic downward extension of both upper limbs associated with contraction of perioral muscles as a reaction to frustrations.

R E F E R E N C ES Dravet, C., Giraud, N., Bureau, M., Roger, J., Gobbi, G. & Dalla Bernardina, B. (1986). Benign myoclonus of early infancy or benign non epileptic infantile spasms. Neuropediatrics, 1 (17), 33–8. Fahn, S., Marsden, C.D. & Van Woert, M.H. (1986). Definition and classification of myoclonus. In Myoclonus. Advances in Neurology, ed. S. Fahn et al., vol. 43, pp. 1–5. New York: Raven Press 43. Fejerman, N. (1977). ‘Mioclonías benignas de la infancia temprana. Comunicación peliminar. Actas IV Jornadas Rioplatenses de Neurología Infantil, 1976, pp. 131–4. Neuropediatría Latinoamericana. Montevideo: Delta. Fejerman, N. (1980). Myoclonies bénignes du nourrisson. Réunion de la Societé de Neurologie Infantile, Luxembourg. Fejerman, N. (1984). Mioclonías benignas de la infancia temprana. Annals Espana Pediatrics, 21(8), 725–31. Fejerman, N. & Medina, C.S. (1986). Convulsiones en la Infancia, 2nd edn, Buenos Aires: El Ateneo (1st edn, Buenos Aires: Ergon, 1977). Fejerman, N. (1991). Myoclonies et epilepsies chez l’enfant. Revue Neurologique, 147(12), 782–97. Fejerman, N. (1994). Differential diagnosis. In Infantile Spasms and West Syndrome, ed. C. Dulac, H.T. Chugani & B. Dalla Bernardina, pp. 88–98. London: W.B. Saunders. Fejerman, N., Medina, C.S. & Caraballo, R. (1997). ‘Trastornos paroxísticos y síntomas episódicos no epilépticos.’ In Neurología Pediátrica, 2nd edn, ed. N. Fejerman & E. Fernández Alvarez, pp. 584–99. Buenos Aires: Panamericana. Fejerman, N. (1998). Nonepileptic neurologic paroxysmal disorders and episodic symptoms in infants. In Epilepsy. A Comprehensive Textbook, ed J. Engel & T.A. Pedley, vol. 3, pp. 2745–54. Philadelphia: Lippincott-Raven. Lombroso, C.T. & Fejerman, N. (1977). Benign myoclonus of early infancy. Annals of Neurology, 1(2), 138–48. Pachatz, C., Fusco, L. & Vigevano, F. (1999). Benign myoclonus of early infancy. Epileptic Disorders, 1, 57–61. Sorel, L. (1978). Le syndrome de West atypique ou incomplet: à propos de 80 observations. Boll Lega Italiana Contro L’Epilessia, 22/23, 181–2.

22

Epilepsy and cerebral palsy John Stephenson1 and Charlotte Dravet2 1 2

Department of Neurology and Child Development, Royal Hospital for Sick Children, Glasgow, UK Centre Saint Paul, Marseille, France

Introduction From an everyday clinical point of view, the management of cerebral palsy demands an understanding of the epilepsy which commonly co-occurs. A prelude to such management is ensuring the correctness of both the diagnosis of cerebral palsy and the diagnosis of epilepsy. Definitions The definitions of epileptic seizures, symptomatic epileptic seizures, and epilepsy are as generally recognized (Stephenson, 1990; Engel & Pedley, 1997), as is the definition of anoxic seizures (Stephenson & McLeod, 2000). Movement disorders are paroxysmal disorders of movement which are the result neither of epileptic nor anoxic seizures. Cerebral palsy is generally defined as ‘a persistent disorder of movement and posture caused by nonprogressive defects or lesions of the immature brain’ (Aicardi & Bax, 1998). Clinical imitators of cerebral palsy It is increasingly realized that what superficially appears to be cerebral palsy in an infant may be the result of a rare treatable biochemical error, such as glucose transporter (GLUT 1) deficiency, guanidinoacetate methyltransferase deficiency with creatine deficiency, argininemia, or one of the defects in serine biosynthesis. In all these conditions epileptic seizures may co-occur. Other rare biochemical mimics include disorders of purine and pyrimidine metabolism, and organic acid disorders such as 3-methylcrotonyl-CoA carboxylase deficiency. Hyperekplexia is an example of an ion channelopathy in which the young infant Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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is variably hypertonic, with non-epileptic convulsions giving profound syncopes. The autosomal recessive Aicardi–Goutières syndrome may appear to be clinically static, but the cerebral lesions are slowly progressive. We emphasize these points because the care of young patients with cerebral palsy is often undertaken by pediatricians with no special training in neurology. Best practice would seem to be that all children with ‘cerebral palsy’ see a specialist pediatric neurologist at least once, preferably with a clinical geneticist, to allow appropriately targeted diagnostic investigations (Stephenson & King, 1991). Differential diagnosis of epilepsy Infants and children with cerebral palsy are not immune from common syncopes which may induce anoxic seizures(Stephenson & McLeod, 2000). Even more than in the neurologically intact child, it is important to resist any temptation to perform an EEG to help with the question is it epilepsy. Although it has been asserted that spikes or so-called epileptiform discharges are more common in children with cerebral palsy who have epilepsy than in those who do not have epilepsy, cerebral palsy individuals who have never had epileptic seizures often have EEG spike discharges (Perlstein et al., 1953). When an individual with cerebral palsy is already known to have suffered some epileptic seizures in the past, it is even more ridiculous to try to use the EEG to make the diagnosis of a new unexplained paroxysmal event (Stephenson, 1990). Two non-epileptic disorders of movement deserve mention. Benign nonepileptic infantile spasms or benign non-epileptic infantile myoclonus are well recognized in normal infants in the waking state, and likely represent a form of stereotypy. Similar semiperiodic movements may also be seen in awake infants with cerebral palsy (unpublished observations). Secondly, in sleeping infants with cerebral palsy, repetitive very brief tonic contractions may be seen, described as ‘sleep starts’ (Fusco et al., 1999). These children had epilepsy in addition to cerebral palsy, but the sleep starts were non-epileptic and so did not require additional aggressive anti-epileptic therapy. Risk factors for epilepsy Since the early studies of Ellenberg and Nelson (1979), there has been an increase in the understanding of the risk factors for epilepsy in those with cerebral palsy, but knowledge of this complex subject remains patchy and imperfect. Epidemiological studies have been few, but a Scottish study (Goulden et al., 1991) looked at a cohort of mentally retarded individuals with or without cerebral palsy born in Aberdeen between 1951 and 1955. In the subgroup of those with

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cerebral palsy defined as having a presumed prenatal or perinatal onset, the cumulative risk of acquiring epilepsy was 28% age 5 years, 31% age 10 years and 38% age 22 years. This compared with a much lower risk for those with mental retardation, but no cerebral palsy and a much higher risk for those with postnatal brain injury, defined as there being a significant brain insult after 28 days of life which might reasonably account for the child’s functioning. A clinic population study from Italy (Curatolo et al., 1995) looked at the risk factors for the co-occurrence of partial epilepsy, cerebral palsy and mental retardation. Of 64 children with all three conditions, neuroimaging identified 32 with cerebral malformations and 32 with encephalomalacia, periventricular leukomalacia or diffuse atrophy. These two groups were compared with a much larger group of normal children. In this study partial epilepsy meant persistent partial seizures starting in the first three years of life, provided the child did not have West or Lennox–Gastaut syndromes. Cerebral palsy was defined as in Aicardi and Bax (1998) and mental retardation was diagnosed if the IQ was less than 70. Analysis of the relative risks of familial factors and for maternal and neonatal factors indicated that a number of genetic and prenatal risk factors interact in the genesis of early partial epilepsy with cerebral palsy and mental retardation. Overall, it seems that similar genetic and prenatal factors underlie both cerebral palsy not of postnatal origin and coexisting epilepsy. The risk of epilepsy in different subtypes of cerebral palsy varies, not surprisingly. It is highest in those with what some call double hemiplegia and some quadriplegia and some severe tetraplegia (Edebol-Tysk, 1989). In hemiplegic cerebral palsy the epilepsy risk appears to vary with the pathological substrate (Cioni et al., 1999), albeit epidemiological studies are needed to confirm the findings. Cioni et al. (1999) studied 91 children with hemiplegic cerebral palsy who had had brain MRI. The authors were able to classify the MRI pathology (no MRI was normal) into four groups: (1) brain malformations, 13 children (2) periventricular white matter lesions, 41 children (3) cortical/subcortical lesions, 27 children and (4) those with static postnatal pathology, ten children. Epilepsy was seen in 54% of group 1, and 52% of group 3, but in only 20% of group 2 (EEG abnormalities were seen in 50% of this group, re-emphasizing the uselessness of EEG in epilepsy diagnosis). Only three of the postnatal group 4 had epilepsy. Like other authors, Cioni et al. (1999) found a relationship between epilepsy and mental retardation, but this relationship is complex and poorly understood . Characterization and clinical features of the epilepsy in cerebral palsy It may be argued that there are difficulties in classifying the true epilepsies which may often co-occur with cerebral palsy, according to the international

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classification, in that these epilepsies ought to be either partial or secondary generalised. However, there is no a priori reason why genetic, ‘idiopathic’ epilepsies, ion channelopathies perhaps, should not co-occur in cerebral palsy with or without mental retardation. Typical absences with 3/second spike and wave may be seen in children with cerebral palsy (Aicardi, 1990) and one cannot, on clinical or EEG grounds, say whether that individual had secondarily generalized absences or whether there is a coincident ‘primary generalized’ absence epilepsy. This applies to many of the epilepsies seen in those with cerebral palsy. It has been suggested that this argument is specious insofar as there may be a common genetic aetiology for the cerebral palsy and the epilepsy (Stephenson, 1997), but advances in the molecular mechanisms of the genetic epilepsies may allow some clarification here. Although, as indicated earlier, hemiplegic cerebral palsy is pathologically heterogeneous, something may be learned from looking at the group as a whole. A study from London, England (Vargha-Khadem et al., 1992) showed that, in children with hemiplegic cerebral palsy who had overall intelligence within the normal range, the presence of epilepsy within the first 5 years of life was associated with defects of cognition language and memory. The authors found that, in hemiplegia without early epilepsy, non-verbal functions were almost exclusively impaired, and it was inferred that language had displaced spatial abilities. However, when early epilepsy complicated the hemiplegia, nearly all measures of psychological function were impaired, verbal and non-verbal alike. The occurrence of early epileptic seizures seemed to be more important than the presence of EEG discharges. Early epileptic seizures appeared to be more important than the size of the lateralized lesion on imaging, such that children with severe neuroradiological deficits and no early epileptic seizures did better than children with mild neuroradiological deficit, but early epilepsy on tests of verbal IQ, memory quotient and third-trial paired associate learning. Whether attempts to prevent early epilepsy would improve language development is not known. Prognosis of the epilepsy in cerebral palsy One’s clinical impression of the intractability of epilepsy in cerebral palsy is no doubt to some extent biased by patient referral and differential follow-up of those with good and bad outcomes. A study from Dallas (Delgado et al., 1996) looked at the outcome in 531 children with present or previous epilepsy and cerebral palsy (out of a total of 2086 children with cerebral palsy under follow-up). Since 1985 only 69 children (13%) had become free of epileptic seizures for 2 years or more. After baseline EEG, these children were studied prospectively during stepwise withdrawal of anti-epileptic drugs, therapy being reduced by 15–20% every 2 weeks.

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Sixty-five of these children (four were lost to follow-up) were reviewed until seizure relapse or until at least two years without seizures. Around 60% remained in remission without therapy. The seeming paradox of an increased rate of relapse with normal intelligence was explained by the higher relapse rate in those with hemiplegic cerebral palsy, in whom normal intelligence was more likely to be found than in other types of cerebral palsy. From this study one can say that only a small percentage of children with cerebral palsy become seizure free, but of those who do the majority will be able to stop antiepileptic medication. The exception is children with hemiplegic cerebral palsy, who are likely to need indefinite therapy. There is an increased mortality rate in cerebral palsy (Crighton et al., 1995), independent predictors of this being the type of cerebral palsy, the presence of severe to profound mental retardation and the presence of epilepsy of any type. Not surprisingly, the highest mortality is associated with severe tetraplegia/double hemiplegia. Easily the best outcome is in hemiplegic cerebral palsy with normal intelligence. Conclusions All children with a label of cerebral palsy should be seen by a pediatric neurologist at least once to ensure the correctness of the diagnosis. Albeit individually rare, several mimics of cerebral palsy are treatable in the curative sense. It is also important to recognize non-epileptic seizures and movement disorders which may occur in children with true cerebral palsy. The most common mistakes are to mistake non-epileptic convulsive syncope for epilepsy and to use an EEG examination to decide the diagnosis. Non-epileptic sleep starts are also important to recognize, a recognition made more difficult since these children may also have epilepsy. The population of children who have both true cerebral palsy and true epilepsy is heterogeneous, with complex prenatal and genetic etiological factors. The epilepsy is likely to be refractory, but if it is not then medication may often be withdrawn. Of the clinical types, hemiplegic cerebral palsy has been best studied. Even in this apparently rather homogeneous clinical situation, the pathological substrate is distinctly heterogeneous. The complication of early epilepsy often has a marked effect on language functions but intelligence is commonly within normal limits. While the epilepsy in hemiplegic cerebral palsy may be completely controlled by medication, relapse is likely on drug withdrawal. In the future, there remains much to be learnt from both epidemiological and case studies with respect to the aetiology and prevention of the disorders of higher cerebral function which may so distressingly complicate cerebral palsy when epilepsy co-occurs.

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R E F E R E N C ES

Aicardi, J. (1990). Epilepsy in brain-injured children. Developmental Medicine and Child Neurology, 32, 191–202. Aicardi, J. & Bax, M. (1998). Cerebral palsy. In Diseases of the Nervous System in Childhood, 2nd edn, ed. J.Aicardi. London: MacKeith Press. Cioni, G., Sales, B., Paolicelli, P.B., Pettacchi, E., Scusa, M.F. & Canapicchi, R. (1999). MRI and clinical characteristics of children with cerebral palsy. Neuropediatrics, 30, 249–55. Crighton, J.U., Mackinnon, M. & White, C.P. (1995). The life-expectancy of persons with cerebral palsy. Developmental Medicine and Child Neurology, 37, 567–76. Curatolo, P., Arpino, C., Stazi, M.A. & Medda, E. (1995). Risk factors for the co-occurrence of partial epilepsy, cerebral palsy and mental retardation. Developmental Medicine and Child Neurology, 37, 776–82. Delgado, M.R., Riela, A.R., Mills, J., Pitt, A. & Browne, R. (1996). Discontinuation of antiepileptic treatment after two seizure-free years in children with cerebral palsy. Pediatrics, 97, 192–7. Edebol-Tysk, K. (1989). Epidemiology of spastic tetraplegic cerebral palsy in Sweden. I. Impairment and disabilities. Neuropediatrics, 20, 41–5. Ellenberg, J.H. & Nelson, K.B. (1979). Birth weight and gestational age in children with cerebral palsy or seizure disorders. American Journal of Disease in Childhood, 133, 1044–8. Engel, J. & Pedley, T.A. (1997). Epilepsy: A Comprehensive Textbook. Philadelphia: LippincottRaven. Fusco, L., Pachatz, C., Cusmai, R. & Vigevano, F. (1999). Repetitive sleep starts in neurologically impaired children: an unusual non-epileptic manifestation in otherwise epileptic subjects. Epileptic Disorders, 1, 63–7. Goulden, K.J., Shinnar, S., Koller, H., Katz, M. & Richardson, S.A. (1991). Epilepsy in children with mental retardation: a cohort study. Epilepsia, 32, 690–7. Perlstein, M.A., Gibbs, E.L. & Gibbs, F. A. (1953). The electroencephalogram in infantile cerebral palsy. American Journal of Physical Medicine, 34, 477–96. Stephenson, J.B.P. (1990). Fits and Faints. London: MacKeith Press. Stephenson, J.B.P. (1997). Cerebral palsy. In Epilepsy: A Comprehensive Textbook, ed. J.Engel Jr. & T.A. Pedley, pp. 2571–7. Philadelphia: Lippincott-Raven. Stephenson, J.B.P. & King, M.D. (1991). Handbook of Neurological Investigations in Children. London: Butterworth-Heinemann. Stephenson, J.B.P. & McLeod, K.A. (2000). Reflex anoxic seizures. In Recent Advances in Paediatrics, ed. T.J. David, vol. 18. Edinburgh: Churchill-Livingstone. Vargha-Khadem, F., Isaacs, E., Van der Werf, S., Robb, S. & Wilson, J. (1992). Development of intelligence and memory in children with hemiplegic cerebral palsy. Brain, 115, 315–29.

23

Sydenham chorea Marjorie A. Garvey1 and Fernando R. Asbahr2 1 2

Pediatric and Developmental Neuropsychiatry Branch, NIM, Bethesda, MD, USA Laboratório de Investigaçao Médico (LIM-23), Medicina da Universidade de São Paulo, Brazil

The choreic child is punished thrice ere his condition is recognised – once for general fidgetiness, once for breaking the crockery, and once for making faces at his grandmother. S. A. Kinnier Wilson.

Chorea has been called insanity of the muscles. W.R. Gowers

Introduction First described in 1684 (Comrie, 1922), Sydenham chorea (SC) is now known to be a major manifestation of rheumatic fever (RF) and occurs in 20 to 40% of RF cases. The disorder is still common in some parts of the world, occurring in as many as 1% of children in Australian Aboriginal communities (Carapetis & Currie, 1997), although it is uncommon in non-Aboriginal communities of Australia and in other developed countries. The disorder appears to have recently resurfaced in the United States with increasing numbers of sporadic cases nationwide (Bisno et al., 1988; Kaplan & Markowitz, 1988) and scattered epidemics in regions such as Ohio River valley, and the intermountain region of Utah (Veasy et al., 1987, 1994; Leads from the MMWR, 1998a,b; Hosier et al., 1987). The diagnosis of rheumatic fever requires the presence of two major, or one major and two minor manifestations, as well as evidence of a recent streptococcal infection (Special Writing Group of the Committee on Rheumatic Fever, 1992). SC is an exception to these criteria, because it is known to occur up to 9 months after a streptococcal infection (Berrios et al., 1985), in the absence of any other manifestations of RF. Thus, SC is frequently a diagnosis of exclusion. Since it is now a rare diagnosis, it is important for the physician to recognize the clinical syndrome, to

Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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be aware of other disorders that cause chorea and to know which investigations are necessary to detect the more important of these alternate diagnoses. This chapter will describe the clinical manifestations of the disorder, outline important differential diagnoses and discuss treatment issues. Etiology Pathophysiology

It is generally accepted that RF is caused by antibodies directed against Group A beta-hemolytic streptococcal bacteria which cross-react with host tissue via molecular mimicry (Froude et al., 1989; Cunningham, 1996). Two separate investigators have identified antineuronal antibodies in children with SC that react against both streptococcal cellular proteins and human caudate and subthalamic nucleus tissue (Husby et al., 1976; Kotby et al., 1998). These antineuronal antibodies may be responsible for the pathologic immune reaction leading to the neuropsychiatric symptoms in SC (Cunningham, 1996; Zabriskie, 1985), though Kotby et al. (1998) showed that the antineuronal antibodies correlated only with the presence of chorea, not with its severity. Furthermore, a 45 kilodalton antineuronal antibody was recently identified in both SC and anticardiolipin-induced chorea (Frucht et al., 1997), implying that the molecular mimicry model may not fully encompass the pathophysiologic mechanisms that give rise to SC. Histopathology

Little is known about the pathological features of isolated SC (Graham & Lantos, 1997). Fatalities typically occur only when the patients have severe cardiac involvement. Thus, the majority of postmortem studies show cerebral abnormalities suggestive of embolic or terminal hypoxic events (Copeland, 1821; Greenfield & Wolfsohn, 1922; Ziegler, 1927). Autopsy studies in patients with isolated chorea have not identified any consistent abnormality. In particular, there is no published evidence to support vasculitis as a cause for both the chorea and some of its complications (for example, central retinal artery occlusion) (see below). Clinical features Since the diagnosis of SC is primarily clinical, it depends substantially upon recognition of the pattern of neurologic and psychiatric symptoms that occur in this disorder. Children may have very severe chorea with little or no psychiatric symptoms or mild chorea with more pronounced psychiatric symptoms. Chorea is the initial symptom in the majority of children, though approximately 30% of children will experience a change in behaviour (emotional lability or obsessive compulsive

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symptoms) prior to the onset of the chorea (Asbahr et al., 1998). Thus, although the complete clinical picture of SC is unmistakable, a confident diagnosis may not be possible until all or most of the symptoms are present. Psychiatric symptoms

Patients with SC have often been described as irritable, emotionally labile, sensitive, anxious, and easily distracted (Osler, 1894; Diefendorf, 1912; Ebaugh, 1926). In the 1950s and 1960s, three studies with small numbers of patients were published suggesting that obsessive–compulsive phenomena were associated with SC. Chapman et al. (1958) studied the relationship between psychiatric and emotional problems and personality structure in a group of eight children with SC. Four of them had obsessive–compulsive symptoms (OCS), such as washing and ordering rituals. Conversely, Grimshaw (1964) studied the prevalence of previous neurological disorders in patients with obsessive neurosis (N103) contrasted with nonobsessional subjects (N105) and found 28 patients (27%) with one or more neurological disorder. Six of the obsessional patients had a history of SC compared to only two of the comparison group. Finally, in a retrospective follow-up study, Freeman et al. (1965) compared the psychological state of 40 adults with previous history of SC with those of 30 control patients (with history of glomerulonephritis, osteomyelitis and rheumatic fever without chorea). ‘Personality disorders’, including compulsive personality, were observed in 26 of the 40 subjects with history of chorea, but in only eight of 30 control patients. ‘Psychoneurosis’ (phobias, obsessive–compulsive symptoms, anxiety, and conversion) was observed in seven of the 40 patients with chorea, but was absent in the control group. A subsequent study has suggested that SC patients have a relative risk of 3.4 for developing psychopathologies later in life (Wilcox & Nasrallah, 1988). In the late 1980s, the first study to systematically investigate OCS in patients with SC was conducted by Swedo and colleagues (1989) at the National Institute of Mental Health in the United States of America. These authors retrospectively assessed 37 children and adolescents with history of rheumatic fever, 23 of whom had SC. Approximately 70% of the patients with chorea had obsessions and compulsions with three of them meeting diagnostic criteria for obsessive–compulsive disorder (OCD). None of the rheumatic fever patients without chorea had obsessive compulsive symptoms. In a subsequent prospective study of psychological symptoms in 11 patients with SC, the same authors (Swedo et al., 1993) found that nine patients experienced an acute onset of OCS (four patients met DSM-III-R criteria for OCD). The obsessions and compulsions observed in these patients were indistinguishable from those found in patients with classic OCD. Moreover, four of the 11 patients had also presented with new symptoms of attention deficit/hyperactivity disorder (ADHD) concomitantly with their chorea onset.

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These results were recently replicated by Asbahr et al. (1988), who prospectively studied the presence and intensity of psychiatric symptoms and disorders in 50 patients with rheumatic fever (30 patients with chorea and 20 without chorea). The patients were evaluated three times during the acute episode of their illness. Twenty-one (70%) patients had an abrupt onset of OCS. There was no simple relationship between the appearance of psychiatric and choreatic symptoms. The OCS preceded the onset of chorea in approximately one-third of patients, while OCS onset accompanied or followed the appearance of the abnormal movements in the remaining patients. Although five (17%) of these 21 patients met DSM-IV criteria for OCD, there was no correlation between the intensity of psychiatric symptoms and chorea severity (F.R. Asbahr, 1999, personal communication). In most patients, OCS subsided within 4 months. None of the non-choreatic patients with rheumatic fever had obsessions or compulsions. Hyperactivity, distractibility, and impulsivity were also observed in 11 patients (37%) and started at the time they developed chorea; ten of these children had concurrent onset of OCS. The symptoms of impaired attention and impulsivity did not meet diagnostic criteria for ADHD since they had commenced after the age of 7 and were short lived (less than six months). During this study, four of the 30 SC patients had two distinct episodes of chorea and each one was reassessed and followed for a further 6 months (Asbahr et al., 1999). All four subjects developed OCS in their second episodes, and three of them met diagnostic criteria for OCD. Although two of these patients had met criteria for OCD in their initial episode, their obsessions and compulsions were clearly more severe during the recurrence. This was in contrast to their chorea, which was of similar intensity in both episodes. The onset and peak of the OCS occurred during the first 2 months after the reappearance of the chorea, as had been observed during the initial choreatic episode. These observations suggest that later recurrences of SC may increase the patient’s risk of developing psychopathology. Although thought to be self-resolving, these data suggest that the pathophysiologic process of SC may cause permanent damage to the basal ganglia, especially with repeated episodes. Further support for this hypothesis comes from the data showing an increased incidence of chronic cardiac abnormalities in patients with recurrences of rheumatic carditis (Lue et al., 1979) Neurologic signs and symptoms

The three most prominent neurologic symptoms of SC are involuntary movements, voluntary movement incoordination and muscular weakness (Gowers, 1888). The movement abnormalities frequently start in the hands and face. When the lower limbs are affected, the abnormal movements are typically less problematic than those in the upper limbs, except in more severe cases of chorea. The

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majority of children have bilateral chorea, though choreatic symptoms are asymmetric in as many as 50% of cases. Only 10 to 15% of patients will have pure hemichorea (Nausieda et al., 1980; Money, 1882). Many children have difficulty with fine motor control early in the course of the illness, which may first manifest as a deterioration of their handwriting. Dressing then becomes troublesome, particularly tying shoes and buttoning, and with more severe chorea these and other tasks of daily living become impossible for the child. Facial expression is typically decreased and superimposed upon this are fragmentary movements of the face, particularly the mouth. These movements constitute the facial grimacing so typical of SC. Hypophonic or rushed speech is common even in mild cases, although slurred speech or anarthria may be seen as the chorea increases in severity. Choreatic movements in SC are best characterized by an unpredictable pattern of muscle activity (Marsden et al., 1983) unlike the regular, tremor-like movements of vascular chorea (Hashimoto & Yanagisawa, 1994) or the repetitive or sterotyped movements typical of tic disorders. The movements in chorea give the impression of restlessness as they flow from one body part to another, from side to side, and from upper to lower extremity (Klawans & Brandabur, 1993). Choreatic movements may appear to be purposeful and can be disguised as such, particularly by older children and adults. Minimal or absent when the patient is relaxed, the abnormal movements become more obvious with attempts to speak, to carry out mental arithmetic or to suppress involuntary movements (frequently in response to the request to ‘stay still’). Synkinetic involuntary movements involving the more proximal areas of the limb as well as mirror movements in the contralateral limb occur when affected children attempt fine motor movements (finger tapping, hand grip, etc.) (Wilson, 1955; Russell, 1899). A useful rule of thumb for children with moderate to severe SC is that almost all attempts at voluntary movements make the chorea worse. There are few exceptions to this and a diagnosis of SC should be questioned in these cases (Wilson, 1955). In addition, the voluntary movements themselves are incoordinated. Thus, the finger-to-nose test may be dysmetric and rapid alternating movements are typically dysrhythmic. Episodes of ‘unintended relaxation’ (Gowers, 1888) or motor impersistence are also a hallmark of SC. Motor impersistence is an inability to maintain a posture for more than a few seconds resulting in intermittent relaxation and subsequent reactivation of the involved muscles. This can best be seen in attempts at active eye closure, tongue protrusion and hand grasp (‘milk-maid’s grasp’). Hypotonia is frequently seen with chorea and tends to vary in severity in concert with the chorea, though a small number of patients with chorea mollis may have little or no chorea with very profound hypotonia (see below). In milder cases, hypotonia is associated with floppy limbs and hyperextensibility of the wrist joints. Children with moderate to severe chorea may be able to appose their elbows behind the back without difficulty.

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Spooning (flexion of the wrist, over-extension of the meta-carpo-phalangeal joints and extension of the fingers) and the pronator sign (pronation of the affected wrist and internal rotation of the arm) are other useful signs (Wilson, 1955). Best elicited with arms outstretched in front of or above the head of the patient, these signs may be difficult to elicit in milder cases and are more readily recognized when the choreatic symptoms are asymmetric. Deep tendon reflexes are usually reduced, but may be normal. The hung-up reflex is typical of choreatic disorders, and can best be elicited by hanging the leg down, and tapping the quadriceps tendon a number of times in quick succession. If the reflex is ‘hung up’, there will be a brief period during which the knee will remain in extension prior to returning to baseline. The ankle jerk may also show this phenomenon, although it is most easily appreciated in the knee jerk. A diagnosis of SC commits the patient to years of streptococcal prophylaxis and regular checkups for cardiac involvement. The presence of other definite signs of rheumatic fever may help confirm the diagnosis, but occur in only 40% of patients. Since streptococcal infections are common in the ages at which SC is most likely to present, the diagnosis depends upon proper recognition of the pattern of clinical signs and subsequent clinical course, rather than on the presence of a streptococcal infection or other laboratory tests. Duration

SC is considered to be a self-resolving disorder but the natural history is widely variable (Lessof & Bywaters, 1956). Although mean time to resolution is thought to be between 6 and 9 months (Swedo et al., 1993; Cardoso et al., 1997), a recent study (Cardoso et al., 1998) described a group of patients who continued to have symptoms more than 2 years after their initial episode. These data call into question the self-resolving nature of the disorder and suggest that SC may not be as benign as previously considered. Unusual or atypical neurologic signs and symptoms

A variety of unusual symptoms and signs have been reported in patients with SC. Some are variants of the more typical course of SC. Others, however, are extremely rare in SC and may point to another underlying disorder. For this reason, when atypical or unusual signs are present, the clinician should carefully consider alternate diagnoses before concluding that the patient has SC. Chorea mollis

Some children with SC have very profound hypotonia and few choreatic movements. This is referred to variously as paralytic chorea (Gowers, 1881), flaccid chorea (Wilson, 1955), or chorea mollis (Thiebaut, 1996). Gowers’ case series of

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this variant (Gowers, 1881) described five children who complained of severe unilateral weakness of the upper extremity (four left and one right). Choreatic movements had been reported prior to the onset of the weakness, and were seen as the children recovered. No weakness was observed in the face or ipsilateral leg and recovery occurred over the next 1 to 5 months. Later publications made reference to generalized cases and described the children as ‘powerless but not paralysed’ (Thiebaut, 1996; Cathala & Very, 1958). Four patients in our case series with this variant have had generalized symptoms with such profound hypotonia that they were unable to sit or stand without full support. All had few, if any, involuntary movements at the peak of the illness, although as the hypotonia resolved the choreatic movements became apparent. Motor impersistence was so severe that all efforts at sustained voluntary movements lasted less than 5 seconds and attempts at whole limb actions, e.g. holding arms out in front, resulted in ballistic movements. Fine motor functions, such as writing, were severely affected in all four and speech was limited to monosyllabic sounds in three children while the fourth was anarthric. Three of the children had difficulty swallowing, although only one required a nasogastric tube to ensure adequate fluid and caloric intake. All four children were fully dependent upon their parents for all activities of daily living. Although rare, this variant can cause significant morbidity for many months. Encephalopathy

Gowers’ report makes mention of delirium and a ‘mental dullness . . . which may amount to practical dementia’ (Gowers, 1888) though some of the ‘mental dullness’ may be accounted for by the lack of facial expression that is common in this disorder (Wilson, 1955). A large retrospective series published in 1980 (Nausieda et al., 1980) reported that less than 10% of patients had encephalopathy, disorientation, confusion, and delirium, but did not give precise descriptions of how the patients were investigated and the other disorders that were considered prior to assigning the diagnosis of SC. Tics

There have been few reports clearly documenting the presence of tics in patients with SC. Vocal tics were noted by Mercadante and colleagues (1997), and Cardoso et al. (1997) recorded tics (unspecified whether motor or vocal) in two of 13 children with chorea one of whom also had oculogyric crises. Only one patient in our series of 40 patients with SC, complained of a ‘tic’ long after the SC episode had resolved. This movement was not a typical motor tic, but consisted of repetitive bouncing leg movements, only performed when sitting. There was no urge to do the movement, and no build-up of tension if the movement was not performed and there were no other tic-like movements present.

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The distinct pattern of the two movement disorders (random nature of chorea; repetitive nature of motor tics) usually helps the clinician make a distinction between tics and chorea, although in milder cases of SC the choreatic movements may be mistaken for tics. However, the movements of SC typically lack the premonitory urge frequently seen in patients with motor tics and it is rare to see significant degrees of hypotonia and motor impersistence in patients with motor tic disorders. Seizures

Most early authors agree that convulsions are most likely a result of embolic events from rheumatic carditis (Gowers, 1888; Wilson, 1955; Aron et al., 1965). The retrospective study of Nausieda and colleagues (1980) reported one of 240 patients (0.4%) who had a convulsive event, but they did not give the clinical details of the case. More recently, there have been a small number of case reports documenting seizures in patients with SC in the absence of carditis (Lavy et al., 1964; Ch’ien et al., 1978; Ganji et al., 1988). In all the reports, the clinical histories were atypical for SC (Ch’ien et al., 1978; Ganji et al., 1988) or seizures had been present prior to the onset of the chorea (Lavy et al., 1964). Ocular symptoms

Papilledema and raised intracranial pressure have been reported infrequently in patients with SC (Wilson, 1955; Johnston, 1946). Because of the small number of patients reported, it is uncertain whether the benign intracranial hypertension in these cases was incidental or a very rare accompaniment to SC. A small number of case studies have also reported central retinal artery occlusion (Hearn & RoperHall, 1961; Willetts, 1961). In most of these cases, a vasculitic cause for the visual loss was considered, as there was no evidence of cardiac lesions. The clinical details of each of the cases were somewhat atypical for SC suggesting that other vasculitic disorders were responsible for both the ocular and choreatic symptoms. This possibility is further supported by the fact that both chorea and retinal vasculitis have been reported in documented cases of systemic lupus erythematosis (Graham et al., 1985). Differential diagnosis Table 23.1 lists the disorders that cause chorea in childhood. Chorea can be distinguished clinically from other movement disorders such as tics, myoclonus, tremor, and dystonia. Choreoathetosis is a mixture of both the faster, random movements seen in chorea and the slower, sinusoidal movements of athetosis. This is often distinct from chorea and occurs in a number of heredodegenerative and encephalitic disorders. Up to 15% of school-aged children will have a positive throat culture for strep-

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Table 23.1. Differential diagnosis of chorea

Infectious and postinfectious disorders Sydenham chorea Lyme disease Mycoplasma pneumoniae Viral encephalitides Acquired immunodeficiency syndrome Vasculitides Systemic lupus erythematosis Behçet’s disease Moya moya disease Endocrine disorders Hyperthyroidism Parathyroid dysfunction Hyperglycemia Drugs that induce chorea Anticonvulsants Anti-emetics Oral contraceptives Psychotropic agents Theophylline Stimulants and dopa agonists

Other causes Chorea gravidarum Structural/ vascular /ischemic lesions Cardiopulmonary bypass surgery Cerebral palsy Cerebral infarcts / hemorrhage Heredodegenerative diseases Benign familial chorea Hepatolenticular degeneration (Wilson’s disease) Neuroacanthocytosis Huntington disease Familial paroxysmal choreoathetosis Hallervorden–Spatz disease Lesch–Nyhan Syndrome Spinal cerebellar ataxias Ataxia telangiectasia Pelizeus–Merzbacher Neuronal ceroid lipofuscinosis Phenylketonuria and related disorders of biopterin metabolism Abetalipoproteinemia

tococcus pyogenes (Kaplan, 1980; Cornfeld et al., 1961) at some time during the school year. Therefore, a positive throat culture or raised antistreptococcal antibody levels are insufficient to confirm the diagnosis of SC unless the patient has clinical features usually seen in the disorder and follows a clinical course that is typical for SC. Patients with some forms of cerebral palsy can develop choreoathetosis in the setting of a febrile illness (Harbord & Kobayashi, 1991). While a diagnosis of SC should be considered in these patients, assigning such a diagnosis should be undertaken with caution, since it commits the patient to many years of penicillin prophylaxis. Typically, the abnormal movements associated with fever in patients with cerebral palsy are choreoathetotic or ballistic in nature and tend to be short lived once the fever has resolved. In contrast, RF and SC are sequelae of streptococcal infections and typically follow the pharyngitis. The non-neurologic symptoms of RF occur at a latency of 10 to 21 days (Collis, 1931; Coburn, 1931) while the choreatic symptoms are most commonly seen 3 to 5 months after the infection (Taranta & Stollerman, 1956). However, chorea may present in a small number of

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patients at the time of the acute infection (Catanzaro et al., 1958). Some children with cerebral palsy may have hereditary metabolic disorders which cause involuntary movements (Hoon et al., 1997). Typically, the clinical course for these patients is not at all similar to that seen in SC, thus they are seldom mistaken for each other. Chorea due to Huntington disease (HD) is unusual in children who more typically have the Westphal variant with rigidity, dystonia and parkinsonism (Quinn & Schrag, 1998). However, SC can occur in young adults (Leads from the MMWR, 1988a,b). When an adult presents with chorea, HD should be considered, especially if the clinical course is unusual for SC. A positive or suspicious family history for HD is helpful, if present. Neurologic manifestations of systemic lupus erythematosis (SLE) may present at a younger age than the systemic symptoms, thus the patients frequently fall into the correct age range for SC. Furthermore, as with other vasculitic disorders, SLE may cause chorea before the systemic signs of the disorder are present (Arisaka et al., 1984; Bruyn & Padberg, 1984a,b; Vlachoyiannopoulos et al., 1991; Piccolo et al., 1999; Kok et al., 1993; Brogan et al., 1990; Bussone et al., 1982; Takanashi et al., 1993). One helpful distinction is that chorea due to vasculitis may recur frequently and other clinical or laboratory features of the vasculitis usually become apparent within the year following the initial onset of chorea. It could be argued therefore, that once a diagnosis of SC is assigned, it should be revised if the laboratory evidence and clinical course suggest an alternate diagnosis. It was for this reason that the 1955 Jones’ criteria revision included this statement: ‘The Jones criteria were not meant to substitute for the wisdom and judgement of the clinician. They are designed only to guide him toward a diagnosis of the disease’(Rutstein et al., 1955). Careful follow up of all children with chorea, therefore, is mandatory and is especially important in teenage patients who are more likely to have SLE. In general, viral encephalitides tend to cause choreoathetosis rather than chorea, and this is typically accompanied by seizures and encephalopathic behaviour (for example, confusion, delerium). Serological evidence to support the diagnosis of viral encephalitis may be difficult to obtain. Given the high prevalence of streptococcal infections in school-aged children, a child with a positive throat culture or raised antistreptococcal antibody levels in the setting of choreoathetosis, encephalopathy and /or seizures is more likely to have encephalitis than SC. Ancillary investigations Laboratory tests

No tests can confirm the diagnosis of SC, though evidence of other manifestations of rheumatic fever provides strong support. However, chorea, carditis, arthritis and skin rashes are also found in patients with SLE. Therefore, when considering a

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diagnosis of SC, the most important laboratory tests are those that are diagnostic for alternative causes of chorea. Antinuclear antibodies (ANA) are usually positive in SLE but may also be positive in SC. In the latter, ANA are usually of low titre and the pattern is typically smooth rather than speckled (Abraham et al., 1997). Hematologic features typical of SLE (thrombocytopenia, etc.) are not found in SC. Serum copper, ceruloplasmin and a 24 hour urine for copper excretion are screening tests for Wilson’s disease. Patients with this disease may also have Kayser–Fleischer rings seen on slit lamp examination. In addition, the involuntary movements in Wilson’s disease are not limited to chorea but include dystonia and tremor. Metabolic abnormalities can also cause chorea, particularly hyperglycemia, hyperthyroidism, and hyper- or hypoparathyroidism. Chorea may also occur in neuroacanthocytosis and abetalipoproteinemia. As with Wilson’s disease the movements in both these disorders are not primarily chorea, but include choreoathetosis, dystonia or ataxia. Both are associated with acanthocytes on the peripheral blood smear. Neuroacanthocytosis may be familial and typically presents in adulthood, while abetalipoproteinemia may present in early childhood with diarrhea and failure to thrive and is associated with an abnormal serum lipoprotein profile. Chorea may also be present in childhood encephalitides. Thus, serology and cerebrospinal fluid analysis should be performed in any patient with chorea who has a history suggestive of such a diagnosis. Genetic testing for HD may be considered in adult patients who present with chorea. Neuroimaging

The largest series of magnetic resonance imaging in children with SC showed no consistent structural abnormalities other than a 5 to 13% increase in the size of the caudate, putamen and globus pallidus compared to healthy controls (Giedd et al., 1995). While statistically significant, this was not of clinical relevance and was only detected using volumetric analysis of the MRI scans. A small number of published case reports have identified gross structural abnormalities or magnetic resonance signal intensity changes in the basal ganglia of patients with SC (Ikuta et al., 1998; Traill et al., 1995; Konagaya & Konagaya, 1992; Kienzle et al., 1991; Heye et al., 1993; Emery & Vieco, 1997). Many of these cases had atypical clinical symptoms and the diagnosis of SC was based solely on a positive throat culture or raised antistreptococcal antibodies in many of the reports. Given the paucity of neuropathologic evidence for either vasculitis or vasculopathy in SC, it is possible that alternative diagnoses were responsible for the chorea in some of these patients. Functional imaging studies have shown reversible striatal hypermetabolism and hyperperfusion using positron emission tomography (PET) (Goldman et al., 1993; Weindl et al., 1993) and single photon emission computed tomography (SPECT) (Hill et al., 1994) in the basal ganglia. Thalamic involvement has also been reported

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in one case studied serially (Lee et al., 1999), but this child carried a diagnosis of cerebral palsy at the time she developed the movement disorder. Electrophysiology Electroencephalography

EEG abnormalities occur in up to 30% of SC patients. Typical findings consist of slow wave abnormalities varying from a mild slowing of the background to generalized delta slowing, and it has been suggested that the degree of slowing is proportional to the severity of the movement disorder (Johnson et al., 1964; Usher & Jasper, 1941; Kooi et al., 1978). The slowing may be diffuse, but frequently has maximal expression over the posterior head regions (Johnson et al., 1964). Lateralized slow wave activity may be present in hemichorea (Kooi et al., 1978). Epileptiform abnormalities are rarely observed (Johnson et al., 1964) and when reported, they are associated with a very atypical clinical course (Ch’ien et al., 1978). Typically, improvement in the EEG lags behind the resolution of clinical symptoms (Lavy et al., 1964; Kooi et al., 1978). Electromyography

Muscle recording reveals no single pattern of EMG activity in chorea, mirroring the unpredictable movements seen clinically. Abrupt, brief bursts of EMG occur, reminiscent of myoclonus, as well as long-lasting contractions similar to dystonia (Hallet & Kaufman, 1981). However, the key feature of chorea is the continuous change from one muscle to another and within an individual muscle, from one type of movement to another (Marsden et al., 1983). The hung up knee jerk appears to be a choreatic movement superimposed upon the underlying deep tendon reflex. It is these choreatic movements that cause the knee to ‘hang up’. Hallett and Kaufman (1981) elicited choreatic movements only when repeated taps to the quadriceps tendon were delivered at short interstimulus intervals (200–300 ms). The choreatic activity was first seen in the quadriceps muscle with spread to other leg muscles with continued tapping. Sudden cessation of the choreatic activity occurred when the tapping ended, but was also observed while the taps were still being delivered. The triphasic pattern of muscle activation during ballistic movements is abnormal in chorea. Normally ballistic movements are initiated with a burst of activity in the agonist muscle, e.g. biceps for elbow flexion, lasting less than 100 ms followed by a burst of activity in the antagonist, e.g. triceps, of the same length. In choreatic patients the initial agonist burst is prolonged and the agonist burst may be absent (Hallett & Kaufman, 1981; Berardelli et al., 1996). Yanagisawa et al. observed involuntary brief suppression of voluntary contraction in patients with chorea (Yanagisawa, 1992; Yanagisawa et al., 1976). Several of

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these EMG interruptions (lasting from 200 to 700 ms in both agonist and antagonist muscles) occurred over a 10-second period of sustained muscle activity. In Huntington disease (HD), the cessation of muscle activity occurred only in those patients with pure chorea, not in those who had rigidity. It was seen in all patients with SC and was more profound than in the HD patients. Clinically, this EMG pattern correlated with the clinical observation of ‘unintended relaxation’ or motor impersistence present in the patients with SC (Yanagisawa et al., 1976). Transcranial magnetic stimulation

A number of factors suggest that inhibitory and facilitatory systems of the motor cortex may be abnormal in patients with SC. TMS reveals abnormalities of the inhibitory systems in patients with OCD and HD. In HD, TMS-induced motor responses (Meyer et al., 1992) and cortical inhibition are abnormal (Tegenthoff et al., 1996; Priori et al., 1994; Abbruzzese et al., 1997). Cross-sectional data in these patients have suggested a correlation between cortical physiologic abnormalities and the severity of clinical symptoms. However, no longitudinal TMS studies have been performed. Patients with primary OCD also show decreased intracortical inhibition (Greenberg et al., 1998). These findings are particularly relevant to SC and suggest that TMS may reveal abnormalities of the motor cortex in these patients during the acute phase of the illness. In view of the frequency of chronic neuropsychiatric symptoms in SC, TMS may also be a useful tool to study recovery in patients with SC. Treatment strategies in SC Very few randomized controlled treatment trials have been successfully completed for SC. Such trials are faced with the rarity of the disorder and the variable natural history of both severity and time to resolution. Open treatment trials have found neuroleptic drugs, such as haloperidol and chlorpromazine (Shelburne & Bates, 1979; Shenker et al., 1973; Tierney & Kaplan, 1965) effective for chorea. This has provided support for the hypothesis that chorea results from dopaminergic dysfunction induced by an autoimmune process (Nausieda et al., 1983; Naidu & Narasimhachari, 1980). However, a number of case series suggest that other treatments may also ameliorate choreatic symptoms. These include tetrabenazine (Hawkes & Nourse, 1977), phenobarbital and other sedating compounds (Wilson, 1955) and more recently valproic acid (Daoud et al., 1990; Dhanaraj et al., 1985; Cornelio-Nieto et al., 1991; Kulkarni, 1992). Tetrabenazine and the neuroleptic drugs appear to control chorea more effectively than valproic acid. Phenobarbital probably acts by sedating the patient with a subsequent reduction in the choreatic movements. None of these medications offers a curative treatment, and it is

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unlikely that any provide a better long-term outcome than that which occurs as part of the natural history of the disorder. The relationship between SC and streptococcal infections became clear at the early part of the 20th century (Collis, 1931; Coburn, 1931; Newsholme, 1895; Schik, 1907), and our present understanding of the postinfectious autoimmune pathophysiology for the disorder arose from these studies. Presently corticosteroids are prescribed for patients with severe chorea, although there is a paucity of evidence of their effectiveness. Most of the studies of corticosteroid treatment for chorea report an early partial amelioration of choreatic symptoms in the majority of patients (Schwartzman et al., 1953; Ainger et al., 1955; Fletcher, 1960; Green, 1978; Kalra & Ghai, 1980). However, the only study to use a placebo control found no benefit in three of four patients studied and only minimal improvement in the remaining child (Dixon & Bywaters, 1952) and one patient in another study deteriorated during the corticosteroid administration (Aronson et al., 1951). Furthermore, it is difficult to draw meaningful conclusions from these studies, as they used different agents at varying doses for widely divergent time periods. Given the variable natural history and the inconsistent effect of steroids, it is also possible that, in some patients, improvement of symptoms was due to spontaneous resolution of the disorder. No studies have addressed whether corticosteroid treatment alters the quality of long-term outcome in this disorder. Future studies of immunomodulation in Sydenham chorea

Plasma exchange (PEX) and intravenous immunoglobulin (IVIG) are more effective than steroids in the treatment of other postinfectious autoimmune disorders (Neudorf, 1993; van der Meche & van Doorn, 1995; Pollard, 1987; Mendell et al., 1985; Singh & Gupta, 1996), and it is possible that they may also be useful in SC (May & Koch, 1999). Preliminary data from an ongoing randomized trial comparing prednisone, IVIG and PEX have been promising (Garvey & Swedo, 1997). However, a large cohort of patients is required to reach both statistical and clinical certainty regarding the potential benefit of these therapeutic agents both for the acute symptoms and for long-term outcome.

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24

Alternating hemiplegia of childhood Jean Aicardi Department of Child Neurology, l’Hôpital Robert Debré, Paris, France

Introduction Alternating hemiplegia of childhood (AHC) is a typical example of a disease that combines movement disorders and epileptic manifestations in addition to other neurological features, especially hemiplegic episodes. The latter were first recognized (Verret & Steele, 1971) and the condition named after them. Progressively, other symptoms were reported, including abnormalities of ocular motor function (Dittrich et al., 1979), dystonia and choreoathetosis either paroxysmal or permanent (Dittrich et al., 1979; Krägeloh & Aicardi, 1980; Dalla Bernardina et al., 1987), quadriplegic episodes and autonomic dysfunction (Bourgeois et al., 1993). These features proved to be an integral part of the clinical picture of AHC and served to separate the condition from other forms of episodic hemiplegia, especially hemiplegic migraine to which AHC was initially thought to belong. AHC is a rare disorder; less than 150 cases have been reported up to now (Bourgeois et al., 1993; Sakuragawa, 1992; Campistol Plana et al., 1990; Silver & Andermann, 1993). Recently, Mikati et al. (2000) systematically collected 71 cases so far detected in the United States and were able to perform a detailed study of 44 of these patients. The clinical picture is generally stereotyped. All patients have repeated attacks of hemiplegia or hemiparesis involving either side of the body alternatively. However, hemiplegias are never the sole clinical manifestation of the disorder and are always associated with and often preceded by, other manifestations, especially dystonic or choreoathetotic attacks, abnormal ocular movements, autonomic abnormalities and episodes of quadriplegia, that are described below. No cause for the disorder has been recognized. The disease has its onset in infancy and is usually sporadic. Only one familial case has been fully documented (Mikati et al., 1992). Atypical cases are uncommon but have been reported in the past decade (Andermann et al., 1995a,b; Hart et al., 1997) and emphasized recently by Mikati et al. (2000) suggesting that the condition might be heterogeneous. In most Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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cases the diagnosis is easy, although it is often made only after many years as AHC is not well known outside child neurology circles. Despite these atypical cases, it is possible to describe a common clinical picture based on 29 personally observed patients, which is largely confirmed by findings in other large series. Some precisions, especially on atypical forms are drawn from cases reported in the literature. Clinical findings The main series included 14 girls and 15 boys with a median age of 5.4 months at the time of diagnosis. None had a family history of a similar disorder. Only five of these 29 patients had a family history of migraine and two of epileptic seizures. The frequency of a familial history of migraine is higher in several published series where it was found in 25% (Mikati et al., 2000) to over 50% (Silver & Andermann, 1993) of cases, although we systematically enquired about such a history. Several infants had a history of neurological abnormalities. Nine were remarkably hypotonic at birth and four of these underwent a muscle biopsy on this account with normal results. A similar history is suggested in other reports (Sakuragawa, 1992; Silver & Andermann, 1993; Mikati et al., 2000; De Stefano et al., 1995), although some muscle abnormalities were sometimes found. Five infants were reported to have had ‘neonatal convulsions’ although the possibility of early paroxysmal manifestations of AHC (tonic seizures) cannot be excluded. The first definite manifestation of AHC appeared before 6 months of age in all cases but three, and before 3 months in most. However, cases of later onset have been reported (Mikaki et al., 1992, 2000; Andermann et al., 1995a) with onset of the first manifestation up to 3.5 years and, especially, with delayed appearance of the hemiplegic episodes (preceded, sometimes for several years, by ocular or dystonic attacks). The major clinical manifestations of AHC can be divided into paroxysmal events that are usually the only abnormal events during the first year or so of the disease, and permanent abnormalities that tend to emerge progressively in late infancy or early childhood (Table 24.1). Paroxysmal features

Paroxysmal features include several types of attacks that recur frequently, usually at least once or twice a week. The exact frequency is sometimes difficult to assess, especially for hemiplegic episodes, because brief attacks sometimes occur in clusters and long episodes may be interrupted by brief periods of partial or total recovery. Paroxysmal phenomena are precipitated by a variety of stimuli in a large proportion or possibly in all cases. Most commonly reported are emotional triggers, e.g. birthday or Christmas parties, and fatigue. Medical examination frequently

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Table 24.1. Clinical findings in 29 cases of alternating hemiplegia of childhood

Sex: 13 boys; 16 girls Age of onset of attacks: 3 days – 13 months Paroxysmal features Onset with tonic attacks: 14 Onset with bouts of hemiplegia: 5 Hemiplegic episodes: 29 (shifting bilateral involvement in 24) Tonic attacks: 27 (unilateral in all cases; bilateral attacks in 9) Paroxysmal nystagmus: 23 (unilateral in 17) Paroxysmal strabismus: 11 Screaming, apparent pain: 28 Vasomotor disturbances: 22 (pallor, flushing, coldness, sometimes unilateral) Disappearance with sleep: 29 Paroxysmal respiratory disturbances: 14 Non-paroxysmal features Mental retardation/learning difficulties: 25 Neurological signs: Choreoathetosis: 29 Ataxia: 27 Pyramidal tract signs: 8

provokes an attack. Hot bath, cold and hot weather and possibly bright lights are commonly reported precipitants. Tonic or dystonic attacks

These are usually the earliest manifestation of AHC. They may occur as early as a few days of age and in most cases during the first year, especially its first half. In rare children, they can occur later but in virtually all cases before 3.5 years (Bourgeois et al., 1993; Mikati et al., 2000). Unilateral attacks are most frequent, with rotation and tilting of the head to the affected side and stiffening of one side of the body which may be extreme, sometimes resulting in a vibratory tremor. Eye deviation to the same side is present. Bilateral tonic attacks feature arching of the back and upward deviation of gaze. The onset of attacks is sudden, associated with fussiness and crying as if in pain. In some cases, a premonitory feeling has been noted (Mikati et al., 2000). Dystonic attacks are brief, usually lasting only a few minutes but may recur in rapid succession for up to a few hours (Bourgeois et al., 1993; Sakuragawa, 1992). They are often but not consistently associated with oculomotor phenomena, dyspneic episodes or hemiplegia, although this is usually

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observed later, after weeks, months or, rarely, several years (Bourgeois et al., 1993; Mikati et al., 2000). Ocular motor phenomena

These can also be seen very early in life, characterized by nystagmus, most often unilateral, or acute strabismus (see below). The nystagmus may be bilateral and of large amplitude and occasionally persist for long periods (days) although most episodes are of short duration (30 seconds to 3 minutes). Like other paroxysmal features of AHC, abnormal eye movement may appear as a part of a dystonic/ hemiplegic episode or occur in isolation. Hemiplegic episodes

These rarely occur as an isolated manifestation, especially in the early period but often follow a dystonic attack so they are often misdiagnosed as Todd’s paralysis. Their frequency and duration vary widely. All personal patients had more than one episode monthly and most had weekly or more frequent attacks. However, some children had unexplained periods of remission, lasting up to two years in one case. Brief episodes lasted from a few minutes to about an hour. Long attacks could last several hours to several days, up to 2 weeks, with an average duration of 6–8 days. In some patients, paralysis occupied up to 50% of their time awake. In some children, there was a clear predominance on one side and this has also been reported by other investigators. Remarkably, the intensity of hemiplegia was fluctuating, occasionally disappearing briefly. In most cases, no pyramidal signs were present but they have been seen in several cases (Bourgeois et al., 1993; Mikati et al., 2000; Fusco & Vigevano, 1995). Dystonic posturing often alternated with flaccid weakness and often resulted from attempts to move the hemiparetic arm. A disturbance of speech, apparently of motor origin, was experienced by some children notwithstanding the side involved. The effect of sleep is remarkable and mentioned in all reports (Dittrich et al., 1979; Krägeloh & Aicardi, 1980; Bourgeois et al., 1993; Mikati et al., 2000). Symmetrical movements are resumed within a few minutes of the child falling asleep. In long-lasting attacks, paralysis would reappear in the same location 10 to 30 minutes after awakening. Episodes of hemiplegia could disappear abruptly, especially when brief, but usually progressively over hours or days in more prolonged episodes. Bilateral episodes

These are a very specific feature of AHC and occur in virtually all cases. As described below, they may appear in two different circumstances, either in the course of a hemiplegic episode at the time hemiplegia, having started on one side,

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shifts to the opposite one (shifting attacks), or constituting the whole attack from onset. Such episodes (see below) may be extremely severe and, when prolonged, may be followed by a considerable behavioural and cognitive deterioration, usually with slow recovery. Quadriplegic attacks can fluctuate in severity with waves of transient improvement, and paralysis temporarily disappears on awakening. Parents often take advantage of this brief period to feed their child without the risk of choking and aspiration (Krägeloh & Aicardi, 1980; Bourgeois et al., 1993). Dyspneic episodes

Laboured, noisy breathing is commonly observed, especially during bilateral episodes, as are irregularities in respiratory rhythm. In a minority of patients, severe attacks of dyspnea and cyanosis, which can be life threatening, occur. Such episodes probably include a spasmodic element and are associated with intercostal retraction and stridor. In one patient, such dramatic attacks were considerably alleviated by tonsillectomy. Other autonomic phenomena

These are frequent during or between attacks and variably include sweating, peripheral cyanosis, diarrhoea, abdominal distention, fever, mydriasis, pallor or flushing, the latter three being unilateral in some cases. Headache is present in a significant proportion of older children and vomiting in a few. Patients often yawn and appear sleepy but cannot get to sleep and appear extremely uncomfortable and fussy. Epileptic seizures

It is not clear that epileptic seizures are a feature of AHC. The frequency of epileptic seizures in AHC patients varies with the reports from a low of 19% (Mikati et al., 2000) to a high of 50% (Sakuragawa, 1992). In a few cases (Dalla Bernardina et al., 1995), ictal EEG recorded typical partial seizures with a characteristic sequence of fast rhythms and spikes in patients who had only some slowing of EEG rhythms during hemiplegic episodes. However, the actual incidence of epileptic seizures is difficult to assess because the clinical features of AHC may be suggestive of epilepsy and because the seizures may appear only late in the course of the disorder. In three of my patients, clonic seizures, undoubtedly epileptic in nature, appeared at the peak of a hemiplegic attack, on the same side, whereas in five, they occurred independently. Status epilepticus occurred in two children. Non-paroxysmal features Delayed development or mental retardation

This is present in most patients but is of very variable degree. Only three of personal cases had a normal or border-line development and 90% of those of Mikati

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et al. were developmentally delayed. A majority of affected children have moderate to severe cognitive retardation and approximately 15 to 20% do not develop communication skills. Patients with early onset of AHC are more affected than those with late paroxysmal manifestations. Delay in motor milestones is the rule. In my series, independent walking was acquired at an average age of 44 months and three patients cannot walk after 4 years of age. Fine motor control remains poor in all cases. Fixed neurological abnormalities

These include gross hypotonia in most cases. Choreoathetotic movements involving the face, trunk and limbs are invariably noted with variable intensity. A dystonic component with the assumption of abnormal postures and slow torsional movements is also present in many children. Cerebellar ataxia is also present in most cases. It is essentially static in type and may be difficult to assess because of the interference of abnormal movements with balance and normal movements. A minority of patients developed pyramidal tract signs and weakness on one side or bilaterally. Clinical course

The course of AHC is difficult to schematize as the severity of symptoms, frequency and duration of episodes and ultimate degree of neurodevelopmental disturbances are so variable. However, the overall course of AHC seems to be progressive at least in its initial period. Although the onset may sometimes be in the neonatal period and in spite of the fact that 10 to 30% of infants may be hypotonic and delayed from a very early age (Bourgeois et al., 1993; Mikati et al., 2000), the clinical findings tend to change with time. During the first 12 to 18 months of life, abnormal ocular motor abnormalities and dystonic attacks usually predominate, whereas hemiplegic episodes are not a major part of the symptomatology and may be absent altogether. Developmental delay is mild or even undetectable. Subsequently, the complete clinical picture sets in with repeated hemiplegias, often of long duration and often shifting from one side to the opposite and quadriplegic attacks with severe autonomic manifestations. Severe attacks, especially quadriplegias, are at times followed by definite loss of previously acquired milestones and an impression of cognitive deterioration. Such features then tend to improve but no detailed follow-up of cognitive and behavioural development is available to decide whether full recovery eventually results. There is however an overall decrease of IQ which may also result from absence of new acquisitions. Later in the course, usually after 4 to 7 years of age, the frequency of hemiplegic and quadriplegic episodes may decrease but they have always persisted up to adulthood in patients followed up to age 30 years. The hemiplegias may lose at least part of the associated dystonic and autonomic com-

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ponents, although few long-term studies are available. Neurological deficits become prominent. In all personal cases, choreoathetosis, dystonia or ataxia were present by 5 years of age although their appearance was often later than the florid period of paroxysmal attacks – usually between the ages of 2 to 5 years. All abnormalities then seem to remain static, e.g. in the father and paternal grandmother of the patient of Mikati et al. after age 40 years, although complications such as pulmonary infections, choking and nutritional problems often supervene in severe cases and can result in early death (Bourgeois et al., 1995). However, one patient (Nezu et al., 1997) first developed paroxysmal ataxia at 23 years of age. The outcome of AHC is rather poor. Virtually all children have at least some degree of learning difficulties which are compounded by the high incidence of ataxia, choreoathetosis and dystonia to produce a severe educational handicap. Only occasional children have normal or borderline mentality. Some may additionally exhibit severe behavioural disorders as was the case in three of my patients. A significant proportion have major disabilities including inability to walk, talk and swallow and are severely retarded. Atypical forms

In some cases, a less stereotyped picture emerges. The most common atypical feature is a late onset of paroxysmal events after the first 18 months of life up to the age of 3–4 years (Mikati et al., 1992, 2000; Andermann et al., 1995a,b; Hart et al., 1997). Such a ‘late’ onset was observed by Mikati et al. (1992) in their familial cases and later, in a few other patients (Mikati et al., 2000). In an occasional patient, the appearance of hemiplegic episodes is even later (up to 8 years) although dystonic attacks may have started during the first semester (Mikati et al., 2000). In late onset cases, the severity of the disease and development delay tend to be milder. A familial form of AHC has been reported in five members of the same pedigree in three generations (Mikati et al., 1992). In this family, the disorder may have been associated with a balanced translocation 46,XY, t(3;q) (p26;q34) that was found in four affected patients. Another possible familial case (unpublished case quoted with the kind permission of Professor T. Deonna and Dr A. Ziegler, Lausanne, Switzerland), concerns a girl with a characteristic picture of AHC, having started with dystonic and hemiparetic attacks at 3.5 years and whose mother had had hemiplegic and dystonic episodes of short duration starting at the age of 12. I also heard of two possible cases in sisters, but those cannot be retained for want of precise information. Other reported possible atypical variants of AHC include the cases of infantile hypotonia with paroxysmal dystonia (Andermann et al., 1995a), those of benign familial nocturnal alternating hemiplegia (Andermann et al., 1995b) and of symptomatic alternating paroxysmal dystonia and hemiplegia (Hart et al., 1997). For

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those cases, the diagnosis of AHC remains dubious in the absence of a biological marker for the condition. Laboratory findings The paucity of abnormal laboratory findings in AHC patients is in striking contrast with the florid clinical manifestations. Because of the strangeness of the clinical findings, most patients undergo extensive investigations. Routine biochemical studies

These have been negative in all patients studied. These included serum and urinary amino acids and organic acids, plasma and CSF lactate and pyruvate levels, as well as CSF endorphin values, and histological and histochemical study of muscle and liver biopsies. However, an increase of lipids or subsarcolemmal mitochondrial clusters have been found in some cases (Mikati et al., 2000). Karyotypes were normal (except in Mikati’s family). Electrophysiological studies

These have also been of little help. Interictal EEG are normal in most cases. Ictal tracings may show a mild to moderate slowing over the hemisphere involved. They mainly demonstrate the absence of epileptic discharges, except when epileptic seizures, mostly clonic in type are recorded (Dalla Bernardina et al., 1995). Evoked potentials have been normal in several cases (Di Capua & Bertini, 1995). Nerve conduction velocities when measured, have been normal. Neuroimaging

Especially MRI does not show abnormalities although, in some cases studied lately, a mild degree of atrophy is found (Bourgeois et al., 1993; Sakuragawa, 1992). Progressive microcephaly has been reported (Mikati et al., in press) clinically. No change in signal is recognized. Progressive atrophy of the cerebellar vermis has been reported (Saito et al., 1998). Pulse Doppler study of the carotid artery contralateral to the hemiplegia showed an increased flow velocity (47 cm/s) in one child and no difference in two other patients (Bourgeois et al., 1993). SPECT has given variable results with either hyper- or hypoperfusion of the involved hemisphere (Zupanc et al., 1991, 1995; Aminian et al., 1993; Mikati & Fishman, 1995). Most probably there is decreased perfusion during the initial phase of the attack, followed by compensatory hyperperfusion during the recovery phase (Mikati et al., 2000; Zupanc et al., 1995). The limited results of PET scan are difficult to interpret. Reduced glucose metabolism or cerebellar hypometabolism have been demonstrated in a few cases. Phosphorus magnetic resonance spectroscopy of muscles and proton MRS of the

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brain may show some evidence of mitochondrial dysfunction (Arnold et al., 1993; Kemp et al., 1993). Thus, there may be a primary mitochondrial dysfunction in muscle although this may fluctuate and remains difficult to interpret. The reality of mitochondrial abnormalities in AHC has been questioned (Kyriakides & Drousiotou, 1994). The low NAA/Cr ratio in the brain more probably reflects some neuronal loss. Differential diagnosis A common cause of misdiagnosis of AHC is the failure to appreciate that it is a much more specific diagnosis than simply alternating or recurrent hemiplegia as this can be observed in many different conditions (Table 24.2). Epilepsy is a common diagnosis of AHC, especially at an early stage. Lateralized tonic attacks, followed by transient unilateral weakness are often misinterpreted as seizures followed by Todd’s paralysis. Additionally, vibratory tremor accompanying dystonic events can be mistaken for clonic activity and genuine epileptic seizures are not rare. Hemiplegic migraine may be pathophysiologically related to AHC but differs clinically by the absence of dystonic and ocular phenomena, of quadriplegic episodes and is not followed by neurologic sequelae or mental retardation. Some rare types such as familial hemiplegic migraine may be associated with progressive cerebellar ataxia, or other neurological features (Vahedi et al., 1995; Greenberg, 1997), but not with bilateral paralysis and cognitive difficulties. Some features, especially the occurrence of dystonic or choreoathetotic events, are common to AHC and various types of paroxysmal dyskinesias, especially the non-kinesigenic forms and residual symptoms such as ataxia can follow the acute episodes. No other disorder, however, shares such distinctive features as quadriplegia or mental deficiency. All other conditions listed in Table 24.2 usually do not represent major diagnostic problems. However, rare cases of cutis marmorata congenita (Baxter et al., 1993) and perhaps of Osler–Weber–Rendu disease (Myles et al., 1970), may present some difficulties. Likewise, some of the features of AHC may suggest the possibility of mitochondrial disorders such as MELAS (Mikati et al., 2000), but no actual infarct has ever been detected in that condition, and the biochemical features of mitochondriopathies are never found. Treatment No satisfactory therapy for AHC is currently available. Antiepileptic agents are ineffective, except against true epileptic seizures when present. However, the

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Table 24.2. Differential diagnosis of alternating hemiplegia of childhood

Epilepsy Postictal (Todd’s) paralysis Inhibitory seizures Epileptic encephalopathies Migraine and related conditions Hemiplegic migraine Basilar migraine Migraine – coma and atypical forms Paroxysmal dyskinesias Atypical kinesigenic dyskinesias Paroxysmal choreoathetosis (Mount and Reback) Paroxysmal torticollis of infancy Paroxysmal episodic ataxia (type 2) Metabolic diseases Mitochondrial disorders, especially mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS) Leigh’s subacute encephalomyopathy Pyruvate dehydrogenase deficiency Ornithine transcarbamylase and other ammonia cycle enzyme deficiencies Intermittent forms of organic acids and amino acid disorders Vascular diseases and blood coagulation abnormalities Vascular (arteriovenous) malformations Multiple emboli, e.g. atrial myxomas Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease) Cutis marmorata, livedo reticularis, Sneddon’s disease Homocystinuria Thrombocytemia Demyelinating diseases Acute disseminated encephalomyelitis (chronic forms) Multiple sclerosis Schilder’s disease

benzodiazepines, especially clonazepam, may be effective in occasional cases, perhaps more so when combined with flunarizine. Flunarizine, a calcium channel blocker, has proved to be of some value (Casaer, 1987; Silver & Andermann, 1993) in 50 to 85% of patients at doses of 5 to 15 mg/day. The main effect seems to be a reduction of the duration and severity of the attacks rather than a decrease in their frequency (Bourgeois et al., 1993; Silver & Andermann, 1993). In some cases, a highly significant reduction of the time with

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paralysis is obtained. However, total disappearance of the attacks is very rare. Whether successful treatment with flunarizine protects the patients against neurodevelopmental sequelae is currently unknown. It has not prevented the late appearance of cerebellar ataxia and atrophy in the case of Nezu et al. (1997). Undesirable side effects, especially extrapyramidal symptoms and signs that have been reported in adults, have not been observed to our knowledge in the treatment of AHC in children. Other agents such as haloperidol have been used and may also produce a reduction in the frequency of attacks (Salmon & Wilson, 1984). However, no controlled study is available and side effects may occur in the long term. A different approach to the treatment of AHC is represented by intermittent therapy of the incipient attacks. Administration of chloral hydrate rectally has been used by Siemes (1990) and interrupted the hemiplegia without side effects without inducing sleep if a low dose was used, i.e. 300 mg dissolved in sesame oil. A similar method using niaprazine by oral route has been proposed by Venizelli et al. (unpublished data). Comments The clinical features of AHC are quite characteristic in a vast majority of cases, even though the occurrence of some atypical cases is also recognized. In contrast, the causes and mechanism(s) of the disorder remain elusive. Although AHC was initially considered as a migraine variant (Verret & Steele, 1971), a number of its features are difficult to reconcile with migraine, especially the progressivity of the condition and the alterations of cognition and behaviour. In addition, the incidence of a family history of migraine, although variably appreciated, appears to be less than reported in migraine patients. Some vascular participation is suggested by the demonstration in some cases of hypoperfusion of the involved hemisphere, followed by transition to iso- then hyperperfusion during hemiplegic attacks (Nezu et al., 1997; Zupanc et al., 1991, 1995; Aminian et al., 1993). However, these findings are non-specific and may well be secondary to a primary neural dysfunction. The possibility of a mitochondrial disorder suggested by similarities to the MELAS syndrome, or other less well classified cases of probable mitochondrial cause, has not been confirmed by direct demonstration, even though phosphorus MRS in muscle was occasionally shown to be consistent with mitochondrial dysfunction and muscle pathology suggestive in a few patients (Mikati et al., 2000; Arnold et al., 1993; Kemp et al., 1993). Such anomalies have not been fully characterized and they may well be secondary to an unknown undetermined etiology (Kyriakides & Drousiotou, 1994). The recent demonstration that some cases of autosomal dominant hemiplegic

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migraine are due to mutations affecting a subunit of a P/Q type voltage-gated calcium channel suggests the hypothesis that a ‘channelopathy’ might also be responsible for AHC. Some cases of familial hemiplegic migraine due to mutations of the CaCNL1 A4 gene on chromosome 19 (Greenberg, 1997) also can feature nystagmus, ataxia and progressive cerebellar atrophy, thus showing that neurological sequelae can occur in ionic channel disorders. Such a hypothesis would account for many of the characteristics of AHC, especially its paroxysmal nature and the prominence of dystonic manifestations. Although most ‘channelopathies’ are genetically determined and this seems to be the case only rarely in AHC, acquired ionic channel disorders do occur, the most common example being myasthenia gravis. There is currently no confirmation to this hypothesis but further work along these lines is clearly indicated. Hopefully, this could lead to the discovery of more effective therapies.

R E F E R E N C ES

Aminian, A., Strashun, A. & Rose, A. (1993). Alternating hemiplegia of childhood: study of regional blood flow using 99m Tc-hexamethylpropylene amine oxime single-photon emission computed tomography. Annals of Neurology, 33, 43–7. Andermann, E., Andermann, F., Silver, K. et al. (1995a). Benign familial nocturnal alternating hemiplegia of childhood. In Alternating Hemiplegia of Childhood, ed. F. Andermann, J. Aicardi & F. Vigevano, pp. 145–9. New York: Raven Press. Andermann, F., Ohtahara, S., Andermann, E. et al. (1995b). Infantile hypotonia and paroxysmal dystonia. A variant of alternating hemiplegia of childhood. In Alternating Hemiplegia of Childhood, ed. F. Andermann, J. Aicardi & F. Vigevano, pp. 151–7. New York: Raven Press. Arnold, D.L., Silver, K. & Andermann, F. (1993). Evidence for mitochondrial dysfunction in patients with alternating hemiplegia of childhood. Annals of Neurology, 33, 604–7. Baxter, P., Gardner-Medwin, D., Green, S.H. & Moss, C. (1993). Congenital livedo reticularis and recurrent stroke-like episodes. Developmental Medicine and Child Neurology, 35, 917–21. Bourgeois, M., Aicardi, J. & Goutières, F. (1993). Alternating hemiplegia of childhood. Journal of Pediatrics, 122, 673–9. Bourgeois, M., Nevsimalova, S., Aicardi, J. & Andermann, F. (1995). Alternating hemipelgia of childhood: long-term outcome. In Alternating Hemiplegia of Childhood, ed. F. Andermann, J. Aicardi & F. Vigevano, pp. 49–54. New York: Raven Press. Campistol Plana, J., San Fito, A., Pineda, M. & Fernandez-Alvarez, E. (1990). Hemiplegia alternante en la infancia: forma de presentacion, evolucion y tratamiento. Annals of Espanol Pediatrics, 332, 336–8. Casaer, P. (1987). Flunarizine in alternating hemiplegia in childhood. An International study of 12 children. Neuropediatrics, 18, 191–5. Dalla Bernardina, B., Capovilla, G., Trevisan, E. et al. (1987). Alternating hemiplegia of

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Alternating hemiplegia of childhood infants. In Migraine and Epilepsy, ed. F. Andermann & E. Lugaresi, pp. 189–201. London: Butterworths. Dalla Bernardina, B., Fontana, E., Colamaria, V. et al. (1995). Alternating hemiplegia of childhood: Epilepsy and electroencephalographic investigations. In Alternating Hemiplegia of Childhood, ed. F. Andermann, J. Aicardi & F. Vigevano, pp. 75–87. New York: Raven Press. De Stefano, N., Silver, K., Andermann, F. & Arnold, D.L. (1995). Mitochondrial dysfunction in patients with alternating hemiplegia of childhood. In Alternating Hemiplegia of Childhood, ed. F. Andermann, J. Aicardi & F. Vigevano, pp. 115–21. New York: Raven Press. Di Capua, M. & Bertini, E. (1995). Evoked potentials and blink reflex studies in alternating hemiplegia of childhood. In Alternating Hemiplegia of Childhood, ed. F. Andermann, J. Aicardi & F. Vigevano, pp. 95–8. New York: Raven Press. Dittrich, J., Havlova, M. & Nevsimalova, S. (1979). Paroxysmal hemiparesis of childhood. Developmental Medicine and Child Neurology, 21, 800–7. Fusco, L. & Vigevano, F. (1995). Alternating hemiplegia of childhood: clinical findings during attacks. In Alternating Hemiplegia of Childhood, ed. F. Andermann, J. Aicardi & F. Vigevano F., pp. 29–41. New York: Raven Press. Greenberg, D.A. (1997). Calcium channels in neurological disease. Annals of Neurology, 42, 275–82. Hart, Y.M., Farrell, K., Tampieri, D. et al. (1997). Symptomatic alternating paroxysmal dystonia and hemiplegia. Annals of Neurology, 42, 159–71. Kemp, G.L., Taylor, D.J., Barnes, P.R.J. et al. (1993). Skeletal muscle mitochondrial dysfunction in patients with alternating hemiplegia of childhood. Annals of Neurology, 33, 604–7. Krägeloh, I. & Aicardi, J. (1980). Alternating hemiplegia in infants. Report of five cases. Developmental Medicine and Child Neurology, 22, 794–1. Kyriakides, T. & Drousiotou, A. (1994). No structural or biochemical evidence for mitochondrial cytopathy in a case of alternating hemiplegia of childhood. Annals of Neurology, 35, 289–93. Mikati, M.A., Maguire, H., Barlow, C.F. et al. (1992). A syndrome of autosomal dominant alternating hemiplegia: clinical presentation mimicking intractable epilepsy: chromosomal studies; and physiologic investigations. Neurology, 42, 2251–7. Mikati, M.A. & Fishman, A.J. (1995). Positron emission tomography in children with alternating hemiplegia of childhood. In Alternating Hemiplegia of Childhood, ed. F. Andermann, J. Aicardi & F. Vigevano, pp. 109–14. New York: Raven Press. Mikati, M.A., Kramer, U., Zupanc, M. & Shanahan, R. (2000). Alternating hemiplegia of childhood: Clinical manifestations and long term outcome. Pediatric Neurology, 23, 134–41. Myles, S.T., Needham, C.W. & Leblanc, F.E. (1970). Alternating hemiplegia associated with hereditary hemorrhagic telangiectasia. Canadian Medical Association Journal, 103, 509–11. Nezu, A., Kimura, N., Ohtsuki, N. et al. (1997). Alternating hemiplegia of childhood: report of a case having a long history. Brain and Development, 19, 217–21. Saito, Y., Sakuragawa, N., Sasaki, M. et al. (1998). A case of alternating hemiplegia of childhood with cerebellar atrophy. Pediatric Neurology, 19, 65–8. Sakuragawa, N. (1992). Alternating hemiplegia in childhood: 23 cases in Japan. Brain and Development, 14, 283–8. Salmon, M.A. & Wilson, J. (1984). Drugs for alternating hemiplegia. Lancet, ii, 980.

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25

Motor attacks in Sturge–Weber syndrome Alexis Arzimanoglou Department of Child Neurology, l’Hôpital Robert Debré, Paris, France

Introduction Sturge–Weber syndrome (SWS), is a sporadic, congenital, frequently progressive, neurological disorder classically characterized by the association of a congenital facial capillary angioma with leptomeningeal angiomatosis. Epilepsy, mental retardation, and focal neurological deficits are the major neurologic abnormalities (Alexander & Norman, 1960; Alexander, 1972; Gomez & Bebin, 1987). The motor attacks include, in addition to epileptic seizures, transient hemiparesis or hemiplegia, often leaving a definite neurological deficit. Other features of the syndrome include hemiatrophy, homonymous hemianopia, glaucoma, dental abnormalities, and skeletal lesions (Roach & Bodensteiner, 1999). Vascular abnormalities Although the cutaneous capillary angioma is the hallmark of the SWS, most children born with facial port-wine stains do not have the syndrome. The SWS facial angioma is classically found on the forehead and upper eyelid. For a patient with any facial port-wine stain, the risk of having the SWS is only about 8%. It increases to 25% when half of the face, including the ophthalmic division of the trigeminal nerve, is involved (Morelli, 1999). Intracranial leptomeningeal angiomatosis is almost always ipsilateral to the cutaneous nevus. Exceptions to the rule are not infrequent and the correlation between the extent and location of the naevus and that of the pial angioma is poor (Alexander, 1972; Gomez & Bebin, 1987; PascualCastroviejo et al., 1993). Some children have bilateral nevus with unilateral pial involvement or vice versa. Angiomas may extend beyond the face and involve the neck, trunk or limbs on one or both sides (Uram & Zubillaga, 1982). In a recent series of 20 surgically treated SWS patients, six presented with extensive cutaneous angiomatosis, which was bilateral in three (Arzimanoglou et al., 2000). Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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The leptomeningeal venous angiomatosis is striking and affects mainly the occipital and occipital parietal regions but does not extend into the cortex. Children with bilateral intracranial angiomatosis have a greater risk of neurologic impairment (Bebin & Gomez, 1988). The underlying cerebrum contains extensive calcification with or without involvement of the white matter. Some of the calcifications are oriented around blood vessels but most lie in the neuropil unrelated to obvious vasculature (Wohlwill & Yakovlev, 1957). Despite the extensive calcification, gliosis is surprisingly minimal. The embryologic continuity of the vascular plexus of the skin, eye and telencephalon suggests that an abnormality of the embryologic vascular plexus would explain the simultaneous existence of these separate lesions. The presence of an intracranial pial angioma is a prerequisite for the diagnosis of SWS but facial angioma may be lacking. A more extended use of MRI techniques for the detection of pial angiomatosis probably explains higher percentages of SWS without facial angioma in recent series. A pial angioma may be present in isolation or in association with choroidal angioma without facial nevus. For all practical purposes, such cases pose the same problems as the complete forms and should be regarded as belonging to the same syndrome (Arzimanoglou & Aicardi, 1992). Diagnoses to be ruled out in patients without facial angioma include the syndrome of cortical bilateral calcifications related to coeliac disease (Gobbi et al., 1988, 1992). The neuroradiological characteristics of this syndrome can be distinguished from those of SWS by their bilateral and cortico-subcortical localization and by the absence of visible injection by gadolinium (Arroyo et al., 1997). The ocular complications of SWS patients result principally from vascular abnormalities of the conjunctiva, episclera, retina, and choroid. Glaucoma is the most serious ophthalmologic complication, present in 30 to 70% of the affected patients (Cheng, 1999). Paroxysmal attacks Epileptic seizures

Epilepsy is an essential feature of SWS, as seizures are present in 75 to 90% of patients. It is the most common and usually the first neurological manifestation of the disorder and it is of major significance for prognosis and treatment. Evolution of the seizures in SWS patients is variable. Some patients may present an initial cluster of seizures, then remain seizure free for several months or years, even without medication. In others, epilepsy is of rather later onset and seizures may be rare. Remissions may last for several months before recurrence. Sujansky and Conradi (1995) reported that the age of onset of seizures, given for 133/136 patients, ranged from birth to 23 years of age, with a median of 6 months. In a series

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of 23 SWS children with epilepsy (Arzimanoglou & Aicardi, 1992) the age at onset ranged from 2 months to 14.5 years (median 10 months). In this study (Arzimanoglou & Aicardi, 1992) the first seizure was an episode of partial or unilateral status in six of the 23 patients. Episodes of convulsive status epilepticus had been recorded in the history of 12 patients. They were mostly longlasting clonic seizures, followed by permanent hemiparesis in at least six cases. In the majority of cases the fits included focal features, usually on the side opposite the facial angioma. Seventeen children had mainly clonic partial seizures involving one segment or half of the body. Partial sensory seizures were described by two patients (paresthesias in one leg by one and visual hallucinations by the other). Partial seizures with alteration of consciousness were recognized in 11 cases. Most commonly, they consisted of head rotation or eye deviation to the side opposite the angioma or initial clonic phenomena in the limbs followed by loss of consciousness and often hypotonia. Oro-alimentary automatisms were conspicuously absent. Twelve children had apparently generalized seizures, usually tonic–clonic in type but, in some, purely tonic or atonic. Bilateral myoclonic seizures were seen in two children. One girl presented with classical infantile spasms and later developed myoclonic, atonic and partial seizures. The occurrence of bilateral seizures and/or paroxysmal EEG abnormalities in association with unilateral leptomeningeal angiomatosis has been repeatedly reported (Rosen et al., 1984; Chevrie et al., 1988) and may be attributable to electrical diffusion or to secondary epileptogenesis. The course of the epilepsy is highly variable. All authors agree on the fact that an early age at onset of epilepsy is more commonly associated with a poor neurological and mental outcome. The natural history of the syndrome is unpredictable and is often parallel to that of seizures. Transient motor attacks

More than 50% of SWS patients present some type of focal deficit (Sujansky & Conradi, 1995; Pascual-Castroviejo et al., 1993; Roach & Bodensteiner, 1999). Visual field defects are frequent as a result of the usual posterior location of the pial angiomatosis, but the deficit most often noted is hemiparesis. Approximately 30 to 40% of SWS patients developed slowly progressive neurological deficits, both motor and cognitive, and became moderately or severely disabled (Ito et al., 1990). Transient motor deficits may be either postconvulsive or may occur at a distance from a seizure (Gilly et al., 1977). Transient postconvulsive hemiparesis or hemiplegia

This first appears in most cases following an episode of repeated seizures or status. It often becomes more severe with further recurrence of epileptic attacks. Hemiparesis often is progressive and is associated with increasing hemisphere

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Fig. 25.1

(b)

Progressive atrophy and appearance of calcifications in a boy with Sturge–Weber syndrome, who experienced only two partial seizures, but who also presented with migraine-like episodes. (a) The first CT scan was performed at the age of 16 months and (b) the control CT scan at 2 years later

atrophy (Fig. 25.1), as observed in hemiconvulsion–hemiplegia–epilepsy syndrome (Chauvel et al., 1991; Arzimanoglou & Dravet, 1999) and extension of calcifications. Definitive, acquired hemiplegia is common. These signs of neurologic deterioration may occur in an episodic, stepwise manner, they undoubtedly indicate progression and must be considered as elements favouring an early surgical solution (Arzimanoglou et al., 2000). Episodes of transient hemiplegia or acute weakness of a segment may occur without preceding seizures

Arzimanoglou and Aicardi (1992) reported acute episodes of transient hemiplegia unassociated with other features suggestive of epilepsy in seven of their 23 patients. One of their patients (Fig. 25.2) presented a first episode of partial status at the age of 9 months, accompanied by left hemiparesis. CT scan revealed diffuse calcifications over the right hemisphere. No more seizures were reported but she often complained of migraine-like episodes, characterized by a throbbing headache and vomiting, accompanied by a transient aggravation of her focal deficit. CT scan and MRI control 14 years later showed no evolution of the calcified, but already quite extensive, lesion. Transient motor attacks not related clinically to seizures are sometimes accompanied by headache, vomiting or other migraine-like phenomena. EEG recording during a transient attack of hemiparesis did not show epileptic activity (Arzimanoglou & Aicardi, 1992). Apparently this is not a

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Motor attacks in Sturge-Weber syndrome (a)

Fig. 25.2

(b)

(a) CT scan showing extensive calcifications over the right hemisphere of a young girl who experienced only one episode of partial status at the age of 3 months. No further seizures were reported but she regularly complained of migraine-like episodes. (b) MRI realized 14 years later showed no progression.

constant finding since, in a child with SWS who did not suffer from clonic seizures, we had the occasion to record occipital spikes during a migraine-like episode with vomiting. As discussed by Roach and Bodensteiner (1999) headache seems to be common among Sturge–Weber patients and it is unknown whether the frequency of headaches is higher within this setting as compared to the general population. Factors such as glaucoma or the commonly observed postictal headaches may be responsible. Furthermore, it can be difficult to distinguish complicated migraine from episodic neurologic deficits, similar to transient ischemic attacks, generated by the syndrome itself (Van Emde Boas et al., 1986; Cambon et al., 1987; Roach 1989). Maria et al. (1998) reported ‘stroke-like episodes’ (defined as the sudden onset of unilateral weakness, with or without seizure activity) in 14 out of 20 patients of their series. Seizures were observed at the time of the stroke-like events in five of the six patients aged 1 to 3 years (referred to in the study as Group A and representing young SWS patients with a short history of seizures) and in seven of the eight older children (aged 10 to 22 years, representing established SWS and referred to as Group B). Twelve of the 14 cases had stroke-like events lasting 24 hours and longer. Nausea and vomiting was reported in 7 out of 14. Six of the 14 cases experienced severe headaches either just before or at the time of stroke-like events. Cognitive deterioration, reported by Sujansky and Conradi (1995) in 58% of their patients (97/171), may also be a consequence of the seizures as shown by its development more or less parallel to seizures. Most patients without epilepsy, even

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with bilateral pial angioma, have a normal mentality, whilst 75% or more of those with seizures have cognitive or behavioural problems, or both (Gomez & Bebin, 1987). The mechanisms involved are not obvious. Cognitive regression probably implies bilateral functional brain disturbances, as unilateral lesions even extensive are not usually responsible for loss of cognition. This may be due in some cases to the EEG epileptic activity, as suspected in other epileptic syndromes such as infantile spasms with hypsarrhythmia and continuous slow spike waves during sleep. An abrupt deterioration was clearly correlated temporally to worsening of seizures and of EEG abnormalities in some SWS cases (Fukuyama & Tsuchiya, 1979; Rosen et al., 1984). Bilateral diffusion of EEG paroxysms and the occurrence of secondary epileptogenesis in the contralateral hemisphere could account for widespread brain dysfunction (Rosen et al., 1984). However, such a diffusion is not often present as in many cases only sporadic contralateral activity is seen. Furthermore, when bilateral, synchronous activity is present, it is not systematically accompanied with cognitive deterioration (Chevrie et al., 1988). The natural history of other neurological disorders with intractable epilepsy makes it difficult to accept, that the only mechanism responsible for the severe deterioration and progression in SWS, are seizures. Pathophysiology Although MRI, and additionally functional neuroimaging, permit the diagnosis and delineation of the pial angioma and of associated intracranial abnormalities (Lipski et al., 1990; Terdjman et al., 1991; Griffiths, 1996; Maria et al., 1999), it remains difficult to evaluate the progressive nature of the disease (Bebin & Gomez, 1988; Ito et al., 1990; Oakes, 1992; Arzimanoglou & Aicardi, 1992). The fact that most patients with SWS have normal neurologic function at birth but are impaired as adolescents or adults suggests a deterioration of function associated with the disease. The mechanisms of progressive atrophy and calcification are poorly known. All Sturge–Weber patients will not present with transient episodes of hemiparesis or hemiplegia and will not experience migraine-like episodes. Similarly, they will not necessarily show progressive cognitive deterioration. Although the presence of epileptic seizures aggravates the neurological outcome, the natural history of other neurological disorders with intractable epilepsy makes it difficult to accept, that the only mechanism responsible for the severe deterioration and progression in SWS, are seizures. An extensive literature has described the effects of hypoxia on CNS biochemistry, tissue perfusion, regional susceptibility, time course of damage, and reversibility from the insult (Auer & Siesjo, 1988; Siesjo, 1988; Volpe, 1987). A recent extensive review by Maria et al. (1999) of imaging brain structure and function in

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SWS, allows to suggest that almost all of the consistent findings of the disease (cortical calcifications, progressive cerebral atrophy underlying the pial angioma, thickening of the diploe, choroid plexus enlargement, development of prominent transmedullary and subependymal veins) implicate vascular mechanisms. Decreased cerebral blood flow and venous stasis may alter neurologic function by affecting cerebral glucose metabolism. Norman and Schoene (1977) have suggested that the calcifications may be related to diminished blood flow in the area underlying the pial angioma. This in turn may produce, hypoxia and increased capillary permeability. Hypoxic damage may result from the venous congestion secondary to failure of cortical vein development. Increased venous stasis and pressure will account for progressive hypoperfusion and hypometabolism. Progressively, the superficial drainage capacity, which is developmentally adapted to an extremely slow and probably turbulent flow pattern (Rotzin et al., 1959), may become insufficient (Probst, 1980). Severe hypoxia may result, especially when the increased metabolic rate resulting from the seizures requires an increased blood flow which cannot be sustained, the more so, as vasomotor and thrombotic phenomena may also occur (Garcia et al., 1981; Di Trapani et al., 1982). The most consistent angiographic features of the SWS are abnormal venous drainage patterns, lack of cortical vein visualization over the affected cortex, large and tortuous deep subependymal veins (Poser & Taveras; 1957), thus supporting the suggestion that deficient blood flow is a constant finding in SWS patients. Although transient paroxysmal attacks in SWS patients could be regarded as inhibitory epileptic seizures, their clinical manifestations are reminiscent of vascular dysfunction and they are probably due to vasomotor phenomena in and around the pial angioma. The pattern of stepwise thrombotic episodes producing an apparent gradual loss of function was first suggested by McCaughan et al. (1975), who interpreted them as transient ischemic attacks. The two patients reported by Garcia et al. (1981) support this hypothesis. They both had venous occlusions on arteriography and CT scans suggestive of infarction ant they were both successfully treated with aspirin to prevent thrombosis. The 19-year-old patient reported by Cambon et al. (1987) presented during a 6-month period more than 40 attacks suggestive of classic migraine, accompanied by moderate hemiparesis, aphasia and alexia. All manifestations ceased during a 4-year period under aspirin therapy. An identical episode was recorded 8 months after the discontinuation of treatment. A PET study with oxygen 15 continuous inhalation, realized while the patient was on aspirin, revealed a ‘misery perfusion’ syndrome with alterations of regional cerebral blood flow (rCBF) and oxygen extraction fraction without alteration in oxygen consumption. In all 20 cases studied by Maria et al. (1998), there were 119 strokelike episodes. Thirty-one of the 119 stroke-like events occurred in patients treated

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with aspirin. In the younger group of patients (Group A), there were 0.06 strokelike episodes per month when treated with aspirin and 0.19 if untreated. Additional arguments favouring the participation of a vascular mechanism are furnished by functional imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT). Chugani et al. (1989) showed that, in children with advanced SWS, the local cerebral metabolic rate for glucose was markedly depressed in the anatomically affected hemisphere, and in a distribution that extended beyond the abnormalities found on the CT scan. SPECT also showed a marked reduction of blood flow in the abnormal cortical and subcortical regions (Fig. 25.3). However, blood flow may be increased in the first few months and decrease only secondarily after the repetition of seizures (Riela et al., 1985; Chiron et al., 1989; Adamsbaum et al., 1996), indicating progression. To evaluate the involvement of an hemodynamic compromise in the progression of symptoms in SWS, Okudaira et al. (1997) measured regional CBF before and after acetazolamide (ACZ) activation using stable xenon computed tomography in six children and two adolescents. Four of them presented with intractable epilepsy and signs in favour of progression. The most evident difference between the groups was acetazolamide vasoreactivity in the primarily healthy area remote from lesion. ACZ vasoreactivity was significantly lower in the ‘progression group’, concerning both the distant areas of the affected side and the contralateral side. Values were similar for both groups in the area of primary lesion. The results reported by Maria et al. (1998), based on HMPAO and FDG SPECT studies, are also consistent with the hypothesis that hypoperfusion affects cellular glucose metabolism in SWS. In the younger group of patients (Group A), six children showed decreased perfusion on SPECT, while only four showed decreased glucose metabolism and two others presented with an increase in glucose metabolism. In the group of adolescents with established SWS (Group B) eight of the ten had decreased perfusion, while seven showed decreased glucose metabolism. Hemodynamic response to seizures was also evaluated by the Great Ormond Street group (Aylett et al., 1999) in three infants with SWS, by measuring rCBF using transcranial Doppler sonography and 99mTc HMPAO SPECT. SPECT showed hemispheric hypoperfusion interictally in all three and also ictally in one of the three. During seizures, increases of 6 to 30% in middle cerebral artery velocity (MCAV) were recorded for the clinically seizing hemisphere compared with 24 to 170% for the contralateral size in four of the seizures recorded. In one infant, MCAV fell bilaterally during a seizure that generalized (18% and 43% in the predominantly affected and contralateral side respectively). Sequential recordings in one infant suggested that, with time, the hemodynamic response to seizures of the unaffected hemisphere may decrease. Ictal SPECT in one of our patients revealed hyperperfusion in the pathological

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cortical and subcortical regions, with concomitant marked, bilateral hypoperfusion of the remaining cortex (Fig. 25.3: see colour plate section). Crossed cerebellar diaschisis is recognized as a cerebellar hemispheric hypometabolism, owing to the remote effect of a contralateral supratentorial infarction, arteriovenous malformation or tumour. Yoshikawa et al. (1990) reported the case of a 20-month-old SWS patient who presented with reduced CBF in the anatomically affected right parieto-occipital region. PET study also revealed contralateral cerebellar hypometabolism and reduction of metabolic rate of oxygen. Two other cases have been reported by Griffiths et al. (1997) and we observed a similar phenomenon in one of our patients. Cerebral hemodynamics during seizures are not fully understood. Particularly in patients with SWS interpretation of the various results is delicate. This is partly because of the variability in age at onset of seizures, brain maturation, incomplete developmental metamorphosis of the vasculature and extension of the pial angioma. The type of seizures, propagation of the discharges, the presence of secondary epileptogenesis and the eventual evolution of a partial seizure to a secondarily generalized one also may affect the results. Non-availability of techniques with adequate temporal and spatial resolution may represent an additional factor. However, all the above-mentioned data points to the fact that in SWS patients we are dealing with compromised cerebral hemodynamics and that failure to increase CBF appropriately during seizures leads to increased deficit. Treatment strategies Patients with Sturge–Weber syndrome usually present with an identifiable pathological substrate to their epilepsy, that may be responsible for intractable seizures and a progressive course of the disease. Transient neurologic deficits may progressively increase in frequency. They most probably implicate mechanisms resulting from haemodynamic incompetence but seizures have an aggravating role. The main target of therapy in SWS is prevention of epileptic seizures and treatment is clearly indicated from the first seizure. The rules applicable to epilepsies of other causes, especially to refractory cases, should be followed. In our series of 23 patients (Arzimanoglou & Aicardi, 1992) treatment was with antiepileptic drugs only in 14 patients, the remaining 9 presenting a rather intractable epilepsy, which necessitated surgical treatment. We often used carbamazepine, valproate or vigabatrin, but therapy should be individualized according to the patient’s response. The use of acetazolamide, when associated to carbamazepine, was beneficial for three patients. Episodes of status epilepticus should be arrested as soon as possible, using benzodiazepines or intravenous fosphenytoin, in an effort to prevent the appearance of post convulsive hemiplegia.

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We do not dispose of controlled studies supporting systematic antiplatelet drugs to prevent thrombosis. However, in the presence of transient paroxysmal attacks and in the light of available data favouring a hemodynamic compromise, the possibility of a vascular mechanism must be considered and the appropriate therapy prescribed. It is not unusual to find that medical therapy cannot prevent seizures. In such cases, surgery should be considered early, before irreversible damage is done (Arzimanoglou et al., 2000; Hoffmann et al., 1979; Ito et al., 1990; Ogunmekan et al., 1989; Rasmussen et al., 1972). The therapeutic approach of SWS should be considered as a typical example of lesional epilepsy surgery. We do not dispose convincing data to support the practice of performing hemispherectomy merely on the basis of early seizure onset. Initially treatment should always be medical. Parallel to medical treatment trials, all procedures permitting to evaluate extension of lesions (EEG, MRI, eventually PET or SPECT) should be undertaken and progression of lesions should be carefully monitored. When sufficient data to evaluate the potential benefits and risks of surgery is available, this solution must be proposed. A decision is relatively easy to reach in cases of unilateral pial angiomas limited to the occipital lobe especially if hemianopia is already present, as is often the case. The issue is much more complicated when intractable seizures are associated with normal neurological examination and the pial angioma involves the motor strip. In our experience, and despite the inherent difficulties related to an unpredictable natural history, surgery is better to be decided early for patients who present with intractable seizures and a progressive symptomatology. Neurologic deterioration is usually the case of patients who initially present with focal motor seizures that progressively increase in frequency and duration and/or evolve to attacks with frequent secondary generalization. Transient postictal deficits tend to last longer and development of sensory, motor and visual hemideficit is the usual outcome. Serial CT scans may document progression of initial focal atrophy of the structures underlying the pial angioma or progressive enlargement of calcified lesions (Arzimanoglou et al., 2000). Patients with hemiplegia, hemianopia or evidence of intellectual and behavioural deterioration must also be considered for surgery. Timing and type of surgery (hemispherectomy, cortical resection of the abnormal cortex or lobectomy) must be decided on the basis of clinical analysis, EEG and neuroimaging data and performed in centres with age-appropriate facilities for preoperative evaluation, postoperative care, as well as experience in paediatric epilepsy surgery (Roach et al., 1994). Although general experience indicates that, in focal epilepsies, best results follow resection of neurophysiologically defined epileptogenic zone, this does not seem to be valid for corticography in SWS. Our results (Arzimanoglou et al., 2000) suggest that lesionectomy is sufficient to control

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seizures, provided we are dealing with a unilateral pial angioma and that resection can be complete. The impairment of the cerebral hemodynamic response discussed above, suggests that a functioning deep venous drainage system would appear to make an early resection of the pial angioma meaningful as this would eliminate the flow deviation from the angiodysplastic area towards the depths. When lesions are diffuse and progression is evident, hemispherectomy may be undertaken, provided that the expected benefit is sufficiently high in a given patient to offset definite neurological sequelae. Epilepsy probably plays an important role in the aetiology of the mental and neurological deterioration in addition to being a disability per se. The cause(s) and mechanism(s) of the inhibitory influence that the abnormal hemisphere is thought to exert on the more normal one remains mysterious. It seems, however, to be real as indicated by the rapid improvement observed following surgery in reported cases. Other mechanisms, particularly vascular, are also involved. More research is needed to better understand their role and prevent their damaging effects.

R E F E R E N C ES

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Syndromes with epilepsy and paroxysmal dyskinesia Renzo Guerrini1, Lucio Parmeggiani2 and Giorgio Casari3 1

Neurosciences Unit, Institute of Child Health, The Wolfson Centre, London, UK Institute of Child Neurology and Psychiatry, University of Pisa, Italy 3 Department of Human Molecular Genetics IRCCS San Raffaele Hospital, Milan, Italy 2

Introduction Epilepsy and paroxysmal dyskinesia (PD) may sometimes be difficult to differentiate clinically. Although for this reason in the past it has been hypothesized that episodes of PD could represent a form of epilepsy (Lishman et al., 1962; Whitty et al., 1964; Burger et al., 1972), the current understanding is that the two disorders are distinct (Fahn, 1994). However, there are several recent reports of families in which some individuals presented either or both paroxysmal disorders, with different age-related expression. Co-occurrence makes it likely that a common, genetically determined, pathophysiological abnormality is variably expressed in the cerebral cortex and in basal ganglia. A rather homogeneous syndrome of autosomal dominant infantile convulsions and paroxysmal (dystonic) choreoathetosis (ICCA) was described in 20 families from France, China, Japan, and the United States (Szepetowski et al., 1997; Lee et al., 1998; Guerrini et al., 1999; Swoboda et al., 2000; Tomita et al., 1999). Linkage analysis allowed the mapping of the disease gene to partially overlapping loci in the pericentromeric region of chromosome 16. Additional autosomal dominant pedigrees are on record, from Australia and Italy, in which epilepsy was variably associated with paroxysmal kinesigenic or exercise-induced dystonia (Perniola et al., 1998; Singh et al., 1999). A pedigree in which three members in the same generation were affected by rolandic epilepsy, paroxysmal exercise-induced dystonia (PED) and writer’s cramp was reported from Italy (Guerrini et al., 1999). Linkage analysis showed a common homozygous haplotype in a critical region spanning 6 cM and entirely included Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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within the critical region described in the French families (Szepetowski et al., 1997), partially overlapping with the critical region assigned to the North American families (Swoboda et al., 2000) and distinct but contiguous to the critical region described in the Japanese families (Tomita et al., 1999). Clinical analogies and linkage findings suggest that the same gene could be responsible for these clinically overlapping syndromes, with specific mutations accounting for each of these mendelian disorders. Chromosome 16 could harbour a family of genes which give rise to paroxysmal disorders, as suggested by the linkage to partially overlapping markers spanning from the pericentromeric region to 16q22.1 of two large pedigrees of Indian and African American origin with autosomal dominant paroxysmal dyskinesia. Ion channel genes are potentially interesting candidates for syndromes featuring both these paroxysmal neurological disorders. Ion channel gene defects have recently been demonstrated in some genetic forms of epilepsies (Wallace et al., 1998; Singh et al., 1998; Charlier et al., 1998), of paroxysmal movement disorders (Browne et al., 1994; Litt et al., 1994; Vahedi et al., 1995) and of other neurological disorders associating different paroxysmal manifestations (Ophoff et al., 1994, 1996; Joutel et al., 1994) with considerable clinical variability. Moreover, different mutations in the same ion channel gene (CACNL 1A4) cause two different paroxysmal non-epileptic disorders in humans (episodic ataxia type 1 (Ophoff et al., 1996); and familial hemiplegic migraine (Joutel et al., 1994)) and absence seizures in the mouse mutant (Fletcher et al., 1996; Burgess et al., 1997). It is therefore, highly probable that ion channel gene disorders could provide the pathophysiological link for co-occurrence of epilepsy and PD. In the present chapter we analyse the clinical elements that support the differential diagnosis between epilepsy and paroxysmal dyskinesia and review the syndromic association of idiopathic epilepsy and paroxysmal dyskinesia. Paroxysmal dyskinesia and epilepsy: differential diagnosis Demirkiran and Jankovich (1995) classified their patients with PD into three main categories: (i) kinesigenic PDs (with attacks usually lasting less than 5 minutes); (ii) exercise-induced PDs (with attacks usually lasting more than 5 minutes) and (iii) non-kinesigenic PDs (with attacks usually lasting hours). Most sporadic and all familial cases of PD are idiopathic. The familial (dominant) form of nonkinesigenic PD is linked to chromosome 2q (Fouad et al., 1996; Fink et al., 1996; Hofele et al., 1997). Putaminal or thalamic lesions have been demonstrated using neuroimaging in some patients with sporadic PD (Merchut & Brumlik, 1986; Camac et al., 1990; Burguera, 1991). Etiologies of symptomatic PD, accounting for a minority of sporadic cases include infarctions (Merchut & Brumlik, 1986; Camac et al., 1990), multiple sclerosis (Burguera, 1991; Miley &

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Forster, 1974), hypoxic encephalopathy (Rosen, 1964); thyreotoxicosis (Fischbeck & Layzer, 1979), hypoparathyroidism (Tabaee-Zadeh et al., 1972), and diabetes mellitus (Clark et al., 1995). Carbamazepine and phenytoin are often effective in controlling attacks at dosages producing the same plasma levels effective in epilepsy or at lower levels (Fahn, 1994; Hwang et al., 1998). Sodium valproate seems to be less effective (Hwang et al., 1998). It has been argued that PDs, either kinesigenic or non-kinesigenic, may represent one expression of epilepsy (Spiller, 1927; Hudgins and Corbin, 1966; Stevens, 1966), because of the paroxysmal character, the possible presence of prodromic aura-like symptoms, the short duration of the attacks and their response to antiepileptic drugs. Most of the cases described as movement-induced epileptic seizures by Lishman et al. (1962), presented with childhood-onset episodes of focal or generalized stiffening followed by choreoathetosic movements, with preserved consciousness. While some of these patients could have had paroxysmal kinesigenic choreoathetosis, others had epileptiform EEG abnormalities and possibly a form of reflex epilepsy akin to startle epilepsy. This is also possible for the patients with spontaneous or movement-induced paroxysmal dyskinetic attacks that appeared following brain injury (Robin, 1977; Richardson et al., 1987). In general, the presence of sustained twisting, athetosic or choreic movements, lack of EEG abnormalities during attacks, lack of episodes of unresponsiveness which would mean spread of seizure activity outside the frontal lobes, all indicate a non-epileptic origin (Fahn, 1994). On the other hand, some ictal manifestations which are typical of frontal lobe seizures have often been misdiagnosed as due to idiopathic PD (for review, see Fish & Marsden, 1994), because of their semiology (Morris et al., 1988) and of their frequent occurrence in patients without any brain lesion and without any accompanying ictal EEG changes (Scheffer et al., 1994). Lugaresi and Cirignotta (1981) introduced the term nocturnal PD when describing a group of patients with frequent brief, sleep-related attacks characterized by predominantly dystonic movements. Lack of any ictal or interictal scalp EEG abnormality has added to the difficulty in correctly diagnosing the nature of such episodes, as confirmed by several subsequent reports (Lee et al., 1985; Rajna et al., 1983; Godbout et al., 1985; Crowell & Anders, 1985). Although it took 20 years from the first description by Lugaresi and Cirignotta (1981), before the paroxysmal dystonic-like nocturnal episodes were found to be accompanied by ictal scalp EEG activity in a few patients (Tinuper et al., 1990), previous studies with depth electrodes had demonstrated that similar attacks were actually the expression of seizure activity in the mesial frontal lobe (Rajna et al., 1983; Niedermyer and Walker, 1971). Absence of ictal EEG changes in the surface EEG is not surprising considering the mesial and deep location of the area of seizure origin in these patients. Using both subdural strips and depth electrodes, Lombroso (1995) demonstrated that choreoathetosis-like

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seizures may be accompanied by ictal activity involving both the supplementary sensorimotor cortex and the homolateral caudate nucleus. Although such a spread might be particularly frequent due to the strong cortico-subcortical connections existing between the supplementary sensorimotor cortex and the basal ganglia (Goldman & Nauta, 1977; Selemon and Goldman-Rakic, 1985; Walker, 1966), its actual frequency and the respective role of the cortical and subcortical structures in producing the dyskinetic-like seizure pattern have yet to be determined. Dystonic posturing may also occur during seizures originating in the temporal lobe (Kotagal et al., 1989), during which it is usually accompanied by additional, often prominent ictal features such as unresponsiveness and automatisms, and it is secondary to the spread of the ictal discharge to the frontal and parietal cortex (Bossi et al., 1984). Startle-induced epileptic seizures may sometimes mimic paroxysmal dyskinetic attacks. A sudden stimulus, either acoustic or somatosensorial, may trigger sudden dystonic posturing, or stiffening, which may involve a body segment, a hemibody, or be generalized, often without any obvious impairment of consciousness (Gastaut & Tassinari, 1996; Bancaud et al., 1967; Guerrini et al., 1990). Most patients with startle epilepsy have a brain lesion producing congenital hemiplegia and present, in addition, spontaneous seizures which may be similar or different from the reflex-induced attacks. Ictal scalp EEG activity may be difficult to recognize in those patients whose attacks are characterized by diffuse stiffening, which determines a great amount of scalp muscle activity obscuring the concomitant ictal discharge. In this type of seizure, depth electrode studies have demonstrated that seizure activity involves the supplementary motor area or the primary motor cortex (Bancaud et al., 1967). The following sequence has been hypothesized (Bancaud et al., 1975): surprise stimulation – startle reaction – afferent proprioceptive volley – epileptic seizure. The initial startle response and the subsequent motor seizure may produce a bizarre paroxysmal dystonic posturing. True association of epilepsy and paroxysmal dyskinesia Co-occurrence of epilepsy and PD in the same individual or their familial aggregation is not infrequent (Lance, 1977; Plant et al., 1984; Fukuyama & Okada, 1968; Pryles et al., 1952; Hwang et al., 1998; Bhatia et al., 1997; Jung et al., 1973). Both paroxysmal non-kinesigenic (or dystonic) choreoathetosis (Lance, 1977; Fukuyama & Okada, 1968; Pryles et al., 1952; Hudgins & Corbin, 1966; Jung et al., 1973) and paroxysmal exercise-induced dystonia (PED) (Plant et al., 1984) have been described in patients also suffering from epilepsy. However, only recently it has become evident that epilepsy and PD can be associated within a definite syndrome with mendelian inheritance (Table 26.1). Szepetowski et al. (1997)

Table 26.1. Syndromes in which epilepsy and paroxysmal dyskinesia or in which either disorder is associated with other paroxysmal neurological manifestations

Epilepsy and other paroxysmal neurological manifestations

Paroxysmal dyskinesia with other paroxysmal neurological manifestations

Autosomal dominant paroxysmal (dystonic) choreoathetosis and benign infantile convulsions (Szepetowski et al., 1997; Lee et al., 1998; Swoboda; et al., 2000; Tomita et al., 2000 Linkage: chromosome 16, pericentromeric

Episodic ataxia type 1 and infantile convulsions (Zuberi et al., 1999) Gene: potassium channel KCNA1

Autosomal dominant paroxysmal choreoathetosis and episodic ataxia (Auburger et al., 1996) Linkage: chromosome 1 p

Autosomal recessive RE with PED and WC (Guerrini et al., 1999) Linkage:chromosome 16p12–11.2

Familial hemiplegic migraine and seizures (Gardner et al., 1997) Linkage: chromosome 1p31

Autosomal dominant paroxysmal dystonic choreoathetosis with classic migraine (Hofele et al., 1997) Linkage: chromosome 2q

Autosomal dominant kinesigenic PD, migraine, hemiplegic migraine and generalized epilepsy with febrile seizures (Singh et al., 1999)

Familial hemiplegic migraine and benign infantile convulsions (Terwindt et al., 1997)

Autosomal dominant PED and migraine (Munchau et al., 2000)

Autosomal dominant PED and epilepsy (Perniola et al., 1998)

Benign infantile convulsions, idiopathic generalized epilepsy, episodic ataxia, migraine (Singh et al., 1999)

Epilepsy and paroxysmal dyskinesia

Notes: PD: paroxysmal dyskinesia; PED: paroxysmal exercise-induced dystonia; RE: rolandic epilepsy; WC: writer’s cramp.

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described four families from the north of France showing a homogeneous syndrome of familial infantile convulsions, expressed as an autosomal dominant trait, together with variably expressed paroxysmal (dystonic) choreoathetosis (ICCA) (Szepetowski et al., 1997). Out of the 29 affected members of the four families, 22 had infantile partial seizures, almost always with early motor signs and beginning between the fourth and tenth month of life; 12 of those with seizures as well as three others had dyskinetic attacks starting in childhood or early adolescence, which were exercise induced in six. While epileptic seizures were limited to infancy, it remains to be clarified whether the dyskinetic attacks were likewise age related. Linkage analysis performed under the assumption of an autosomal dominant pattern of inheritance with a penetration of 0.81, allowed the mapping of the disease gene to the pericentromeric region of chromosome 16, in a 10 cM interval, between D16S401 and D16S517. Lee et al. (1998), confirmed both the syndrome and linkage to the same chromosomal region in a Chinese family in which nine members in three generations were affected. A different phenotypic expression of the disorder was represented in the Chinese pedigree by seizure recurrence at a later age, predominantly generalized rather than partial seizures, episodes of status epilepticus in some individuals and by a very mild expression and duration of dyskinetic attacks. Phenytoin was reported to be effective in stopping both dyskinetic episodes and seizures, which, in any case, disappeared by the age of 20–30 years. Linkage analysis not only confirmed gene assignment to the pericentromeric region of chromosome 16 but also the finding that individuals carrying the disease aplotype in the critical region may be clinically unaffected (Szepetowski et al., 1997). Sadamatsu et al. (1999) described a pedigree in which five members in three consecutive generations were affected by a form of paroxysmal kinesigenic choreoathetosis with attacks precipitated by sudden movement or exercise. Attacks had started during school age in all individuals and had disappeared or were greatly reduced in frequency in the three patients reaching adulthood. Four out of the five affected patients had suffered generalized convulsions during infancy with no recurrence at a later age with or without treatment in most of them. The authors stressed that video-EEG monitoring during dyskinetic attacks in two patients showed no EEG changes, consistently with non-epileptic origin, adding to the evidence that epilepsy and PD are distinct manifestations. To reinforce this observation, they ruled out genetic linkage with five known chromosomal regions previously linked to epilepsy or movement disorders (1p (Auburger et al., 1996), 2q33–35 (Fouad et al., 1996; Fink et al., 1996), 6p21.2–11 (Liu et al., 1995) and 10q23.3–q24). They did not realize, however, that they were describing a syndrome identical to ICCA. However, Tomita et al. (1999), subsequently, linked to chromosome 16p11.2–12.1 the same family and seven other families of whom five presented with paroxysmal kinesigenic choreoathetosis and infantile convulsions and

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two with paroxysmal kinesigenic choreoathetosis alone. This locus partially overlaps the ICCA critical region and is contiguous to but not overlapping with the RE–PED–WC locus. A subsequent report from Swoboda et al. (2000) confirmed the linkage to the pericentromeric chromosome 16 (from D16S3131 to D16S3396) of a syndrome of paroxysmal dyskinesia and infantile convulsions (PKD/IC), clinically similar to ICCA. The PKD/IC critical region partially overlaps with both the ICCA (from D16S3131 and D16S517) and RE–PED–WC (D16S3131) critical regions. These authors reported 11 families with different ethnic backgrounds in which 44 individuals were affected by PKD (42), IC (37) or both (18). Episodes of IC were brief and spontaneous and remitted by age 3 years in the absence of treatment. Onset was between 3 and 18 months of age. Age at onset for PKD was around 11 years. Episodes were triggered by sudden movement in all cases. Three individuals also reported episodes during physical exertion such as running or swimming. PKD episodes lasted uniformly less than 5 minutes, the majority lasting only seconds. Most individuals remained symptomatic at the time of participation in the study; virtually all reported improvement with age over 25 years. In addition to familial observations, two sporadic patients with clinical features and outcome identical to the ICCA syndrome are on record (Koch et al., 1999; Echenne et al., 1999). Singh et al. (1999) described an Australian family of Anglo-Saxon origin in which nine members in three generations presented with epilepsy (febrile seizures and febrile seizures plus), kinesigenic PD, migraine and hemiplegic migraine, in various combinations (febrile seizures and kinesigenic PD co-occurred in two patients). Perniola et al. (1998) reported an Italian family, with six affected individuals in three generations, exhibiting a syndrome characterized by long-duration PED attacks beginning between age 5 and 10 years and disappearing between age 18 and 30 years, accompanied by different seizure types: absences during school age in three patients; complex partial seizures in adolescence and adulthood in one patient; generalized tonic–clonic beginning after 10 years and with uncertain evolution in two other patients. Additional findings were myotonic discharges in one patient and mild mental retardation in three. A pedigree in which three members in the same generation were affected by rolandic epilepsy (RE), PED and writer’s cramp (WC) was recently reported (Guerrini et al., 1999). Both the seizures and PD had a strong age-related expression that peaked during childhood, while the WC, also appearing in childhood, had been stable since diagnosis. Clonazepam had some efficacy in reducing PED attacks in one patient, while acetazolamide had no significant effect. Genome-wide linkage analysis carried out under the assumption of recessive inheritance identified a

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common homozygous haplotype in a critical region spanning 6 cM between markers D16S3133 and D16S3131 on chromosome 16, cosegregating with the affected phenotype and producing a multipoint (LOD) score value of 3.2. Although the RE–PED–WC syndrome has unique features, it presents striking analogies with the ICCA syndrome, linked to a 10 cM region between D16S401 and D16S517, which entirely includes the 6 cM of the RE–PED–WC critical region. The same gene could be responsible for both RE–PED–WC and ICCA, with specific mutations accounting for each of these mendelian disorders. A similar finding has been reported for the chloride channel 1 gene (CLCN1), whose mutations are found in Becker and Thomsen disease, both associated with generalized myotonia. Becker disease is transmitted through an autosomal recessive pattern of inheritance, whereas Thomsen disease is transmitted in an autosomal dominant fashion (Koch et al., 1992). Bennett et al. (2000) recently linked to chromosome 16p11.2–q11.2 an AfricanAmerican family with paroxysmal kinesigenic dyskinesia (PKD). The critical regions for PKD and for ICCA partially overlap by 6 cM between D16S769 and D16S517 and those for PKD/IC and ICCA overlap by 7.4cM between D16S3131 and D16S517 (Fig. 26.1). Different mutations of the same gene or two distinct genes may underlie these disorders. PKD and RE–PED–WC critical regions are contiguous but non-overlapping since D16S3131 (representing the RE–PED–WC lower boundary) and D16S769 (the PKD upper boundary) map at no recombination. These mapping data indicate the presence of more than one gene responsible for these two forms (Guerrini et al., 2000). An additional family with paroxysmal kinesigenic choreoathetosis (EKD2) has recently been linked to a slightly more telomeric region on chromosome 16, partially overlapping with the PKD locus (Valente et al., 2000). EKD2 spans between 16q13 and 16q22.1 (markers D16S685 to D16S503). The EKD2 region, however, does not overlap with those identified in any of the families featuring both epilepsy and paroxysmal dyskinesia. There is therefore, evidence for two or more genes clustering to human chromosome 16 that cause epilepsy, paroxysmal dyskinesia or both. Clinical and neurophysiological abnormalities producing the epilepsy/PD syndromes are possibly caused by disturbances involving the motor cortex as well as the basal ganglia. It also appears that with epilepsy usually being manifested earlier than PD, when defining the syndromic spectrum of genetically determined epilepsy and PD, as well as other paroxysmal neurological disorders, one must make sure that general concepts of idiopathic/benign transient disorders be satisfied rather than expecting a strictly age-related expression. For example, variable phenotypic expressions of epilepsy were observed in association with mutation of the SCN1B gene (Wallace et al., 1998) and variable age of onset of convulsions was present in the family with benign neonatal (extending to infancy) convulsions showing the

Fig. 26.1

Schematic drawing showing loci (in italic bold) where the different disorders featuring epilepsy and paroxysmal dyskinesia have been mapped on chromosome 16.

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KCNQ2 mutation (Singh et al., 1998). Different mutations of the disease gene, the existence of modifier gene(s) and the influence of environmental factors may account for intrafamilial and interfamilial phenotypic variability. Ion channel genes are potential candidates for syndromes featuring both epilepsy and PD, as well as other syndromes in which either epilepsy or PD occur in association with other paroxysmal neurological manifestations (Table 26.1). Different mutations of the same ion channel can produce different phenotypes, presumably via different functional effects. In families with epilepsy and PD, the same mutation causes different age-related phenotypic manifestations. A possible explanation may rely on age-related expression of different subunits of the same ion channel (Tinel et al., 1998). IC could be caused by a mutation in a channel causing cortical hyperexcitability in the first years of life, subsequently remitting when channel function is restored by other subunits. Peaking of functional expression of the mutated ion channel subunits at a later stage in the basal ganglia would lead to later appearance of PKD (Berkovic, 2000). The transient expression of both epilepsy and PD has certainly caused their association to be under-recognized. Only recently, due to better knowledge of the two disorders and widespread use of vido-EEG techniques, has their association been better assessed. Increased awareness of their possible co-occurrence in the same patient, either in the same period of life or at different ages, will certainly increase the number of observations in the next few years.

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Epilepsy genes: the search grows longer Antonio V. Delgado-Escueta1, Marco T. Medina2, Maria Elisa Alonso3 and G.C.Y. Fong4 1

Comprehensive Epilepsy Program, UCLA and VA Greater Los Angeles Healthcare System, CA, USA Department of Neurology, Autonomous University, Tegucigalpa, Honduras 3 Department of Genetics National Institute of Neurology and Neurosurgery, Mexico City, Mexico 4 Division of Neurology, University Department of Medicine, Queen Mary Hospital, Hong Kong 2

Introduction This chapter initially reviews the new advances in molecular genetics of idiopathic epilepsies in infants, children, adolescents and adults and provides a progress report on the search for chromosomal loci of epilepsy syndromes. After presenting an overview on the molecular genetics of idiopathic epilepsies, this chapter focuses on phenotypes and genotypes of genetic epilepsies that are commonly mistaken for movement disorders. Understanding the genotypes and phenotypes of movement disorders and epilepsies in infants, children and adolescents is important because some motor signs of idiopathic epilepsies of infants, children and adolescents are mistaken for movement disorders and some movement disorders of children and adolescents are mistaken for the epilepsies. Moreover, understanding the new advances in the molecular genetics of movement disorders and epilepsies is important because they provide us with more than a glimpse of the new practice of molecular neurology. The epilepsies have traditionally been classified and subtyped on the basis of clinical and neurophysiologic concepts. The complexity and variability of phenotype and overlapping clinical features limit the resolution of phenotype-based classification and confounds epilepsy nosology. Identification of tightly linked epilepsy DNA markers and discovery of epilepsy causing mutations provide a basis for refining the classification of epilepsies. Table 27.1 lists some of the epilepsies commonly mistaken for movement disorders and Table 27.2 gives some descriptions used by the referring physicians that made them mistakenly suspect a movement disorder in patients with juvenile myoclonic epilepsy (JME). Patients initially diagnosed to have movement disorders Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Table 27.1. Some epilepsies mistaken as movement disorders

Benign familial neonatal convulsions Familial infantile convulsions and paroxysmal choreoathetosis Generalized epilepsy with febrile seizures plus Autosomal recessive idiopathic myoclonic epilepsy of infancy Myoclonias in JME Myoclonias in CAE evolving to JME Photogenic childhood absence with eyelid myoclonia evolving to JME Tonic adversive seizures in frontal lobe epilepsy Benign adult familial myoclonic epilepsy Extensor or flexor spasms in West syndrome Autosomal dominant nocturnal frontal lobe epilepsy Autosomal dominant partial epilepsy with variable foci Autosomal recessive rolandic epilepsy with paroxysmal exercise induced dystonia and writer’s cramp Rolandic epilepsy Generalized clonic seizures in idiopathic generalized epilepsies Segmental myoclonias in progressive myoclonus epilepsies Epilepsia partialis continua

were verified to have myoclonias and rapid spike-wave complexes on CCTV-EEG telemetry. Involuntary muscle movements of the lips, tongue or jaw impairing speech or eating, segmental myoclonias of limbs, massive body jerks propelling or retropulsively moving the patient were suspected to be movement disorders. Examples of diagnostic dilemma in epilepsy and movement disorders are the syndromes of familial infantile convulsions with paroxysmal choreoathetosis in chromosome 16p12–q12, autosomal recessive idiopathic myoclonic epilepsy of infancy in chromosome 16p13, benign familial neonatal convulsions in chromosomes 20q or 8p, benign myoclonic epilepsy of infancy, severe myoclonic epilepsy of infancy, juvenile myoclonic epilepsy and progressive myoclonic epilepsies of Lafora or Unverricht–Lundborg, where jerks of partial seizures or myoclonias from various parts of the body are often looked at as symptoms or signs of a movement disorder. Similar mistakes can occur in the syndrome of childhood absence epilepsy evolving to JME, photogenic absence with eyelid myoclonia evolving to JME and in the syndrome of primary myoclonic seizures of early childhood. Somatomotor jerks in the syndromes of benign familial neonatal convulsions, benign familial infantile convulsions, autosomal dominant familial frontal lobe epilepsy, benign rolandic

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Table 27.2. Myoclonic seizures (verified on video-EEG) mistaken as movement disorders

Movement disorder symptoms (number of patients) Tremors/nervousness of hands/legs (9) Propulsive ataxia (3) Tics (nervous habits) (1) Slurred speech (jerks of mouth, tongue muscles) (2) Torsions/unilateral jerks (4) Frequent sighs and deep breathing after repeated jerks (3) Early morning nervousness/tremors (5) Retropulsive steps backwards (2) Difficulty eating, chewing and swallowing (2)

epilepsy of childhood can also be mistaken as signs of a movement disorder. Rarely, both epilepsy and movement disorder may be present in a family such as that reported by Sperfeld et al. (1999), from the Netherlands where a mutation in the tau gene on chromosome 17 produced an autosomal dominantly inherited frontotemporal dementia, parkinsonism and epileptic seizures. The idiopathic generalized epilepsies Forty to 100 million persons worldwide suffer from epilepsy. Approximately 50% are due to generalized epilepsies (Hauser & Hesdorfer, 1990). Amongst the generalized epilepsies, the most common are epilepsies of infancy, childhood and adolescence, such as neonatal convulsion, febrile seizures, JME, childhood absence epilepsy and pure grand mal tonic clonic epilepsy (ILAE Commission, 1981, 1989). Febrile convulsions are the most common form of seizures in infancy and childhood affecting 2% to 5% of North American and European children between 6 months and 6 years. Febrile seizures affect 6% to 9% of Japanese infants and up to 14% of children in certain Pacific Islander populations (Peiffer et al., 1999). JME is probably the most common form of generalized epilepsies accounting for 10% to 30% of all epilepsies (Gooses, 1984; Janz, 1969, 1985). Childhood absence epilepsies with or without grand mal account for another 5% to 15% of all epilepsies. Although grand mal on awakening is reported to account for 22% to 37% of all epilepsies, they are less common since CCTV-EEG telemetry or polygraphy show that grand mal seizures are most often preceded by myoclonic seizures or absences (Delgado-Escueta & Enrile-Bacsal, 1984; Loiseau, 1964; Janz, 1969). Thus in reality, the most common idiopathic generalized epilepsies are epilepsies of

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infancy, childhood and adolescence, namely, febrile convulsions, JME and childhood absence epilepsy. The generalized epilepsy syndromes of infancy and early childhood, such as Xlinked infantile spasms, benign familial neonatal convulsions, benign familial infantile convulsions, familial infantile convulsions and choreoathetosis are rare, but extremely important epilepsies. Experiments of nature, they are treasured for their illumination of human genetics and the insights they provide in the molecular basis and pathogenesis of the epilepsies. The majority of epilepsies listed in Tables 27.3–27.6 have been mapped to specific chromosomal regions; although for most, the specific gene affected by mutations has not been identified. In the last 5 years, at least 16 chromosomal loci of mendelian forms of idiopathic generalized epilepsies of infancy, childhood and adolescence have been identified (Tables 27.3–27.6). Autosomal dominant gene loci for familial febrile seizures that probably remit have been localized by Wallace et al. (1996) to chromosome 8q13–21 and by Dubovsky et al. (1996) and by Johnson et al. (1998) to chromosome 19p. Generalized epilepsy with febrile seizures plus (GEFS), a syndrome of febrile convulsions whose affected members also have various epilepsy phenotypes, was mapped by Wallace et al. (1998) to chromosome 19q, where a missense mutation in the beta1 subunit gene (SCN1B) of the neuronal sodium channel was found. In addition, three reports of GEFS or febrile convulsion kindreds with linkage to the same interval of chromosome 2q23–q31 have been published (Baulac et al., 1999; Moulard et al., 1999; Peiffer et al., 1999). The phenotypes in two families (Baulac et al., 1999; Moulard et al., 1999) were reported as ‘GEFS’ and were similar to those of the Australian kindred reported by Scheffer and Berkovic, in 1997. The phenotype in the family reported by Peiffer et al. (1999) was reported as ‘febrile seizures’ or ‘FS’ but the phenotype was typical of GEFS, according to LopesCendes et al., 2000. A mutation in the alpha 1 subunit of the sodium channel was recently identified in two French families with GEFS in chromosome 2q23 (Escayg et al., 2000). Families whose affected members only have febrile seizures that do not develop into epilepsy, should be distinguished from families whose affected members have other forms of epileptic seizures, such as myoclonic astatic seizures, absences and myoclonic seizures, in addition to febrile convulsions. Families ascertained through a proband with febrile convulsions whose affected members do not develop epilepsy later in life, should also be distinguished from families with febrile convulsions that develop epilepsy later in life. Approximately 2% to 7% of children with febrile seizures develop afebrile seizures and epilepsy later in life. Defining and distinguishing between febrile convulsion genes that remit and febrile convulsion/epilepsy genes that persist is important.

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Table 27.3. Chromosomal loci of genetic epilepsies of infancy and early childhood Country of origin and number of families

Reference

Phenotype

Genotypea

Claes et al. (1997)

Infantile spasms syndrome (MIM308350)

Xp11.4–Xpter Two families from Leuven, Belgium

Leppert et al. (1989); Malafosse et al. (1992); Hirose et al. (2000)

Benign familial neonatal convulsions (EBN1)

20q

KCNQ2 Mutation initially detected in one family from Sweden and then in six families from Newfoundland, Sweden, Quebec (Canada), USA, six families from France and one family from Japan

Lewis et al. (1993); Hirose et al. (2000)

Benign familial neonatal convulsions (EBN2)

8q24

KCNQ3 mutation in one family USA (Texas) and one family from Japan

Guipponi et al. (1997)

Benign familial infantile convulsions

19q13

Families from Italy

Szepetowski et al. (1997)

Familial infantile convulsions and Paroxysmal choreoathetosis

16p12–q12

Four families from France and one family from China

Wallace et al. (1996)

Familial febrile seizures (FEB1)

8q13–21

One family from Australia

19p

One family from the Midwest, USA

Dubovsky et al. Familial febrile seizures (FEB2) (1996); Johnson et al. (1998) Nakayama et al. (2000)

Familial febrile seizures (FEB4) by 5q14–q15 non-parametric GENEHUNTER and transmission linkage disequilibrium

One large and 39 nuclear families from Japan

Peiffer et al. (1999)

Familial febrile seizures (FEB3), (possibly GEFS)

2q23–24

One family from Utah, USA

Lopes-Cendes Generalized epilepsies with et al. (2000); febrile seizures plus (GEFS) Scheffer & Berkovic (1997); Baulac et al. (1999); Moulard et al. (1999)

2q23–q31

One family from Northern Victoria, Australia SCN1A mutation in two families from France

Escayg et al. (2000); Wallace et al. (1998)

19q13

SCN1B mutation in one Tasmanian family from Australia

Generalized epilepsies with febrile seizures plus (GEFS)

Note: Unless indicated all evidence acquired by model-dependent linkage analyses

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Table 27.4. Chromosomal loci of common generalized epilepsies of childhood and adolescence

Reference

Phenotype

Genotype

Country of origin and number of families

Greenberg et al. Juvenile myoclonic epilepsy (1988a, b) Liu et al. (1995); Serratosa et al. (1996), Bai et al. (2000)

6p HLA area 6p11 (EJM1)

42 families from Los Angeles (CA), Belize and Mexico

Elmslie et al. (1997)

Juvenile myoclonic epilepsy

15q14

34 families from UK and Sweden

Westling et al. (1996)

Childhood absence evolving to JME

1p or 4p

Ten families from Mexico and California (USA)

Delgadoand Escueta et al. (in press)

Photogenic childhood absence

Unknown

Five families from Mexico

with eyelid myoclonia evolving to JME

Fong et al. (1998)

Childhood absence epilepsy with or without grand mal

8q24 (ECA1)

Seven families from Bombay, India, Argentina, LA, CA (USA), Spain, Saudi Arabia

Zara et al. (1995, 1998)

Idiopathic generalized epilepsy with generalized spike waves

3p14.2-p12.1

One family from Italy

Durner et al. (1999)

Adolescent-onset idiopathic generalized epilepsies with generalized spike-waves (nonJME random grand mal and juvenile absence seizures)

8p11–12

23 families (15 grand mal and 8 juvenile absence) from New York

Mikami et al. (1999); Plaster et al. (1999)

Benign adult familial myoclonic 8q23.3-q24.1 epilepsy

Zara et al. (2000) Autosomal recessive idiopathic (in press) myoclonic epilepsy of infancy

California (USA)

16p13

Five families from Japan

One family from Sardinia, Italy

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Table 27.5. Chromosomal loci of partial epilepsies

Reference

Phenotype

Genotype

Country of origin and number of families

Phillips et al. Autosomal dominant nocturnal (1995); Steinlein frontal lobe epilepsy et al. (1995b); Hirose et al. (1999); Ito et al. (2000); Scheffer et al. (1995a) Saenz et al. (1999)

20q

NACHR-4 subunit mutation in two families from Australia, one family from Norway, one family from Japan and one family from Spain

Phillips et al. (1998)

Autosomal dominant nocturnal frontal lobe epilepsy

15q24

Three families from Quebec, Canada, Italy and England

Ottman et al. (1995); Poza et al. (1999)

Temporal lobe epilepsy with auditory symptoms

10q

One family from New York; One family from Basque region, Spain

Scheffer et al. (1998)

Autosomal dominant partial epilepsy with variable foci

2q (preliminary)

One family from Australia

Xiong et al. (1999)

Familial partial epilepsy with variable foci

22q11–q12

Two families from Quebec; One family from Spain

Guerrini et al. (1999)

Autosomal recessive rolandic epilepsy with paroxysmal exercise induced dystonia and writer’s cramp

16p12–q12

One family from Italy

Neubauer et al.,1998)

Centrotemporal spikes in families with rolandic epilepsy

15q14

22 families from Germany

Scheffer et al. (1995a)

Rolandic epilepsy and speech dyspraxia

?

Australia

Berkovic et al. Familial TLE (1994); Berkovic et al. (1996)

?

Australia

Kanemoto et al. (2000)

2 (association studies)

50 patients with TLE HS from Japan

Familial TLE with hippocampal scleroses and Interleukin (IL)-1, IL-1, and IL-1 receptor antagonist gene

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Table 27.6. Chromosomal loci of other epilepsies combined with other neurological syndromes

Reference

Phenotype

Genotype

Country of origin and number of families

Gigli et al. (1993); Fink et al. (1995)

Familial Spastic paraparesis and epilepsy

14q; 15q

One family from Italy

Zuberi et al. (1999)

Episodic ataxia Type I (EA-1) and epilepsy

Mutation in potassium channel gene KCNA1

One family from Glasgow, Scotland

Sperfield et al. (1999)

Frontotemporal dementia parkinosonism-17 (FTDP-17)

17q21–22 (missense One family from mutation at nucleotide Germany 1137 C to T in tau gene)

Two or possibly three chromosomal loci have been identified in JME, namely, (i) chromosome 6 within or approximately 10cM below the HLADQ region observed in families from New York, Austria and Germany (Greenberg et al., 1988a,b; Durner et al., 1991; Weissbecker et al., 1991; Sander et al., 1997), (ii) 6p11 some 30cM below HLA in families from Los Angeles, Mexico and Belize (Liu et al., 1996; Serratosa et al., 1996; Bai et al., 2000), and (iii) 15q14 observed in families from the United Kingdom and Sweden (Elmslie et al., 1997). It is likely that other chromosomal loci exist for JME since some JME families from Saudi Arabia (A.V. DelgadoEscueta, personal observation) and Spain do not link to either 6p or 15q14. In 1999, Durner et al. reported a separate chromosome 8p11–12 locus for idiopathic generalized epilepsies with random grand mal, absences and asymptomatics with generalized spike waves. Earlier, Pandolfo and collaborators from the Italian League Against Epilepsy observed, in one large family from Italy, a susceptibility locus for idiopathic generalized epilepsies with generalized spike waves in 3p14.2–12.1 (Zara et al., 1998). Zara et al. (2000) also reported a chromosome 16p13 locus for a new syndrome, namely, autosomal recessive idiopathic myoclonic epilepsy of infancy. Three and possibly five chromosomal loci underlie the syndrome of childhood absence epilepsy (CAE), namely, (i) remitting pyknoleptic childhood absence in 15q12 (Tanaka et al., 1999; Feucht et al., 1999); (ii) CAE that evolves to and persists as JME in 1p as observed in one large family from the cities of Guadalajara and Mexico City (Westling et al., 1996) and (iii) 8q24 for CAE that persists with grand mal seizures as observed in one large family from Bombay, India and medium-sized families from Argentina, Spain, Saudi Arabia, and California (USA) (Fong et al.,

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1998). The syndrome of photogenic CAE with eyelid myoclonia that evolves and persists as JME is not allelic to the 6p11, 1p, 3p14.2–12.1, 8p11–12, 8q13–21, 8q23–24.1or 8q24 loci and hence is another separate epilepsy locus (A.V. DelgadoEscueta, unpublished observation). A separate locus in chromosome 21q22.3 had been suggested for juvenile absence by Sander et al. (1997b) by association studies with GluR5 kainate receptor gene (GR1K1). Aside from the 8q24 locus for benign family neonatal convulsions (EBN2) responsible for the KCNQ3 mutation, the 8q24 locus for childhood absence epilepsy, the 8q24 locus of idiopathic generalized epilepsy, and the 8q13–21 locus for familial febrile seizures (see Tables 27.3–27.4), a separate chromosomal site for the syndrome of adult myoclonus epilepsy, recognized mainly in Japanese families, was localized in 8q23–24.1 by both Mikami et al. and Plaster et al. in 1999. Many have long argued that the common idiopathic generalized epilepsy syndromes, like childhood absence epilepsy, JME and febrile seizures, are genetically complex diseases. Accumulating evidences, however, are showing that most of these epilepsies are complex Mendelian disorders that have locus heterogeneity (Tables 27.3–27.6). Even in rare idiopathic generalized epilepsy syndromes, such as the benign familial neonatal convulsions, at least two loci have been observed – 20q (EBN1) and 8q (EBN2). In common epilepsy syndromes, such as febrile seizures and febrile seizures plus, locus heterogeneity is also present (8q13–21 and 19p for FEB1 and FEB2; 2q23–31 and 19q13 for GEFS). Clear-cut mendelian inheritance (autosomal dominant), has also been proven in multiplex and multigeneration pedigrees with childhood absence epilepsy, JME and pure grand mal tonic clonic epilepsies. The common epilepsies, such as JME, appear genetically complex when segregation analyses use small nuclear pedigrees. Results are characteristic of either autosomal recessive (Obeid & Panayiotopoulos, 1988), or autosomal dominant disorder with incomplete penetrance (Greenberg et al., 1989) or a two loci model combining AR and AD traits (Greenberg et al., 1988a). The common epilepsies such as CAE also appear genetically complex because of consanguinity and assortative mating (Sugimoto et al., 2000a). To the present, none of the common epilepsies have been proven to have imprinting, trinucleotide repeats or allelic mutations as explanations for genetic complexity. Of the idiopathic generalized epilepsies, the following syndromes are most likely to be mistaken for movement disorders. Benign familial neonatal convulsions (BFNC1 and BFNC2) Phenotype

Benign familial neonatal convulsions (BFNC), a rare cause of neonatal convulsions, is important because it could give clues as to why seizures spontaneously remit. BFNC has been reported in 40 families, with 340 affected family members since the

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first report by Rett and Teubel in 1964. It is an autosomal dominant disorder with favourable outcome. Psychomotor development proceeds normally. In 80% of cases, partial or generalized clonic seizures with tonic, autonomic and oculofacial features, often accompanied by tachycardia and apneic spells, start on the second and third days of life. Ictal EEGs show generalized flattening, followed by diffuse 1Hz slowing. Seizures usually stop by 6 months without any neurologic sequelae. Childhood or adult epilepsy subsequently develops in about 10% to 14% of patients. Genotype

Two genetic loci are responsible, one in chromosome 20q13.2 and another in 8q24. Leppert et al. (1989), were the first to localize the gene to 20q13.2 using a large family of 48 members belonging to four generations of whom 19 were affected with the syndrome. Positional cloning strategies by Singh et al. (1998) were successful in identifying the voltage gated delayed rectifying K gene or KCNQ2 for the 20q (EBN1) locus in seven families. Mutations segregated with affected members and were all located in the S6 domain, channel pore and around the C terminal region of the gene. All regions are involved in ion conduction. Ryan et al. (1991), studied one large family from San Antonio, Texas and found linkage to 8q24. Charlier et al. (1998), performed a BLAST search of human EST databases that led to the identification of clones homologous to KCNQ2. Another voltage gated K channel, which is 40–60% identical to KCNQ2, was identified and proven to be the site of mutations in the 8q24 (EBN2) locus that was originally identified by Ryan et al. (1991). Thus benign familial neonatal convulsions in 20q13 and in 8q24, are both due to mutations in two different novel voltage-gated K channels (Kv). Submicroscopic microdeletion, missense, frameshift and splice site mutations for BFNC in 20q and a missense mutation for the same phenotype in 8q24 reside in KCNQ2 and KCNQ3, respectively (Singh et al., 1998, Charlier et al., 1998). Biervert et al., in 1998 and Biervert and Steinlein in 1999, observed similar potassium channel mutations in KCNQ2 in an Australian family with 20q benign familial neonatal convulsions. Hirose et al., in 2000, observed a novel mutation of KCNQ3 (a T to C substitution or c.925T to C) in a Japanese family with 8q24 benign familial neonatal convulsions. These K channel genes (KCNQ2 and KCNQ3) belong to the superfamily of long Q–T archetype of K channels or Kvlqt channel genes. KCNQ2 and KCNQ3 share about 70% amino acid identity with the KCNQ1 gene that is responsible for the autosomal dominant long Q–T syndrome of cardiac arrhythmia of Roman–Ward and the autosomal recessive Jervell and Lange Nielsen syndrome of deafness and long Q-T syndrome. KCNQ2 and KCNQ3 are co-expressed in most brain regions and mutations in either gene lead to loss of functions and impaired neuronal repolarizations (Schroeder et al., 1998). Wang et al. (1998) observed that the KCNQ2

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Epilepsy genes

and KCNQ3 heteromeric channels account for the M-current seen in the hippocampus. M-current is a non-inactivating potassium current that can be sustained during action potentials. KCNQ2 and KCNQ3 coexpressed in Xenopus oocytes reduce potassium current by 20% to 40%, consistent with loss of function mutations. Because more that 40 Kv channel genes have already been isolated in the C. elegans, it is likely that a similar number (or more) of Kv channel genes are present in the human genome. Mutations in such Kv channel genes may underlie other idiopathic epilepsies. Generalized epilepsy with febrile seizures plus (GEFS1) Phenotypes

The first report by Scheffer and Berkovic (1997), involved two large Australian families with an autosomal dominant epilepsy trait that started in infancy and early childhood and that remitted by mid-childhood. The families were ascertained through probands with infantile febrile convulsions. Affected family members had myoclonic astatic seizures or febrile seizures plus myoclonic astatic seizures, atonic seizures and absences in infancy and early childhood. Hence, these families could really be classified with the idiopathic myoclonic astatic epilepsy of Doose or idiopathic or primary myoclonic epilepsy of infancy and early childhood. These seizure types are easily mistaken for movement disorders. Affected family members who were older than 6 years, gave a history of multiple febrile seizures during infancy and early childhood, afebrile seizures and grand mal tonic clonic seizures. Since then more families with febrile convulsions with similar phenotypes have been reported from northern Victoria (Australia), Utah (USA), Geneva (Switzerland) and Strasbourg in France (see Table 27.3). Three levels of consanguinity are present in the large family from Victoria, Australia. In five of nine families reported from Australia, bilineal inheritance is present. Genotypes

The first locus for the GEFS syndrome was reported by Wallace et al. (1998), who mapped one large Tasmanian family from Australia to 19q13.1 assuming a monogenic model with 64% penetrance and a phenocopy rate of 3%. Positional cloning strategies were successful in proving that the  subunit of the voltage gated sodium channel gene (SCN1B) was responsible for the 19q13 locus and the ‘febrile convulsions plus syndrome’ in the Tasmanian family. The nucleotide variation consisted of a cystein to tryptophan amino acid change. Because the 1 subunit of the voltage gated sodium channel also mapped to the same 19q13 region, mutation analyses were performed in the 1 subunit and a point mutation segregated with affected members. Six of the 12 members affected with febrile seizures did not have the mutation in the SCN1B gene. The 1 subunit modulates channel gating properties

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and sodium inactivation. Mutant  subunits are hypothesized to alter the disulfide bond that maintains the extracellular fold motif of the 1 subunit, produces slower inactivation, slower recovery from inactivation, persistent inward sodium currents and recurrent depolarizations. A sobering result was observed when the mutation in SCN1B was not found in 25 other GEFS families or in 25 other febrile convulsion families, indicating that the SCN1B mutations are rare contributors to GEFS or febrile convulsions (Nakayama et al., 2000). Lopes Cendes et al. reported the second locus for GEFS in 2000 and linked one Australian family to chromosome 2q23–24. Most recently, four separate groups from Australia, Utah (USA), Switzerland and France have reported four unrelated families with the GEFS phenotype that show linkage to the same interval of 2q23–31 (Table 27.3). A mutation in SCN1A has recently been found in two families from France (Escayg et al., 2000). Autosomal recessive idiopathic myoclonic epilepsy of infancy in chromosome 16p13 Phenotype

This syndrome was described in one four-generation Italian family by Zara et al. (2000). The family had two related branches that originated from the same area of Naples. Eight members from the third generation were affected with myoclonic seizures that started between 5 and 36 months of age. The myoclonic seizures persisted to adulthood. Febrile convulsions were present between 5 months and 3 years of age in 5 members, four of which also had afebrile generalized tonic clonic seizures at 4 to 8 months of age. Ictal EEGs showed bisynchronous spike waves. All seizures were well controlled by valproate. Genotype

After screening the genome with 304 STRPs, maximum lod score of 4.48 was obtained for D16S3027 at 0 (Zara et al., 2000). Recombinations defined a candidate region spanning 3.4 cM between D16S3024 and D16S423. Candidate genes include a voltage dependent chloride channel 7 gene (CLCN7), sodium/hydrogen exchanger isoform 3 (SLC9AR2), and synaptogyrin III gene. Autosomal dominant juvenile myoclonic epilepsy in chromosome 6p Phenotypes

There are four phenotypic subsyndromes within JME. The first subsyndrome accounts for 45% of all cases of JME and usually starts with awakening myoclonias during adolescence, most commonly at 13 to 15 years of age. Two years later, grand mal convulsions appear. Rare spanioleptic absences may appear during adolescence. The second phenotype accounts for 27% of all JMEs and starts during late

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Epilepsy genes

childhood as pyknoleptic absences with 3 Hz spike-and-wave complexes as well as 4 to 6 Hz spike- or polyspike-wave complexes. During adolescence, myoclonias and grand mal convulsions follow. The third phenotype accounts for 23% of JMEs and starts with pyknoleptic absences, myoclonias and grand mal convulsions during adolescence. The fourth phenotype starts with myoclonic seizures and grand mal convulsions during adolescence and pyknoleptic absences follow after 18 years of age. This fourth subsyndrome accounts for 5% of all JMEs (Delgado-Escueta et al., 1999). In our genetic studies, we genotyped families with the first three subsyndromes of JME. We initially studied families ascertained through a proband with only adolescent onset myoclonias and grand mal seizures, with or without rare spanioleptic absences. Affected members who were not probands had JME, or grand mal seizures only, or myoclonias only, and rarely absences only. We subsequently studied families ascertained through a proband with JME mixed with late childhood or adolescent pyknoleptic absences. Affected non-proband members of these families also have JME, myoclonias only, grand mal seizures only and rarely absences only. Clinically asymptomatic members who had the EEG trait of 3– to 6Hz multispike wave complexes were also considered affected for purposes of linkage analyses (Delgado-Escueta et al., 1999). Genotype The chromosome 6p11 locus or EJM1 is found in families from Los Angeles (California),

At the Human Gene Mapping 9 Workshop in 1987, we reported for the first time the existence of an epilepsy gene by showing that families with JME from Los Angeles, CA (USA), may be linked to the Bf-HLA loci in 6p (Greenberg et al., 1988a,b). Using clinical and EEG characteristics of affected family members, we reported a pooled maximum lod score of 3.04 at recombination fractions of

m 0.01 and f 0.10 under a recessive model of inheritance assuming full penetrance using HLA and Bf (properdin factor) as markers. Because we subsequently found no significant association with any specific alleles of HLA and because of one recombinant family, we suggested that the JME locus may lie outside the HLA region. Following the initial studies with BF-HLA, pairwise, multipoint, and recombination analyses in a large family from Belize (Serratosa et al., 1995) and 22 small/medium-sized families from Los Angeles (Liu et al., 1995, 1996) assuming an autosomal dominant inheritance with 70% penetrance proved that a JME gene is located in 6p11, centromeric to HLA. When lod scores for small- and mediumsized multiplex families are added to lod scores of the LA–Belize pedigree, Zmax values for D6S294 and D6S257 are 7 ( mf000). The admixture test (H2 vs. H1) was significant (P0.0234 for D6S294 and 0.0128 for D6S272) supporting the Belize and Mexico

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hypotheses of linkage with heterogeneity. Estimated proportion of linked families, was 0.50 (95% confidence interval 0.05–0.99) for D6S294 and D6S272 (Liu et al., 1996). Between 1987 and 1995, we identified and narrowed the locus for juvenile myoclonic epilepsy to a 7 cM area in chromosome 6p11 using the 28 families from Belize and Los Angeles (Serratosa et al., 1996; Liu et al., 1995). Between 1998 to 2000, analyses of 16 medium-sized multiplex and multigenerational families (155 members and 35 affected) from Mexico again confirmed the 6p11 locus and reduced the area to 0.6 cM through new informative recombinations (Bai et al., 2000). A YAC/BAC physical map of the 6p11 area was constructed and we are isolating gene exons from BACs using direct cDNA selection, characterizing candidate genes and analysing for mutations using SSCP and direct sequencing. Mutation analysis has started with serine/threonine protein kinase, our best candidate gene, which maps to the critical 0.6 cM area. Is there a separate JME locus in the 6p21.3/HLADQ area in families from New York

In 1991, Weissbecker et al. in a replication study of the chromosome 6p JME gene, analysed 23 families from Berlin, Germany and confirmed the linkage to 6p. However, they excluded tight linkage to HLA, in agreement with our original suggestions in 1988 that the JME gene is outside the HLA region. Sander et al. (1997a, b) recently enlarged the family number to 29 with 277 members from Germany and Austria. Individuals with idiopathic generalized epilepsies were considered affected but asymptomatic members with the EEG trait of spike wave complexes were considered unknown. Sander et al. (1997a, b) reported peak lod scores of 3.08 at the HLADQ assuming dominant inheritance with 70% penetrance. Multipoint lod scores peaked at a map position 3.3 cM centromeric to HLADQ (Zmax3.27). These authors also observed five recombinations that define a JME candidate region spanning 10.1 cM flanked by HLADQ telomeric and D6S1019 centromeric. In 1996, Greenberg and his collaborators using families from New York suggested that the JME locus resides within the HLA region, between HLA-DP and HLA-B loci. The phenotype of these families from New York are different from the Los Angeles, Belize and Mexico families in that affected members had absences as the sole seizure type in addition to JME and grand mal tonic clonic seizures. Persons who were clinically asymptomatic but who had the EEG trait of paroxysmal parietal theta rhythm were also considered affected. These investigators also claim that the chromosome 6p locus expresses both grand mal seizures on awakening and JME. This argument would make the EJM1 locus distinct from the epilepsy locus, which we and the Berlin group (Sander et al., 1997a, b), claim is below HLA in 6p. The New York group studied HLA-DR and DQ frequencies in 24 JME and Berlin?

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Epilepsy genes

patients and in 24 non-JME forms of adolescent onset idiopathic generalized epilepsies and found the frequency of DR13 and DQB1 alleles to be significantly higher in JME. In 1994, Obeid et al. also noted that DR13 was associated with JME in families from Saudi Arabia with an odds ratio of 4.5. The HLA association studies by Greenberg et al. (1996) and Obeid et al. (1994) suggest that a second epilepsy gene may be present in chromosome 6p, lying within the HLA complex. JME families from Los Angeles, Belize, Mexico and Germany do not have significant association with HLA alleles. Autosomal recessive juvenile myoclonic epilepsy in chromosome 15q14 Phenotypes

In this study of 34 JME families with 165 members ascertained from the United Kingdom and Sweden and enrolled in a European collaborative effort, individuals with pyknoleptic absences only as well as individuals with JME or tonic–clonic seizures only were considered affected. Pyknoleptic absences as the sole seizure type are not part of the phenotype of JME in 6p11. Unlike families that map to 6p11, there were no clinically asymptomatic members that had the EEG trait of spikewave complexes in families from Sweden and the United Kingdom. Persons suffering from clinical seizures did show generalized spike and waves or polyspikeand-wave discharges on their EEGs. Like the linkage study of JME families in 6p12–11, persons with febrile seizures or single seizures were considered unaffected (Elmslie et al., 1997).

The phenotype of JME in 15q14 is different from the phenotype of JME in 6p11

Genotype

Using the GENEHUNTER program, significant evidence in favour of heterogeneity was obtained. Multipoint parametric linkage analysis gave a maximum LOD score of 4.42 at a region 1.7 cM telomeric to D15S144 at  0.65, assuming autosomal recessive inheritance. Non-parametric analyses gave a maximum total score of Zall2.94; P0.00048 at marker ACTC (Elmslie et al., 1997). Candidate genes include the 7 neuronal acetylcholine receptor (CHRNA7). Autosomal dominant benign adult familial myoclonic epilepsy in 8q23–24.1 Phenotype

One large family from Japan was first reported by Mikami et al., in 1999, to map to 8q23–24.1. This single family had 27 members, 17 of whom were affected with tremulous finger movements, myoclonus of the upper and/or lower extremities by 30.5 years of age. Generalized tonic clonic seizures occurred infrequently. Followup studies over nearly 15 years suggest that myoclonus may increase late in the

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disease. None of the patients developed cerebellar ataxia or dementia. Generalized polyspikes and waves were present in EEGs. Photomyoclonus were induced by photic stimulation in some patients. The amplitudes of components P25 and N33 of the sensory-evoked potentials were increased in all patients. Valproate and clonazepam were effective in stopping myoclonus and epilepsy. Four other previously reported Japanese kindreds with similar phenotypes were studied by Plaster et al., in 1999. In most of the reported families SSEP, VEP, and long loop C-reflexes indicated ‘cortical reflex myoclonus’. Skeletal muscle biopsy, rectal biopsy and chromosome analyses were normal. Genotype

Mikami et al. (1999) first genotyped microsatellites in regions corresponding to previously mapped epilepsies and obtained preliminary evidence for linkage with D8S284. After 17 other STRPs were typed, maximum LOD scores were obtained, namely 4.314 at 0 with D8S1779 in two-point analyses. Maximum multipoint LOD score of 5.42 was obtained for the interval between D8S555 and D8S1779, using the program LINKMAP. Plaster et al. (1999) performed a genome wide linkage screen using 98 markers from the Utah marker development group. The LOD score for one large family was 3.0 at 0. The summed LOD scores for the other three families was 1.78 at 0. Obligate recombinants defined D8S514 as centromeric boundary and D8S1804 as telomeric boundary. Candidate genes include the glutamate binding subunit ionotropic receptor, NMDA receptor (GRINA), the 3 subunit of the neuronal nicotinic acetylcholine receptor, Tax interaction protein 43 and phosphodiesterase I/nucleotide pyrophosphatase 2 (PDNP2). Autosomal dominant childhood absence and grand mal tonic clonic epilepsy in chromosome 8q24 Phenotypes

There are three phenotypic subsyndromes within childhood absence epilepsy and 3- to 6-Hz spike- and polyspike and slow-wave complexes (Delgado-Escueta et al., 1999). First is the classic self-remitting pyknoleptic childhood absence that starts between 5 to 10 years of age with multiple petit mal attacks (1 to 200 seizures per day) during regular bilaterally symmetrical and synchronous 3-Hz spike waves. Petit mal absences remit or disappear in one-quarter of cases by 16 to 20 years of age and in three-quarters of cases by 30 years of age. Neither myoclonias or grand mal tonic clonic seizures ever develop. This subsyndrome accounts for 33% to 57% of all childhood absences. The second phenotypic subsyndrome starts also as flurries of pyknoleptic absences between 5 to 10 years of age but grand mal

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convulsions soon develop in late childhood or adolescence. The EEG shows irregular 3- to 6-Hz spike- and polyspike and slow-wave complexes. No myoclonic seizures develop but the epilepsies persist into adulthood. This second subsyndrome is estimated to account for 40% (Loiseau et al., 1983) to 60% (Oller-Daurella & Sanchez, 1981) of all childhood absence epilepsies. The third subsyndrome of childhood absences also start between 5 to 10 years of age but it evolves into JME since myoclonic seizures and grand mal convulsions appear during adolescence. The EEG shows irregular spike- and polyspike-wave complexes. In this third subsyndrome, the patient is also afflicted with many flurries of absences just like classic childhood pyknoleptic absences, but myoclonias and grand mal convulsions develop during adolescence and persist well into mature and geriatric ages. Mai et al. (1990), estimates 5.3% of all JMEs, while Janz (1985) mentions 4.6% of JMEs evolve out of childhood pyknoleptic absences. We estimate this third subsyndrome accounts for 10% to 30% of all childhood absences. Genotype Independent proof for linkage with chromosome 8q24 in one large CAE family and

We first obtained independent proof for linkage to 8q24 microsatellites in a large multiplex, multigenerational 78-member family from Bombay, India, 12 of whom were affected either with absences and/or 3–4Hz spike and multispike wave complexes only (six members) or absences with grand mal (six members). This family was studied in collaboration with Dr. Pravina U. Shah and her team at the K.E.M. Hospital in Bombay. Two point linkage analyses, assuming an autosomal dominant model of inheritance with 50% penetrance, yielded a lod score of 3.7 for D8S502 at mf0.00. We also completed a genome wide screen looking for other major susceptibility loci using another 169 markers and found no other loci with major effects comparable to 8q24 and that fulfilled the standard for significant linkage. We extended our analyses to five smaller multiplex families with the same syndrome and obtained significant lod scores for D8S557 (lod score 4.0) and D8S256 (lod score 3.2) at 0 (Fong et al., 1998) We found recombinant events in nine affected members of the Bombay family and three of the six smaller families that placed the CAE gene in a 2.3 cM area between D8S554 and D8S523. We then completed a YAC-BAC physical map of the area, obtained the correct order of the microsatellite markers, reanalysed recombinations after adding new markers and further reduced the critical CAE region to 700 kb. We ruled out KCNQ3 and the human homologue of the mice jerky gene by position and by mutation analyses (Morita et al., 1999). Large-scale sequencing is ongoing, looking for more candidate gene.

extension to smaller families

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The idiopathic partial epilepsies At the present time, we do not know how much of the partial epilepsies are idiopathic and genetic. However, it seems that more and more families with autosomal dominant nocturnal frontal lobe epilepsy, autosomal dominant partial epilepsy with variable foci and familial temporal lobe epilepsy are being reported from Australia, Quebec and Europe. For some time now we have known that benign childhood epilepsy with centro-temporal spikes (BCECTS) or benign rolandic epilepsy accounts for 15% to 20% of young seizure patients under 15 years of age (Beaussart, 1972; Lerman, 1992). At least six chromosomal regions may be present in these idiopathic partial epilepsy syndromes (see Table 27.5). Partial epilepsy with auditory symptoms that were highly penetrant and segregating an autosomal dominant susceptibility allele was the first form of temporal lobe epilepsy to have a proven chromosome locus, namely, 10q (Ottman et al., 1995). Auditory symptoms such as a ringing noise that grew louder, or humming like a machine suggested involvement of Heschl’s gyrus in 55% of affected individuals. Complex partial and secondary tonic–clonic seizures were also present in some affected members. Interictal EEGs were normal. Age at onset of seizures ranged from 8 to 19 years. Maximum lod scores were 3.99 for D10S192 and 10 individuals shared a haplotype for seven contiguous STRPs spanning 10 cM from D10S200 to D10S205. This syndrome is unlikely to be mistaken for a movement disorder. A chromosome 16p12–11.2 locus near the centromere was reported, in 1997, in an Italian family with autosomal recessive rolandic epilepsy with paroxysmal exercise induced dystonia and writer’s cramps. This 16p locus, reported by Guerrini et al. (1999), could also be the site of the molecular defect for familial infantile convulsions and paroxysmal choreoathetosis. In 1998, linkage between chromosome15q14 and benign rolandic epilepsy and its EEG centrotemporal spikes was established in Swedish families. A putative locus in 2q was reported by Scheffer et al., in 1998, for an Australian family with autosomal dominant partial epilepsy with variable loci while a separate chromosome locus has been identified for two large French–Canadian families in 22q11–q12 by Xiong et al. in 1999. Because motor signs can be present in these above syndromes, their phenotypes and genotypes will be discussed here. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in chromosomes 20q13.2 and 15q24 Phenotypes

Commonly mistaken for sleep disorders, nightmares, hysteria and paroxysmal nocturnal dystonia, seizures start in childhood and early adulthood and usually persist

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through life. Clusters of brief nocturnal seizures have the characteristics of partial motor, tonic, or bilateral motor automatisms with bimanual/bipedal movements. Interictal EEG is usually normal. Ictal EEGs have shown bifrontal spike and diffuse generalized 1–6 Hz slowing. Since the original report of Scheffer et al., in 1994, many families with the same phenotype have been reported from Australia, United Kingdom, Canada, Italy, Norway and, more recently, Japan (see Table 27.5). The phenotype of Norwegian families is slightly different in that some members had complex partial seizures without auras and that seizures only lasted during childhood. Genotypes

This syndrome was linked to chromosome 20q13.2–q13.3 in one large Australian pedigree described by Phillips et al., in 1995. In this relatively rare genotype of autosomal dominant nocturnal frontal lobe epilepsy, positional cloning and mutation analyses successfully identified the molecular defect in the errant gene – a C to T transition that replaces serine by phenylalanine at codon 248 in the CHRNA4 or the 4 subunit of the neuronal nicotinic acetylcholine receptor (Steinlein et al., 1995a,b, 1997) (Table 27.5). Such a mutation was observed in 21 affected members and four obligate carriers in the Australian pedigree. CHRNA4 is predominantly presynaptic, modulates neurotransmitter release and is expressed in all layers of the frontal cortex. Expression studies in Xenopus oocytes showed that a phenylalanine mutant resulted in faster desensitization, slower recovery from desensitization, less inward rectification, and virtually no calcium permeability. Hence phenylalanine mutations in the M2 transmembrane domain of the CHRNA4 are hypothesized to reduce calcium permeability. In 1997, Steinlein et al. characterized a different molecular defect in the same CHRNA4 gene in a second ADNFLE family of Norwegian origin. The defect was characterized as an insertion of a GCT triplet between codon 259 and 260 at nucleotide position 776 in the coding region of the C terminal end of the M2 domain. Functional analyses in oocytes revealed no changes in current amplitude or desensitization kinetics. The mutant channel did have a tenfold increase in affinity for acetylcholine and again a reduced permeability to calcium. In 1999, Hirose et al. reported in four affected members of a Japanese family, a novel C to T missense mutation within exon 5 of the CHRNA4 gene that replaced a serine in the M2 domain with a leucine (Ser252Leu). In one family with ADNFLE from England a second locus was found in 15q24 close to the CHRNA3/CHRNA5/CHRNA4 cluster. In two other families from Italy and Quebec (Canada), haplotypes segregated with affected members consistent with linkage to chromosome 15q24. However, the majority of families with autosomal dominant nocturnal frontal lobe epilepsy may not map to either chromosomes

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20q and 15q24 since four families with ADNFLE from Quebec, Canada, Uppsala, Sweden and Australia do not show linkage to either of the two chromosomal loci. None of the seven families or seven sporadic cases had either of the two known mutations in CHRNA4 (See Table 27.5). Autosomal dominant partial epilepsy with variable foci (ADPEVF) in chromosomes 2q and 22q12 Phenotype

In 1998, Scheffer et al. described one large four-generation family from Australia with 27 members, 10 of whom were affected with frontal, temporal, occipital and centroparietal seizures. Mean age at onset of seizures was 13 years. Seizures occurred predominantly in the awake state. Interictal EEGs showed epileptiform discharges in 6 of 8 living members with clinical seizures. Two individuals were asymptomatic, but had epileptiform discharges on the EEG. In 1999, Xiong et al. described two large families from St-Raymond, Quebec (Canada) who had the phenotype of FPEVF except that seizures were predominantly nocturnal and age at onset of seizures varied and had two peaks around 5 and 25 years. Genotype

After testing 224 markers, D2S133 gave a strong suggestion of linkage (LOD of 2.74 at 0) but did not reach significance in the study of Scheffer et al. (1998). Xiong et al. (1999) obtained more robust LOD scores. Maximum pooled LOD score of 6.58 at 0 was obtained with D22S689. One family (#22) provided independent proof of linkage with a LOD score of 4.8 with D22S689. Recombinations suggest a candidate region 4 Mb in physical size. The Australian family studied by Scheffer et al., in 1998, was not linked to chromosome 22. Candidate genes in the chromosome 22 FPEVF area are synapsin III, one of a family of genes encoding proteins associated with synaptic vesicles and YWMAP, a brain specific n isoform of the 14.3.3 protein involved in intracellular signaling and neurotransmitter release. Autosomal recessive rolandic epilepsy with paroxysmal exercise induced dystonia and writer’s cramp in chromosome 16p12–q12 Phenotype

A brother and sister and their first cousin were affected with rolandic epilepsy, paroxysmal exercise induced dystonia and writer’s cramp seizures (Guerrini et al., 1999). These three persons belonged to a family from Sardinia, Italy and were products of consanguineous marriages between 2 brothers and 2 sisters. Writer’s cramps were right sided and exercise induced attacks were hemidystonic alternately involving right or left or axial muscles. Seizures and paroxysmal dystonia

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peaked expression at childhood and writer’s cramp has persisted. All three patients had spikes over the central regions on the EEGs. Ictal EEGs showed rhythmic bilateral spikes with phase reversal over T3 and T4 with more on left. Genotype

After using 367 markers, D16S401 gave linkage scores (LOD of 2.76 at 0) suggestive of linkage using autosomal recessive inheritance and 80% penetrance (Guerrini et al., 1999). A three point linkage analyses gave LOD scores of 3.68 with D16S401 and D16S3068.The same markers were homozygous in all three affected members. This rolandic epilepsy area overlaps the area mapped for four French families and one Chinese family with benign infantile convulsion with paroxysmal choreoathetosis (Szepetowski et al., 1997; Lee et al., 1998) and the area mapped for one African–American family with paroxysmal kinesigenic dyskinesia (Bennett et al., 2000). Candidate genes include the epithelial sodium channel gamma subunit gene (gamma EnaC), the sodium–glucose cotransporter, the alpha chain IL-4 receptor gene and the ERK1 gene which encodes a polypeptide belonging to the family of mitogen activated protein kinase. Benign rolandic epilepsy with centrotemporal spikes in chromsome 15q14 Phenotype

Neubauer et al. (1998) studied 22 families from Germany and Sweden. The families were identified by (i) their midtemporal–central focal spike and sharp waves described as high amplitude blunted negative 50 to 100 ms discharges preceded by high frequency low amplitude positive waves and followed by three other negative or positive sharp waves; (ii) rolandic epilepsy or brief simple, partial, hemifacial motor seizures, associated with somatosensory symptoms, evolving to tonic–clonic seizures. These occur often during sleep, onset between 3 to 13 years. Maximum or peak age at onset is 7 to 9 years; (iii) remission of seizures and EEG trait by 16 years of age; and (iv) slight male preponderance. Genotype

A DNA linkage study was conducted screening all chromosomal regions known to harbour neuronal nicotinic AchR subunit genes in 22 families. In ‘affected only’ study, the best p values and LOD scores were reached between D15S165 and D15S1010 on chromosome 15q14. In multipoint non-parametric linkage analyses, a nominal P value of 0.000494 was calculated by GENEHUNTER. Best parametric results were obtained under an autosomal recessive model with heterogeneity (multipoint LOD score of 3.56 with 70% of families linked to the locus). Markers were localized in the vicinity of alpha 7 subunit of the neuronal nicotinic AchR gene. The same chromosomal region has been linked to families with JME from the

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United Kingdom and Sweden and families with idiopathic generalized epilepsies from Sweden (Neubauer et al., 1998). Discussion Epilepsy genes: evolutionarily old and ancient vs. new and younger

The genetic complexity that underlies the epilepsies is still largely unknown. One group of common epilepsies is represented by a relatively small pool of common polymorphic epilepsy alleles with a frequency of 0.01 that represents a number of highly restricted alleles from a limited number of epilepsy loci. This may be the case in JME and febrile seizures. Another group is probably represented by a large pool of epilepsy alleles at a large number of loci, at a low population frequency of 0.01 with varying intermediate and small effects on risk. It is likely that such conditions also apply to the common familial and sporadic epilepsies. In addition, there are common forms of genetic epilepsies whose EEG trait are clearly mendelian (the 3 Hz spike waves and the centrotemporal spikes) but whose clinical seizures have low expression, such as absences and rolandic seizures. What is clear is that a growing body of information is showing that the number of epilepsy genes (non-allelic heterogeneity) is high. Whether these alleles represent ‘rare flora in rare soil’ or ‘rare flora in common soil’ or ‘common flora in common soil’ will soon be determined. Tables 27.3–27.5 list 23 known loci for idiopathic epilepsies and efforts to map epilepsy loci worldwide have only just begun. Many epilepsy syndromes identified by rather narrow and strict clinical criteria are showing more than one susceptibility loci. There are at least three loci for JME and perhaps four for CAE. Even in autosomal dominant familial nocturnal frontal lobe epilepsy and autosomal dominant partial epilepsy with variable foci, locus heterogeneity is present. In febrile seizures and idiopathic generalized epilepsies, where a high ascertainment rate has led to the definition of subgroups like generalized epilepsies with febrile seizures plus (GEFS), autosomal recessive idiopathic myoclonic epilepsy of infancy and benign adult familial myoclonus epilepsy, there is extreme diversity. In epilepsies that do not lend themselves to mendelian analyses and model-based linkage studies, a number of genes with intermediate and small effects may give signals that can only be detected by sibpair analyses or a single nucleotide polymorphism (SNP) association or transmission linkage disequilibrium study. It is difficult to form an expectation for the distribution of epilepsy alleles that could be used for designing a mapping strategy for epilepsy alleles, given the presence of a high degree of heterogeneity. In addition, we do not know if the epilepsy alleles recently identified are evolutionarily ancient or genetically young and new. If the epilepsy alleles recently discovered represents epilepsy alleles in outbred

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populations that predated the divergence of the human population more than 100000 years ago, such epilepsy alleles would have been destined to be lost through generations or fixated at a low frequency in outbred populations. However, such ancient genes could reach high frequencies in inbred groups or founder populations. An epilepsy gene that has reached a relatively high frequency in inbred groups could be exemplified by Lafora’s disease in Bangalore, India and in Saudi Arabia. In some situations, population expansion in local areas would have frozen any change in frequency by minimizing genetic drift and we would be detecting epilepsy alleles mainly in special populations. The rare genotypes of autosomal dominant nocturnal frontal lobe epilepsy in chromosome 20q and the generalized epilepsy with febrile seizures plus in chromosome 19q could be examples. On the other hand, if the newly discovered epilepsy mutations are new risk alleles, they could stabilize and lead to high frequencies within a short time if the population is inbred and there is reduced allelic diversity and fixation of otherwise segregating epilepsy risk alleles. This could be exemplified by the absence of grand mal seizures found in Guaymi Indians in the Boca del Toros region of Panama. Such epilepsy allelic enrichment is affected by shared environment and by the interaction of such shared environment with the epilepsy alleles. Epilepsy allele enrichment in affected populations: are they ‘rare flora in rare soil’?

Tables 27.3–27.5 identify some regularly recurring regions where epilepsy genes have been harvested, namely Australia, Quebec, France, Italy, Sardinia, Japan and Sweden, as in idiopathic partial epilepsies (ADNFLE, ADPEVF, RE with CT spikes) and the syndromes of febrile seizures and generalized epilepsy with febrile seizures plus. California, Mexico and Central America are countries where the JME 6p allele seems to be concentrated although they have been reported in Germany, Austria and Japan. The KCNQ2 mutation of benign familial neonatal convulsions was initially detected in a family from Newfoundland and then also observed in a family from Norway. Success in defining epilepsy alleles in these countries could partly be a reflection of the site of work of the investigators or it could be where epilepsy alleles have been enriched by stratification of populations, consanguinity, assortative mating and prolonged inbreeding. Australia, Quebec (Canada), Newfoundland, Mexico and Central America represent relatively very young and new founder populations (20 generations). Relatively speaking, Sardinia and Japan represent less recent founder populations (200 generations). Sardinia and Japan are calculated to have expanded from founders of perhaps 1000 individuals about 100 generations ago. The founder pool size must be very low (100) if epilepsy allele frequencies are high (Kruglyak, 1999). It will be important to determine if the common epilepsy alleles are common or rare in these countries with founder populations and if the epilepsy alleles so far reported are rare epilepsy alleles in a rare population. So far,

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the majority of ADNFLE families do not map to the site of the CHRNA4 20q gene. Also, ADNFLE and ADPEVF represent relatively rare diseases in the outbred populations of Europe and USA. Likewise, the SCN1B mutation is not found in most GEFS families and in febrile convulsion families. Epilepsy alleles of common epilepsies like JME and CAE should be studied in the founder populations of Australia and Quebec. Alleles of common epilepsies are not expected to be found in large numbers in the founder populations of Australia and Quebec. Not all alleles that lead to epilepsies are as yet known

The considerations of these above discussions and the list of epilepsy loci in Tables 27.3–27.5 plus the accelerating progress in completing the sequence of the human genome all show why there should be even more epilepsy alleles to be discovered. Recent discoveries in Australia and Quebec not to mention California and Mexico, demonstrate that this is not merely a theoretical speculation. Founder effects in special population groups can lead to unusually high frequencies of otherwise rare epilepsy alleles. To discover more common epilepsy alleles with a high degree of nonallelic heterogeneity in outbred populations, and to detect more epilepsy alleles with major, intermediate and small effects, we will need to perform model-based linkage analyses as well as sib pair analyses and perhaps a SNP based consortium for association and transmission linkage disequilibrium studies. To acquire large populations for such large-scale genetic studies, an international collaboration is needed. Such epilepsy genetics studies must include very young founder populations like Costa Rica, Quebec and Newfoundland as well as admixed populations of Mexico and California. Epilepsy susceptibility genes may be so numerous and so varied in their genetic effects that they may have a unique profile for special populations. As a result, identification of epilepsy alleles in one population may be difficult to replicate in another population. However, evolutionarily old epilepsy alleles have a high probability of being retained and detectable in ancient civilizations. For such reasons, the populations of Egypt, Israel, other Middle Eastern countries and China should also be included in the international search for epilepsy alleles. Acknowledgements We acknowledge those who have participated as part of the GENES (GENetic Epilepsy Studies) international consortium in recruiting families and mapping common epilepsy genes. Specifically, we wish to mention Drs. Jose M. Serratosa and Ignacio Pascual-Castroviejo (Spain), Drs. P.M. Pai, Dr. S.P. Nirhale and Dr. Pravina Shah and her team (India), Drs. F. Rubio Donnadieu and S. Cordova (Mexico), Dr. Sonia Khan (Saudi Arabia) and our colleagues (Drs. Gregorio Pineda, Gregory Walsh, Lucy Treiman, Jesus Sainz, Berge Miniassian, Dongsheng

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Bai, Miyabi Tanaka, and Robert Sparkes) and staff (Joan Spellman, Adriana Lopez, Bernadette Sakamoto, Aurelio Jara Prado, Susan Shih, Reza Iranmanesh, Nancy Kjeldgaard and Charlotte McTerrell) who worked with us in California. Our studies are partly supported by donations from concerned families and we acknowledge the donation of the McMillin Family, the Cho Family and Mrs. Vera Faludi. Most importantly, our research would not be possible without the participation of individuals and families who participate as study subjects.

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Genetics of the overlap between epilepsy and movement disorders Nicholas W. Wood, Lucy Kinton and Michael G. Hanna Department of Clinical Neurology, Institute of Neurology, London, UK

Epilepsy and movement disorders are found together in many clinical syndromes and a link at a molecular level is being increasingly recognized by the cloning of genes responsible for these conditions. Further evidence for the molecular overlap of movement disorders and epilepsy comes from genes cloned in mutant mice. There are two major groups of disorders causing both movement disorders and epilepsy: neurodegenerative disorders and channelopathies. In this chapter we will briefly review neurodegenerative conditions in which epilepsy and movement disorders are the predominant symptoms. The second part of this chapter will deal with the developing field of channelopathies. Over the past few years, several ion channel genes have been implicated in idiopathic epilepsy and paroxysmal movement disorders. In addition, the cloning of ion channels as the genes responsible for mouse mutants with epilepsy and movement disorders and the creation of mouse knockouts of specific genes, have emphasized the importance of this group of genes in the pathogenesis of these disorders. Neurodegenerative disorders Many neurodegenerative conditions have either epilepsy, or a movement disorder or both as a manifestation of disease in some individuals. In this chapter however, we will describe the genetic abnormalities in three diseases in which both epilepsy and movement disorders are prominent components of the phenotype. Mitochondrial cytopathies

Mitochondrial disease is frequently associated with epilepsy, either generalized tonic-clonic events or myoclonic epilepsy. Movement disorders are also recognized in a number of mitochondrial diseases including several syndromes in which dystonia or extrapyramidal signs are seen (Hanna & Bhatia, 1997; Simon & Johns, Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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Table 28.1. Mitochondrial DNA mutations causing movement disorders and epilepsy

Gene

Nucleotide

Base change

Mt ATP synthase 6 Mt ATP synthase 6 Mt ATP synthase 6 Transfer RNA (Lys)

8993 8993 9176 8344

T⇒G T⇒C T⇒C A⇒G

1999) and are associated with seizures. These presentations are, however, rare. The most common movement disorders seen in primary mitochondrial defects are myoclonus and ataxia, most frequently seen in combination with epilepsy in the MERRF syndrome (myoclonic epilepsy with ragged red fibres). The commonest mitochondrial mutation associated with this syndrome is a missense mutation, A8344G, in the transfer RNA lysine gene (Shoffner & Wallace, 1992). Ataxia is also seen in association with epilepsy in NARP (neuropathy, ataxia and retinitis pigmentosa), caused by a missense mutation in the ATPase 6 gene at nucleotide 8993 (Holt et al., 1990). There is a relationship between mutant load and expression of phenotype. When the mutant load rises above 70%, the more severe phenotype of maternally inherited Leigh syndrome (MILS) results (see below and Table 28.1) (Santorelli et al., 1993). A further mutation in the same gene but at position 9176 has also been reported as causing MILS (Dionisi-Vici et al., 1998). Several rarer individual cases have been described in the literature of other movement disorders and epilepsy being associated in mitochondrial disease. An overlap syndrome between Parkinsonism and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) has been reported (De Coo et al., 1999). Parkinsonism was noted at the age of 6 and progression to a more typical MELAS syndrome with several generalized seizures and strokes from the age of 14 years. The case described had complex III deficiency on biochemical analysis of muscle and a 4 base pair deletion in the cytochrome b gene was subsequently detected. A further case was reported (Sudarsky et al., 1999), with writer’s cramp as the main presenting feature of mitochondrial disease. The dystonia progressed to the face and lower limbs in addition to deafness, exercise intolerance, muscle weakness and ptosis. Analysis of mitochondrial DNA revealed the A3243G mutation in tRNA leucine. Rarely, Leber’s hereditary optic neuropathy is also associated with dystonia (Novotny et al., 1986; Bruyn et al., 1992) although this syndrome does not usually have epilepsy as part of the phenotype. The clinical features and genetic basis of mitochondrial disease are described in more detail elsewhere (Morgan-Hughes & Hanna, 1999; Hanna & Nelson, 1999).

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Leigh syndrome (subacute necrotizing encephalomyopathy).

This is a progressive neurodegenerative disorder caused by respiratory chain dysfunction particularly Complex I and/or IV deficiency. The onset is usually in early childhood but occasional adult onset cases have been reported. Leigh syndrome can be caused by mutations in either mitochondrial (see above and Table 28.1) or more commonly nuclear genes (Morris et al., 1996; Rahman et al., 1996). Nuclear genes which cause Leigh Syndrome (Dahl, 1998) include SURF1, resulting in Complex IV (cytochrome c oxidase) deficiency (Tiranti et al., 1998), and NADH:ubiquinone oxidoreductase 23kD subunit (NDUFS8) causing a deficiency in Complex I (Loeffen et al., 1998). Surveys of patients with Leigh syndrome have reported movement disorders in a high proportion of patients. Macaya et al. (1993) described movement disorders in 22/34 patients (19 dystonia) and a further study (Rahman et al., 1996) 20/67 (13 dystonia). Dentatorubral–Pallidoluysian atrophy (DRPLA).

This rare autosomal dominant condition seen most commonly in Japan, was first described in 1958 by Smith et al. (1958). It consists of a progressive specific neuronal degeneration, the features of which are captured in the name and causes a syndrome of myoclonic epilepsy, dementia, ataxia and choreoathetosis. One or other of these symptoms can be predominant, causing diagnostic confusion with several other disorders. One of these is Huntington’s disease, which can also have epilepsy as part of the phenotype in addition to chorea and dementia in approximately 10% of cases. DRPLA is caused by an expansion in a triplet (CAG) repeat within the DRPLA gene (atrophin-1) (Koide et al., 1994; Nagafuchi et al., 1994). The repeat size varies from 7 to 23 in normal individuals and from 49 to 75 in affected individuals. The molecular characteristics of this expansion are shared by other CAG repeat diseases (Evert et al., 2000) (including Huntington’s disease, X-linked spinobulbar muscular atrophy and some spino-cerebellar ataxias). These features include expansion of the repeat size between generations particularly in paternal transmission, the size of the repeat correlating with disease severity (Komure et al., 1995) and the formation of intranuclear inclusions (Davies et al., 1997). Channelopathies Ion channel mutations cause defects in the electrical properties of excitable cells, whether in the resting potential, depolarization or repolarization of the cell. These defects therefore frequently manifest as paroxysmal disorders, being dependent on changes in or around the cell to trigger an abnormal electrophysiological response. There are numerous paroxysmal neurological conditions which are either proven to be (or there is strong circumstantial evidence to invoke), ion channel dysfunction.

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Table 28.2. Summary of phenotypes resulting from ion channel mutations

Ion channel

Organism

Epilepsy

Ataxia

Paroxysmal dyskinesia

Sodium

Human Mouse

 

 

 

Potassium

Human Mouse

 

 

 

Calcium

Human Mouse

 

 

 

These include disorders such as dystonia, chorea and epilepsy in addition to episodic paralysis, ataxia and migraine. Several of these neurological manifestations can coexist in the same patient or can be associated with different or even identical mutations in the same gene. A summary of the different channels involved in these disorders and the resultant phenotypes is shown in Table 28.2. Although the genetics of several conditions has become clearer over the last few years, the explanation of the symptoms manifested by individuals remains to be explained. Many of the ion channel mutations are changes in one subunit of a larger complex channel or of a group of similar channels. The manifestations of the mutation may therefore be due to a compensatory increase in other channel subunits as much as in deficiency of one particular channel. Sodium channel mutations Generalized epilepsy with febrile seizures plus (GEFS)

A large Australian family with autosomal dominant inheritance of a syndrome of febrile seizures outside the normal age range, generalized epilepsy in other family members and myoclonic astatic epilepsy in one individual was reported (Scheffer & Berkovic, 1997). After linkage of the condition to a locus to chromosome 19 had been reported, the affected members of the family were found to have a mutation in the voltage gated sodium channel SCN1B (Wallace et al., 1998). The non-conservative mutation (Cys121Trp) would be predicted to cause disruption of a disulfide bridge in the extracellular domain of the channel. Neuronal sodium channels consist of a large pore-forming  subunit and two  subunits which alter inactivation of the channel. Coexpression of the mutant form of SCN1B with a wild-type  subunit in Xenopus oocytes, did demonstrate a reduction in the rate of inactivation of the channel. In vivo, this would be predicted to result in increased excitability of neurons and hence increased susceptibility to seizures.

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Three further GEFS families in France (two) and Canada (one) were reported and were linked to a 20 cM region, 2q21–33, which was known to contain a cluster of Sodium channels (Baulac et al., 1999; Moulard et al., 1999; Lopes-Cendes et al., 2000). Different mutations have now been reported in two of these families in the SCN1A gene, namely Arg1648His and Thr875Met (Esayg et al., 2000). Both of these mutated amino acids are located in a transmembrane domain that is known to be important in the gating properties of the channel and are in evolutionary conserved amino acids. The Arg1648His mutation is predicted to cause slower inactivation of the channel. The threonine to methionine substitution is in a conserved heptad repeat. Threonine to methionine substitutions in the equivalent heptad repeat of other sodium channel subunits, cause long QT syndrome (SCN5A) (Wattanasirichaigoon et al., 1999) and hyperkalemic periodic paralysis (SCN4A) (Ptacek et al., 1991), which are paroxysmal disorders of cardiac and skeletal muscle, respectively. SCN8A mutant mouse

A further neuronal sodium channel subunit, SCN8A, is mutated in the med mouse. Complete absence of the normal channel results in paralysis and death by 4 weeks of age. A missense mutation in the same channel gives rise to a phenotype of cerebellar ataxia in the medjo allele (Kohrman et al., 1996). This mutation changes a conserved alanine to a threonine. Introduction of the mutation into the Rat IIA sodium channel, which is closely related to Scn8a, was used for electrophysiological analysis. Although the kinetics of the sodium channel inactivation were not altered, there was a shift in the threshold of the channel, making it require a larger depolarization to open. This would be predicted to reduce the spontaneous firing of the Purkinje cells and hence the inhibitory output from the cerebellum. A splice site mutation (medj allele) in the Scn8a gene, results in the presence of low levels of normal transcript and together with at least one copy of a modifying allele Scnm1H, results in a phenotype of movement-induced dystonia without neurodegeneration (Sprunger et al., 1999). Measurement of sodium current in the cerebellar Purkinje cells from medj mice shows reduced persistent and resurgent sodium currents. The cerebellum is an area of the brain, along with the basal ganglia, thought to be involved in dystonia (Fletcher et al., 1988; Lees 1990; Berardelli et al., 1998). To date, no human dystonic diseases have been caused by sodium channels, but this mouse phenotype does resemble the human exercise-induced movement disorders and so neuronal sodium channels would be excellent candidate genes for these disorders. In addition, several paroxysmal movement disorders respond to antiepileptic drugs such as phenytoin, which act via modulation of sodium channel activity, providing further circumstantial evidence of a channelopathy.

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Potassium channel mutations Episodic ataxia with myokymia (episodic ataxia type 1: EA1)

This autosomal dominant disorder consists of episodes of limb and gait ataxia and variable limb tremor. The attacks usually last up to 15 minutes and are frequently triggered by sudden movement particularly after a period of rest. A sensory aura or warning often precedes the attack. There is no vertigo or nystagmus present, in contrast to episodic ataxia type 2 (EA2). Myokymia is continuously present and varies in severity from visible stiffening of the limbs to myokymia only detectable by EMG. The myokymia originates peripherally from multifocal nerves and is thought to be due to prolonged channel closure time and therefore delayed repolarization of presynaptic nerve terminals. There have been a number of reported cases of individuals within families of EA1 who not only have the myokymia and episodic ataxia but also epilepsy. In a recent report of a case of the co-existence of EA1 and epilepsy, the literature was reviewed and a total of eight cases out of 90 individuals with EA1 have been reported giving a relative risk of epilepsy in patients with EA1 of 17.8 (Zuberi et al., 1999). The genetic defect in classical EA1 is missense mutations in the KCNA1 locus, also called Kv1.1 channel on chromosome 12p (Browne et al., 1994). Expression studies of the mutant channel have revealed a reduction in the current magnitude of the channel in a dominant negative fashion. The mechanism of action of potassium channels is to repolarize the cell, maintain a resting potential and determine the frequency of repetitive depolarization. Any reduction in the potassium current therefore, could lead to hyperexcitability and repetitive firing of neurons. Kv1.1 mouse knockout

A null mutation of the Kv1.1 channel results in mice that are mildly ataxic but have a lethal seizure phenotype (Smart et al., 1998). Although heterozygote mice showed no spontaneous seizure activity, they do have increased susceptibility to seizures induced by flurothyl. This supports the observed association between EA1 and epilepsy, as does the proconvulsant effect of Kv channel blockers such as 4-aminopyridine (Morales-Villagran & Tapia, 1996; Morales-Villagran et al., 1996). There has been no observation of any paroxysmal dyskinesia in the knockout mouse. Benign familial neonatal convulsions (BFNC)

This disorder consists of convulsions occurring in the initial months of life, which then spontaneously remit. There are two genetic defects known to cause this disorder: mutations in KCNQ 2 and 3 found on chromosome 20q and 8q, respectively (Charlier et al., 1998; Singh et al., 1998). The two channels form heteromeric com-

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plexes which result in the M-type current. Mutations in either gene are thought to act by causing a reduction in the number of heteromeric complexes and hence a reduction in potassium current. There have been no movement disorders associated with this condition although a similar condition, benign infantile convulsions, can occur in association with paroxysmal kinesigenic choreoathetosis (PKC) and this condition has been linked to the centromeric region on chromosome 16 (see below). Calcium channel mutations

Voltage-dependent calcium channels are made up of four subunits, 1, 2,  and . They form six electrophysiologically and pharmacologically distinct types of channels: L, P, Q, N, T and R. 1A subunit

There are three human conditions associated with mutations in the 1A subunit of the p/q-type calcium channel; spinocerebellar Ataxia type 6 (CAG repeat in intracellular C terminal tail), familial hemiplegic migraine (missense mutations) and episodic ataxia type 2 (predominantly premature termination mutations). No human mutations in this gene are known to cause epilepsy, but in the mouse (see below) epilepsy can result from an abnormality in this channel. Tottering mouse This spontaneous mouse mutant has a recessive mutation in the voltage-gated calcium channel 1A subunit which causes a phenotype of ataxia, 5–7 Hz spike-wave discharges associated with behavioural arrest and intermittent dystonic episodes (Doyle et al., 1997). The dystonic episodes are very stereotyped, lasting approximately 20 minutes and are not associated with EEG abnormalities. They consist of extension of the hindlimbs followed by abduction of the hip associated with arching of the back. The dystonia then spreads to the forelimbs, head and neck. The hindlimbs recover first followed by the rest of the body. The dystonic episodes can be triggered by restraint of the mice. The mechanism of absence epilepsy in these mice is unclear as absence seizures are thought to result from abnormalities in the thalamo-cortical connections which rely on T-type calcium currents, not high threshold P/Q channels which are the type contributed to by the 1A subunit. Dystonic episodes are thought to be mediated by an upregulation in L type calcium channels and the 1C subunit in specific areas of the brain, most notably the Purkinje cells of the cerebellum, because of the decrease in P/Q type channels. Evidence for this comes from improvement of the dystonic attacks by treatment with specific L-type channel blockers and from measurement of RNA levels in different areas of the brain of mutant mice (Campbell & Hess, 1999).

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4 subunit

There are two reported mutations in the human 4 subunit in association with disease (Escayg et al. 2000). The first (Arg482Stop) is a premature stop mutation 38 amino acids before the end of the protein. This resulted in juvenile myoclonic epilepsy in one patient and an abnormal EEG (3Hz spike-wave discharges) in her daughter. Functional studies of this mutation in Xenopus oocytes revealed a decreased time constant for inactivation, hence increasing the rate of channel inactivation and reducing the amount of calcium flux into the cell. A missense mutation (Cys104Phe) was detected in two apparently unrelated families. One of these families had idiopathic generalized epilepsy and the other had attacks similar to episodic ataxia type 2, which is normally associated with mutations in the 1A subunit. This mutation had no effect on the kinetics of the channel but is still likely to be pathogenic because it lies in a conserved area of the protein thought to be involved in interaction with other proteins and was not present in 510 control chromosomes. Lethargic mouse This mutant has an almost identical phenotype to the tottering mouse with absence seizures, episodes of dystonia and ataxia. It is caused by a mutation in the calcium channel 4 subunit, preventing its association with the pore forming 1 subunit (Burgess et al., 1997). The 4 subunit forms P/Q channels in association with 1A subunits but there are no defects recorded in these channel currents in Purkinje cells from lethargic mice. There is, however, evidence for increased 1A subunit association with other  subunits (McEnery et al., 1998; Lin et al., 1999), and so it is postulated that these different complexes have functionally different kinetics which lead to the clinical phenotype. Unknown genes Paroxysmal kinesigenic choreoathetosis (PKC)

This is a further paroxysmal movement disorder, which consists of brief attacks of involuntary choreiform movement often precipitated by various triggers such as sudden movement, startle or continuous exercise. It has been mapped to the pericentromeric region of chromosome 16. This disorder is seen in association with epilepsy in several families. First, benign infantile convulsions occur in association with PKC in the ICCA (infantile convulsions and choreoathetosis) syndrome (Szepetowski et al., 1997; Lee et al., 1998), which also maps to an overlapping area on chromosome 16. Secondly, a family with PKC has been mapped a distinct locus from the loci for either PKC or ICCA – again on the pericentromeric region of chromosome 16. Within this family there are five individuals who suffered from generalized tonic–clonic seizures with onset between the ages of 6 and 16 years (S.D. Spacey, personal communication). Only two of these individuals also had

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PKC and the linked haplotype only segregated with PKC and not with epilepsy within this kindred (Valente et al., 2000). PKC has some clinical features akin to episodic ataxia Type 1. Both conditions consist of attacks triggered by sudden movement and both are frequently preceded by a sensory aura. There is also a response of both conditions to antiepileptic medication such as phenytoin, although this treatment is less often successful in treating EA1 than PKC. There have been two reported cases, to date, of patients in two separate families affected by EA1 also having paroxysmal choreoathetosis. In one of the families, several family members had episodic ataxia and one individual had both EA1 and PKC (Gancher & Nutt, 1986). In the other family, one individual had episodes of movement-induced choreoathetosis in addition to episodic ataxia and myokymia, although the PKC did not start until after a mild head injury 9 years after the onset of ataxia (Lubbers et al., 1995). Paroxysmal dystonic choreoathetosis

Further association between paroxysmal dyskinesias and EA1 comes from the presence of myokymia in a kindred with paroxysmal dystonic (non-kinesigenic) choreoathetosis (PDC) (Byrne et al., 1991). All families so far described with PDC (but no myokymia) map to 2q31–36 (Fink et al., 1996, 1997; Jarman et al., 1997; Raskind et al., 1998). Episodic choreoathetosis / spasticity (CSE)

This disorder consists of attacks of dystonia similar to PDC: the episodes are triggered by stress, fatigue and alcohol. This syndrome, which has been mapped to chromosome 1p between D1S443 and D1S197 is also characterized by episodic ataxia and spasticity (Auburger et al., 1996). Although the genes for these disorders are as yet unknown, there seems to be some relationship between episodic ataxia Type 1 and both epilepsy and paroxysmal dyskinesia, implying that potassium channels could also be responsible for paroxysmal dyskinesias. Similarly, although no human calcium channel mutations have been reported to cause paroxysmal dyskinesias, voltage-gated calcium channels remain candidate genes for these disorders, in particular PDC, which is most similar to the dystonic mouse phenotype of tottering and lethargic. Conclusion Therefore, the interface between epilepsy and movement disorders can be attributed to two very different pathological processes: ion channel disorders and neurodegenerative disease.

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Within the ion channel disorders there is a large degree of overlap between different central nervous system paroxysmal disorders, particularly epilepsy, ataxia and other movement disorders. A large variation in phenotype is observed in genetic defects caused by allelic mutations within genes or even between individuals with identical mutations. This is likely to be due to a number of genetic and environmental modifying factors. The existence of so many different ion channels and subunits, complicates the analysis of these disorders from a functional point of view, and these functional studies will be important for developing improved treatments for these disorders. Acknowledgements The authors are supported by MRC Programme Grant No. G9706148, the Epilepsy Research Foundation, the Brain Research Trust and The Wellcome Trust. LK is a Wellcome Trust Clinical Training Fellow.

R E F E R E N C ES

Auburger, G., Ratzlaff, T., Lunkes, A. et al. (1996). A gene for autosomal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p, probably within 2 cM between D1S443 and D1S197. Genomics, 31(1), 90–4. Baulac, S., Gourfinkel-An, I., Picard, F. et al. (1999). A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21–q33. American Journal of Human Genetics, 65(4), 1078–85. Berardelli, A., Rothwell, J. C., Hallett, M., Thompson, P.D., Manfredi, M. & Marsden, C.D. (1998). The pathophysiology of primary dystonia. Brain, 121(7), 1195–212. Browne, D.L., Gancher, S.T., Nutt, J.G. et al. (1994). Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1 [see comments]. Nature Genetics, 8(2), 136–40. Bruyn, G.W., Bots, G.T., Went, L.N. & Klinkhamer, P.J. (1992). Hereditary spastic dystonia with Leber’s hereditary optic neuropathy: neuropathological findings. Journal of Neurological Science, 113(1), 55–61. Burgess, D.L., Jones, J.M., Meisler, M.H. & Noebels, J.L. (1997). Mutation of the Ca2 channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell, 88(3), 385–92. Byrne, E., White, O. & Cook, O. (1991). Familial dystonic choreoathetosis with myokymia; a sleep responsive disorder. Journal of Neurology, Neurosurgery and Psychiatry, 54(12), 1090–2. Campbell, D.B. & Hess, E.J. (1999). L-type calcium channels contribute to the tottering mouse dystonic episodes. Molecular Pharmacology, 55(1), 23–31.

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N. Wood et al. Kohrman, D.C., Smith, M.R., Goldin, A.L., Harris, J. & Meisler, M.H. (1996). A missense mutation in the sodium channel Scn8a is responsible for cerebellar ataxia in the mouse mutant jolting. Journal of Neuroscience, 16(19), 5993–9. Koide, R., Ikeuchi, T., Onodera, O. et al. (1994). Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genetics, 6(1), 9–13. Komure, O., Sano, A. & Nishino, N. (1995). DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation. Neurology, 45(1), 143–9. Lee, W.L., Tay, A., Ong, H.T., Goh, L.M., Monaco, A.P. & Szepetowski, P. (1998). Association of infantile convulsions with paroxysmal dyskinesias (ICCA syndrome): confirmation of linkage to human chromosome 16p12–q12 in a Chinese family. Human Genetics, 103(5), 608–12. Lees, A. (1990). Dystonia and cerebellar ataxia [letter; comment]. Movement Disorders, 5(2), 178. Lin, F., Barun, S. Lutz, C.M., Wang, Y. & Hosford, D.A. (1999). Decreased (45)Ca(2)() uptake in P/Q-type calcium channels in homozygous lethargic (Cacnb4lh) mice is associated with increased beta3 and decreased beta4 calcium channel subunit mRNA expression. Molecular Brain Research, 71(1), 1–10. Loeffen, J., Smeitink, J., Triepels, R. et al. (1998). The first nuclear-encoded complex I mutation in a patient with Leigh syndrome [see comments]. American Journal of Human Genetics, 63(6), 1598–608. Lopes-Cendes, I., Scheffer, I.E., Berkovic, S.F., Rousseau, M., Andermann, E. & Rouleau, G.A. (2000). A new locus for generalized epilepsy with febrile seizures plus maps to chromosome 2. American Journal of Human Genetics, 66(2), 698–701. Lubbers, W.J., Brunt, E.R., Scheffer, H. et al. (1995). Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is responsive to acetazolamide. Journal of Neurology, Neurosurgery and Psychiatry, 59(4), 400–5. Macaya, A., Munell, F., Burke, R.E. & De Vivo, D.C. (1993). Disorders of movement in Leigh syndrome. Neuropediatrics, 24(2), 60–7. McEnery, M.W., Copeland, T.D. & Vance, C.L. (1998). Altered expression and assembly of N-type calcium channel alpha1B and beta subunits in epileptic lethargic (lh/lh) mouse. Journal of Biological Chemistry, 273(34), 21435–8. Morales-Villagran, A. & Tapia, R. (1996). Preferential stimulation of glutamate release by 4-aminopyridine in rat striatum in vivo. Neurochemistry International, 28(1), 35–40. Morales-Villagran, A., Urena-Guerrero, M.E. & Tapia, R. (1996). Protection by NMDA receptor antagonists against seizures induced by intracerebral administration of 4-aminopyridine. European Journal of Pharmacology, 305(1–3), 87–93. Morgan-Hughes, J.A. & Hanna, M.G. (1999). Mitochondrial encephalomyopathies: the enigma of genotype versus phenotype. Biochimica et Biophysica Acta, 1410(2), 125–45. Morris, A.A., Leonard, J.V. Brown, G.K. et al. (1996). Deficiency of respiratory chain complex I is a common cause of Leigh disease. Annals of Neurology, 40(1), 25–30. Moulard, B., Guipponi, M., Chaigne, D., Mouthon, D., Buresi, C. & Malafosse, A. (1999). Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS) on chromosome 2q24–q33. American Journal of Human Genetics, 65(5), 1396–400.

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Seizures and movement disorders precipitated by drugs Olivier Dulac1 and Ubaldo Bonuccelli2 1 2

Department of Pediatric Neurology, Hôpital Saint Vincent de Paul, Paris, France Department of Neuroscience, University of Pisa, Italy

Antiepileptic drugs as a cause of worsening of seizures The paradoxical ability of antiepileptic drugs (AED) to induce worsening of seizures has been identified from the very beginning of AED treatment (Zaccara et al., 1990, Garcia & Alldredge, 1994, Stimmel & Dopheide, 1996). It is often overlooked by the non-specialist, who is therefore reluctant to remove the causative agent, even when the patient or relatives have identified the relationship. When children are involved at the onset of their epilepsy, this phenomenon could adversely affect the long-term prognosis. There is accumulating evidence that, in certain epilepsies, such as West syndrome, prevention of seizure recurrence from the very beginning may also prevent the development of cognitive troubles and epilepsy as a chronic disorder. Identification of prognostic factors and a greater awareness of this concept, especially at the primary care level, is therefore most important. Deterioration in seizure frequency after administration of antiepileptic drugs can occur (i) as a non-specific manifestation of overdose or (ii) as a relatively specific effect on selected seizure types. Intoxication as a cause of seizure worsening

It has been recognized for many years and seems to be more common than generally thought. Among patients admitted to the Chalfont Centre for Epilepsy in the early 1970s with a clinical diagnosis of antiepileptic drug intoxication, 25% were reported to exhibit paradoxical seizure worsening (Laidlaw et al., 1980). Phenytoin appears to be most frequently implicated (Levy & Fenichel, 1965; Patel & Crichton 1968; Vallarta et al., 1974; Troupin & Ojemann, 1975; Lascelles et

Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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al., 1970; Cranford et al., 1978; Stilman & Masdeu, 1985; Graham & Bachman, 1986; Osorio et al., 1989), but this may simply reflect its more extensive use at the time most reports were published, and possibly the comparatively higher risk of developing phenytoin intoxication due to its non-linear pharmacokinetic behaviour. Levy & Fenichel (1965) first described an increase in seizure frequency in phenytoin-intoxicated patients and noted that their seizure pattern also changed from typical tonic–clonic convulsions to seizures with opisthotonic posturing. Similar features were described in children (Patel & Crichton 1968). These cases of ‘hydantoin encephalopathy’ included increase in seizure frequency, mental changes, brainstem–cerebellar signs, and unmasking of subclinical focal abnormalities. In some cases, the distinction between epileptic seizures and dystonic or dyskinetic movements may be a challenge, and phenytoin-induced choreo-athetosis may be misdiagnosed as status epilepticus and the dose of phenytoin was consequently increased (Ahmad et al., 1975). In some cases an increase in seizure frequency may be the only presenting symptom of drug intoxication (Troupin & Ojemann, 1975). Exacerbation of partial complex and/or tonic–clonic seizures by excessive dosage is reversible upon dose reduction and unaccompanied by other prominent signs of toxicity. Most reported patients had high serum concentrations of phenytoin (40 mg/l), but a high concentration of carbamazepine may contribute. Evidence that high serum phenytoin concentrations may adversely affect seizure control was also obtained in a recent trial of children receiving intravenous phenytoin for the management of status epilepticus: among 19 patients with complete effect, the mean serum phenytoin concentration after 40 hours (19 mg/l) was lower than that observed (31 mg/l) in 11 children who were treated with the same dosing protocol but showed only a partial response (Richard et al., 1993). Other drugs may also cause paradoxical seizure increase as a result of intoxication (Bauer, 1996; Troupin & Ojemann, 1975; Salcman & Pippenger 1975; Bridge et al., 1994). Increased frequency of partial seizures as the primary manifestation of carbamazepine toxicity (17.4 mg/l) has been reported with dramatic improvement when reducing the dose (Neufeld, 1993). Several reports of seizure deterioration and non-convulsive status epilepticus, including hallucinations are on record after high-dose tiagabine in both adults and children (Schapel & Chadwick 1996; Ettinger et al., 1999). In the case of valproate, increased seizures may be an early sign of severe hepatotoxicity with hyperammoniemia (Valdames et al., 1993; Koenig et al., 1994) may be difficult to distinguish from intolerance of too rapid titration that produces confusion, ataxia, drowsiness and lethargy (Chadwick et al., 1979; Zaccara et al., 1984; Horiuchi et al., 1993). Negative myoclonus, stupor and hyperammoniemia developed in one patient a few days after starting valproate (Aguglia et al., 1995).

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Worsening of seizures may also result from polytherapy irrespective of the plasma levels of the individual agents, as shown by improved seizure control after reducing the number of associated drugs (Bauer, 1996; Lerman, 1986; Reynolds & Shorvon, 1981). Precipitation of seizures has been described also in association with deliberate or accidental acute overdosage: seizures and status epilepticus may complicate carbamazepine poisoning (Sharma et al., 1992; Spiller et al., 1990; Weaver et al., 1988), status epilepticus and myoclonus tiagabine overdose (Parks et al., 1997), nonconvulsive status phenobarbital poisoning (Marioni et al., 1987), and myoclonic seizures valproate overdose (Eeg-Olofsson & Lindskog 1982). Thus, paradoxical seizure worsening is a not uncommon manifestation of antiepileptic drug intoxication. Not all patients given high dosages (or excessive polytherapy) show such deterioration (White et al., 1966). The reason for these differences remains open to speculation. Relatively specific drug effect as a cause of seizure worsening

In many instances, exacerbation of seizures is not a manifestation of overdose but reflects an adverse reaction of an individual patient to the mode of action of the prescribed drug. Although the distinction may not be easy, many of these patients have dosages and serum drug levels well below the toxic range, and improve after drug discontinuation rather than reduction in dosage. Moreover, it is often possible to identify specific syndromic forms or EEG features which are more likely to be associated with a paradoxical seizure response to a given drug. Although most reports have focused on carbamazepine-induced aggravation of generalized seizures, there may be strong selection bias. No randomized study provides unbiased information confirming seizure deterioration. Barbiturates

In one child with benign rolandic epilepsy and minor atypical features, phenobarbital administration aggravated markedly epileptic negative myoclonus and triggered almost continuous unilateral or bilateral central spike-and-wave activity, and discontinuation of the drug led to clinical improvement (Guerrini et al., 1995). Tonic seizures were precipitated or aggravated following amobarbital by intracarotid or intramuscular route in Lennox–Gastaut syndrome (Tassinari et al., 1972). The same children were part of a group who developed tonic status following injection of a benzodiazepine. Since polyspike discharges and tonic seizures in patients with Lennox-Gastaut syndrome have been reported also with fluothane (Tassinari et al., 1972) and the non-barbiturate anaesthetic propanidid (Turner et al., 1971), this response may reflect a general vulnerability of the brain of these patients to changes in inhibitory control mechanisms rather than a specific drug effect.

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Phenobarbital has been implicated in worsening of absence seizures (Bauer, 1996, Wilder & Bruni, 1981). Although this seems to be a relatively common occurrence in pediatric practice, there are few published reports on this effect. Benzodiazepines

While intravenous benzodiazepines are universally considered for the management of status epilepticus, the possibility that these drugs may also induce status is not widely appreciated. Cases of Lennox–Gastaut syndrome have been reported in whom intravenous injection of a benzodiazepine (diazepam or nitrazepam) triggered within seconds or minutes very frequent tonic seizures amounting to tonic status associated with diffuse rhythmic spikes (Tassinari et al., 1971, 1972; Martin 1970; Prior et al., 1972; Waltregny & Dargent, 1975; Amand & Evrard, 1976; Bittencourt & Richens, 1991; Di Mario & Calancy, 1988). Based on time course and EEG, the condition was thought to be unrelated to the hypnogenic action of the benzodiazepine. All patients except one were in a state of confusion when the injection was given, and showed numerous or continuous spike-and-wave discharges. Some of these patients had received other injections of benzodiazepines in the past without adverse effects, and they had had previous episodes of tonic status. Failure to recognize this effect may have serious consequences, because the physician may be tempted to control seizures by increasing the dose of the offending drug. Increased tonic seizures have also been reported after oral benzodiazepines (Tassinari et al., 1971; Gastaut et al., 1971). However, the observation that status was arrested when the same drugs were given intravenously complicates the interpretation of these findings. Seventy-one (5.8%) of 1222 patients with various seizure types showed a seizure deterioration, especially tonic and absence seizures, following clonazepam treatment (Alvarez et al., 1981), thus considered to be druginduced. Tonic-like seizures or ‘microseizures’ following administration of benzodiazepines, mostly clonazepam, involved infants with West syndrome (Bauer, 1996; Ohtahra et al., 1983; Sano et al., 1984; Ichiyama et al., 1990). In one study, clonazepam (but not other benzodiazepines) precipitated absence status when added to pre-existent valproic acid therapy in patients with generalized epilepsy (Sano et al., 1984), but this observation has not been confirmed in subsequent reports (Mireles & Leppik, 1985). Carbamazepine

Carbamazepine may exacerbate typical and atypical absences (Lerman, 1986; Shields & Saslow, 1983; Johnsen et al., 1984; Holowach et al., 1962; Snead & Hosey, 1985; Horn et al., 1986, Caraballo et al., 1989; Marescaux et al., 1990) as well as atonic (Shields & Saslow, 1983; Johnsen et al., 1984; Caraballo et al., 1989), tonic

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(Snead & Hosey, 1985; Mutoh et al., 1993; Kimura et al., 1995) and myoclonic seizures (Shields & Saslow, 1983; Johnsen et al., 1984; Kimura et al., 1995; Parmeggiani et al., 1996) in patients with generalized epilepsy, mostly in children. Patients with these seizure types in their history are particularly at risk, but de novo appearance of these seizures has been reported also in patients who had only tonic–clonic seizures (Lerman, 1986; Shields & Saslow, 1983), benign idiopathic partial epilepsy (Lerman, 1986), juvenile myoclonic epilepsy (Sozuer et al., 1996), unspecified seizure types (Sozuer et al., 1996) or frequent multifocal EEG paroxysms without seizures (Parmeggiani et al., 1996). Absence status has occurred following carbamazepine administration (Johnsen et al., 1984; Snead & Hosey, 1985; Callahan & Noetzel, 1992). This drug increased seizure frequency in patients with Angelman syndrome, and precipitated long-lasting myoclonic–astatic status which ceased after switching to valproate (Viani et al., 1995). Aggravation or precipitation of continuous spike-and-wave activity during sleep in children with Landau–Kleffner syndrome (Marescaux et al., 1990) and benign partial epilepsy (Caraballo et al., 1989, Fejerman & De Blasi, 1987), while aggravation of epileptic negative myoclonus and precipitation of almost continuous central spike-and-wave activity has been reported in children having benign rolandic epilepsy with minor atypical features (Guerrini et al., 1995). Seizure exacerbation in adults is less common, although carbamazepine caused recrudescence of remote absence or de novo appearance of absences (Sachdeo & Chokroverty, 1985; Liporace et al., 1994b). Aggravation of other seizure types by carbamazepine occurs more rarely: exacerbation of tonic–clonic seizures, including status epilepticus, has been seen occasionally in children with generalized epilepsy, the effect being often associated with pre-existence or appearance of generalized spike-and-wave activity in the EEG (Johnsen et al., 1984; Snead & Hosey, 1985; Holowach et al., 1962). Epileptic spasms may also be aggravated by carbamazepine (Talwar et al., 1994), and the risk is likely to be underestimated since this drug is seldom given to children with spasms. Although carbamazepine has been reported to worsen the EEG in patients with partial seizures (Geladse et al., 1996; Rodin et al., 1974a; Wilkus et al., 1978), this is usually without consequences on seizure control, and reports of aggravation of partial seizures by carbamazepine are relatively uncommon when viewed against the background of the very large number of patients with partial epilepsy who are treated with this drug. Aggravation of complex partial seizures after prescription of carbamazepine occurred in two children, one of whom progressed to status epilepticus (Holowach et al., 1962). Adult patients experienced an increase in the frequency of complex partial seizures (Parmeggiani et al., 1996; Hayashi et al., 1993) and occasional cases had visual hallucinations associated with occipital spikes (Horn et al., 1986). One 14-month-old boy with tonic–clonic seizures and interictal left occipital spikes developed de novo very frequent complex partial seizures

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associated with focal right temporal lobe discharges and nonepileptic multifocal myoclonus when carbamazepine was added to pre-existing valproate therapy, and that improved dramatically after carbamazepine was discontinued (Dhuna et al., 1991). Since this patient had a carbamazepine level within the optimal range (8.2 mg/l) but an unusually high carbamazepine-10,11-epoxide level (8.9 mg/l), the suggestion was made that the seizure exacerbation was related to the metabolite. Several authors made a similar suggestion for adults experiencing deterioration in seizure control and partial status epilepticus when treated with carbamazepine (Hayashi et al., 1993; So et al., 1994). These patients showed relatively high serum carbamazepine-10,11-epoxide levels and improved by withholding the carbamazepine dose. However, in some cases the elevation of the epoxide metabolite could have been a coincidental finding related to the fact that some of these patients also received valproic acid, a drug known to elevate carbamazepine-10,11-epoxide levels (Pisani et al., 1986). Non-epileptic myoclonus has been reported in both children (Dhuna et al., 1991) and adults (Wendland, 1968; Chadwick et al., 1976; Aguglia et al., 1987), and this has important implications with respect to the differential diagnosis of carbamazepine-induced seizure disorders. In two children with benign rolandic epilepsy recently described by Guerrini et al. (1995), negative myoclonus aggravated by carbamazepine was clearly epileptic in origin. Risk factors for carbamazepine-induced seizure deterioration have been diversely evaluated, including mixed seizure types (Holowach et al., 1962), or children with childhood absence epilepsy, frontal lobe symptomatic epilepsy, Lennox–Gastaut syndrome and severe myoclonic epilepsy in infancy (Horn et al., 1986). Patients with juvenile myoclonic epilepsy are also at special risk, particularly with regard to precipitation of myoclonic and absence seizures (Sozuer et al., 1996; Timmings & Richens, 1992; Richens & Perucca, 1993; Kivity & Rechtman, 1995) and even myoclonic status (Kivity & Rechtman, 1995). Risk of aggravation of myoclonias has also been noted in children with a syndrome borderline between rolandic and juvenile awakening epilepsies (Dulac et al., 1986). Atypical absence seizures may be mistakenly diagnosed as complex partial seizures, especially when focal EEG features coexist with generalized spike-and-wave discharges, and lead to the inappropriate choice of carbamazepine for treatment (Lerman, 1986). In one series, all children who had exacerbation of atypical absence and tonic–clonic seizures manifested bilateral synchronous spike-and-wave discharges on video-EEG telemetry before initiation of carbamazepine treatment (Holowach et al., 1962). Thus, carbamazepine should be avoided in patients with generalized synchronous spike-andwave discharges of 2.5 to 3 Hz, as this pattern appears to be predictive of the precipitation of absence seizures. In addition, a slower frequency of spike-and-wave bursts may indicate a greater risk of precipitating generalized convulsive seizures.

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The value of EEG data in predicting seizure exacerbation was assessed in a series of 59 children aged less than 6 years started on carbamazepine (Talwar et al., 1994). Only a minority of these (n5) demonstrated spike-and-wave discharges at pretreatment. Following initiation of treatment, the EEG of 33 children was unchanged, improved or minimally modified during treatment, and excellent to complete seizure control was achieved in 67% of cases (group I). In 26 children (group II), the EEG became more abnormal and was characterized predominantly by new appearance of generalized spike/polyspike-and-wave discharges; the majority of these patients (65%) experienced seizure exacerbation. Although EEG findings at pretreatment were similar in the two groups, seizure etiology differed significantly. In group I., symptomatic partial epilepsy (n16), idiopathic partial epilepsy (n3) and complex febrile seizures (n3) were significantly more common, whereas cryptogenic epilepsy was more common in group II. Although in this group almost all patients were initially presumed to have partial epilepsy, some developed later generalized syndromes such as myoclonic-astatic epilepsy (n 2), infantile myoclonic epilepsy (n3), and cryptogenic infantile spasms (n3). No patients in this study had childhood absence epilepsy or Lennox–Gastaut syndrome, but knowledge of seizure exacerbation and/or lack of effect of carbamazepine in these epilepsies most likely contributed to avoidance of the drug in these syndromes. These findings highlight the importance of accurate syndromic diagnosis for correct drug selection, although such diagnosis may be difficult in children with recent onset seizures. In particular, incomplete myelination may contribute to the prominence of focal or multifocal clinical and EEG features, and generalized spike-and-wave activity may not be manifest initially, leading to misdiagnosis of the type of epilepsy (Sarisjulis et al., 2000). In addition, prospective EEG evaluation in children started on carbamazepine may be of great value since new appearance of generalized paroxysmal discharges correlates with seizure exacerbation or suboptimal control and adverse outcome. Ethosuximide

Whether ethosuximide can precipitate or exacerbate tonic–clonic seizures in children with absence epilepsy (Zimmermann & Burgmeister, 1958, Subirana & OllerDaurella, 1961; Findeis, 1990; Friedel & Lempp, 1962) or not (Heathfield & Jewesbury, 1964) remains uncertain. Patients with absence epilepsy may show tonic–clonic seizures later in life as part of the natural history of the disorder. Therefore, occurrence of grand mal seizures in these patients may simply reflect the inability of ethosuximide to protect against convulsive seizures. In one study, 33 (80.5%) of 41 patients treated with a drug specific against petit mal alone developed grand mal seizures over a 5-year follow-up, compared with only 21 (35.6%) of 59 patients who were given phenobarbital in addition to a drug specific for petit

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mal (Livingston et al., 1965). Following this study, it used to be popular to combine ethosuximide with a drug active against convulsive seizures, but this is no longer warranted since valproic acid is effective against both seizure types. Ethosuximide has been reported to exacerbate pre-existing generalized nonconvulsive seizures (Todorov et al., 1978), and to increase atonic seizures in patients with juvenile myoclonic epilepsy (Sozuer et al., 1996). Gabapentin

A 14-year-old boy with Lennox–Gastaut syndrome experienced dramatic exacerbation of absence and myoclonic seizures when given gabapentin (900–1800 mg/day) (Vossler, 1996). In 28 of 188 patients (15%), gabapentin was discontinued because of seizure deterioration (Wong et al., 1996). Other studies reported worsened seizure frequency with gabapentin (Ojemann et al., 1992, Fromm, 1994), but the causal relationship was unclear. Eight cases of reversible gabapentin-induced myoclonus have been reported but it was not possible to determine whether it was an epileptic phenomenon (Scheyer et al., 1996). In three other cases of gabapentininduced myoclonus, the jerks showed no EEG correlation (Asconapé et al., 1995). Lamotrigine

Myoclonic status occurred in a 7-year-old girl with Lennox–Gastaut syndrome when treated with high-dosage lamotrigine in addition to vigabatrin and clobazam, and the condition resolved rapidly following lamotrigine discontinuation, but the causative role of the drug was uncertain in view of a 6-month latency between initiation of treatment and development of status (Guerrini et al., 1999). Although deterioration of myoclonic seizures is uncommon with lamotrigine in children (Schlumberger et al., 1994), five of seven adults with myoclonic epilepsy worsened during lamotrigine treatment (Sander et al., 1990), and 80% of patients with severe myoclonic epilepsy in infancy (Dravet syndrome) experienced increased seizures or status epilepticus (Guerrini et al., 1998). The very slow titration required by the combination with valproate that these patients usually receive when added lamotrigine, caused the recognition of worsening to be delayed by several months. Phenytoin

Phenytoin is supposed to be similar to carbamazepine in its mode of action (blockade of sodium channels). Some observations also suggest seizure deterioration (Bauer, 1996; Osorio et al., 1996), but the overall number of reports is lower than recorded for carbamazepine. Aggravation of absence seizures has been reported (Vallarta et al., 1974; Lerman, 1986; Livingston, 1966), particularly atypical absences misdiagnosed as complex

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partial seizures (Lerman, 1986). Phenytoin has also aggravated myoclonic jerks in patients with juvenile myoclonic epilepsy (Sozuer et al., 1996; Kivity & Rechtman, 1995). This drug exacerbated complex partial seizures induced by photic stimulation in a child (Shufer & Vining, 1991), and precipitated continuous spike-and-wave activity during sleep in children with benign partial epilepsy (Fejerman & De Blasi, 1987). In a recent case, spike-and-waves during sleep and focal seizures were worsened in a 5-year-old child with Landau–Kleffner syndrome (Marescaux et al., 1990), and in one of the original cases reported by Landau and Kleffner (Landau & Kleffner, 1957). Troxidone

Troxidone (trimethadione) has been reported to precipitate tonic–clonic seizures in children with absence epilepsy (Friedel & Lempp, 1962; Schmidt & Wilder, 1968). Again, evidence is inconclusive and it is difficult to determine whether the occurrence of tonic seizures in these patients reflected a drug-induced phenomenon or the natural course of the disease. Valproic acid

There is little or no evidence of this drug causing deterioration of specific seizure types. Combined with clonazepam, it has been said to precipitate absence status in 5 of 12 children with generalized epilepsies of unspecified type (Jeavons et al., 1977). This was not confirmed by Mireles and Leppik (1985) who treated 55 patients with the same combination of drugs. Increase in seizure and/or myoclonus frequency represents a toxic manifestation that does not necessarily occur at high dosages or serum drug levels, but seems to be an early sign of hepatic failure. Combined with vomiting and drowsiness, it should indicate withdrawal of the drug. It may represent an idiosyncratic reaction in susceptible individuals, some of whom may have a pre-existing metabolic disorder as predisposing factor (Horiuchi et al., 1993). Vigabatrin

Vigabatrin is useful in symptomatic or cryptogenic partial epilepsies and infantile spasms (Grant & Heel, 1991; Freucht & Brantner-Inthaler, 1994), but aggravation of absence, tonic and myoclonic seizures in some adult and pediatric patients has been described (Grant & Heel, 1991; Vogt & Stotz, 1996; Lortie et al., 1993). In a retrospective survey of 194 children with refractory epilepsy, a third of whom were below 2 years of age, approximately 10% showed an increase in seizure frequency after starting add-on vigabatrin (Lortie et al., 1993). The increase

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concerned mainly generalized and only rarely partial seizures. All affected children were older than 2 years and most had non-progressive myoclonic epilepsy or Lennox–Gastaut syndrome; in the former cases, the exacerbation in seizure frequency affected tonic and atypical absence seizures rather than myoclonic seizures. Seizure deterioration was unrelated to vigabatrin dose, although some children worsened after a dosage increase. In general, seizure frequency returned to baseline after drug discontinuation, but some patients improved without any alteration in treatment, an observation which underlines the difficulty of differentiating initial drug effects from the natural course of the disease or time-related changes in drug response. About 14% of children in this study developed new seizure types: generalized seizures, mostly myoclonus, often resulted in worsening, whereas de novo development of partial seizures, which occurred mainly in patients with symptomatic infantile spasms following cessation of spasms, was usually perceived as an improvement compared with the previous condition. A number of other reports indicate the potential of precipitating myoclonic jerks, with or without corresponding EEG abnormalities in susceptible patients (Marciani et al., 1995a,b; Neufeld & Vishnevska, 1995). In 100 newly diagnosed adult patients with partial and primarily or secondarily generalized tonic–clonic seizures randomized to vigabatrin or carbamazepine monotherapy, myoclonic jerks affected 14% in the vigabatrin group compared to 2% in the carbamazepine group (Kalviainen et al., 1995). In this study, however, more patients with primarily generalized epilepsy were assigned to vigabatrin than to carbamazepine (4 vs. 1). Three out of 14 infants with symptomatic infantile spasm exhibited de novo development of fragmentary and massive myoclonus (Buti et al., 1993). When vigabatrin was discontinued, myoclonus abated in two cases, but in the third child the condition progressed to myoclonic status. Of 19 patients with localization-related epilepsy given vigabatrin (Bittencourt et al., 1994), two experienced de novo myoclonic jerks and action/spontaneous myoclonus. One of these patients also reported an increase in tonic–clonic seizures, while the other had a mild increase in complex partial seizures. These symptoms subsided after drug discontinuation or dose reduction. Vigabatrin worsens seizures due to Angelman syndrome, and can precipitate myoclonic status (Kuenzle et al., 1998). Vigabatrin has been reported to precipitate partial or generalized status epilepticus in patients with symptomatic generalized or partial epilepsy (Rogers et al., 1993; Van der Zwan Jr & Van der Zwan, 1994; De Krom et al., 1995). In two of the cases described by Rogers et al. (1993), complex partial status was associated with prominent psychiatric features, which made diagnosis more difficult. New seizure types and/or myoclonic status epilepticus may occur within the context of an acute reversible encephalopathy characterized by stupor, dysphoria and slowed EEG

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background, as reported in two patients shortly after initiation of vigabatrin therapy (Salke-Kellerman et al., 1993). Other drugs

ACTH may precipitate tonic seizures or ‘microseizures’ in some infants with infantile spasms (Ichiyama et al., 1990; Kanayama et al., 1989; Uramoto et al., 1980). Precipitation of myoclonus may occur with relatively small doses of tiagabine (8 mg) (Parks et al., 1997). Several cases of non-convulsive status have been reported (Knake et al., 1999, Ettinger et al., 1999). Chlormethiazole has been suggested to cause status epilepticus in one patient with Lennox–Gastaut syndrome (Di Mario & Calancy, 1988). Increased seizure frequency was mentioned as an adverse effect with various new antiepileptic drugs, including felbamate (Liporace et al., 1994a; Wolff et al., 1994), but the information provided in these reports is insufficient to allow meaningful assessment of the precise role of these drugs as a cause for seizure deterioration. Mechanisms of drug-induced seizure-deterioration Although the distinction may be difficult, mechanisms involved are likely to be different according to whether the patient is submitted or not to toxic doses of the compound (Perucca et al., 1998). Drug intoxication

The precise mechanism that determines drug-induced increase in seizure activity remains poorly understood although several causes may be at play. The depressant effect of high concentrations of the drug on inhibitory interneurons may in some cases result in disinhibition of excitatory neurons and consequent facilitation to the epileptic discharges (Woodbury, 1980). A reduction in the level of alertness may also enhance susceptibility to seizures, and drug-induced drowsiness may be an important mechanism of seizure activation in intoxicated patients (Bauer, 1996). For some drugs, effects outside the brain may also be at play. Valproic acid, for example, may stimulate the renal production of ammonia (Matsuda et al., 1986) and/or inhibiting urea synthesis (Hjelm et al., 1986), resulting in a toxic encephalopathy characterized by stupor, epileptic seizures, myoclonus (whose epileptic nature has been questioned) and hyperammonemia. In the case of carbamazepine, precipitation of seizures may be facilitated by hyponatremia secondary to the antidiuretic action of the drug (Hjelm et al., 1986; Van Amelsvoort et al., 1994). Thus in one series, 8 of 52 patients with carbamazepine-induced hyponatremia showed a paradoxical increase in seizure frequency, and sodium levels in these patients was

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significantly lower than in hyponatremic patients with no increase in seizure frequency (Asconapé et al., 1996). Hyponatremia, however, is unlikely to account for most cases of deterioration due to carbamazepine. Specific drug effect

GABAergic transmission has been shown to prevent or to facilitate seizures depending on the primary site at which the action of the transmitter is exerted (Olsen & Avoli, 1997). In animal models elevation in GABA levels in the nigrocollicular pathway and other areas may be proconvulsant, presumably due to suppression of firing of inhibitory neurons (Olsen & Avoli, 1997; Gale, 1989). In addition, GABA-induced hyperpolarization of thalamic neurons enhances oscillatory thalamo-cortical activity, leading to more prominent and prolonged spikeand-wave discharges. This mechanism is likely to account for the seizure worsening effect of GABAergic drugs such as vigabatrin, tiagabine and possibly gabapentin in the genetic models of absence seizures in rats (Marescaux et al., 1984; Marescaux & Vergnes, 1995; Vergnes et al., 1984) and mice (Hosford & Wang, 1997), and in some forms of human epilepsies, namely childhood and juvenile absence epilepsies and other generalized epilepsies, including those associated with myoclonic manifestations, particularly myoclonic–astatic epilepsy. The facilitation of thalamic oscillatory activity by GABAergic drugs appears to be mediated partly by GABAB receptors (Bittiger et al., 1993; Karlsson et al., 1992; Marescaux et al., 1992). Benzodiazepines are devoid of agonist properties at GABAB receptors and therefore their activity profile differs from that of drugs, which act by increasing neuronal or synaptic GABA content (Marescaux et al., 1984). Hence, the occasional observations of benzodiazepine-induced seizure aggravation, mainly in patients with Lennox–Gastaut syndrome, can hardly be ascribed to the thalamic mechanisms discussed above. Carbamazepine and phenytoin are considered to act primarily by blocking voltage-dependent Na channels (McLean et al., 1984). Exacerbation mainly concerns generalized epilepsies. A selective action of the drug on the CNS structures responsible for generalized epileptic discharges is suggested by findings in animal models of absence epilepsy, where carbamazepine produces a seizure aggravating effect (Loscher & Schmidt, 1988). Exacerbation of seizures and/or EEG paroxysms by carbamazepine is associated with a slowing in background activity (Pryse & Jeavons 1970; Rodin et al., 1974a). Since generalized slow EEG activities may be paced by the same thalamo-cortical network responsible for spike-and-wave generation (Steriade et al., 1991; Currò Dossi et al., 1992), an action of carbamazepine on this network could facilitate generalized epileptogenesis. Paradoxical seizure responses was associated with high blood levels of carbamazepine-10,11-epoxide

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(Dhuna et al., 1991, So et al., 1994), thus this metabolite may play a pathogenetic role. Conclusions Drug induced worsening of seizures is well documented. It may result from drug intoxication and resolve upon reduction of dosage or elimination of unnecessary polypharmacy. In other instances, it seems to result from an adverse interaction between the mode of action of the drug and the pathogenetic mechanisms underlying specific seizure types or syndromes. Rare cases are particularly intriguing since exacerbation occurs at therapeutic dosages and in patients with types of epilepsy which usually respond favourably to the offending drug. The most commonly reported is precipitation or exacerbation of absence, myoclonic and atonic seizures in patients with generalized epilepsies given carbamazepine, but aggravation of these or other seizure types has been reported with other antiepileptic drugs. The large majority of reports involve pediatric patients. Movement disorders precipitated by drugs Drugs frequently cause movement disorders through various mechanisms depending on the type of drug. This section of the chapter focuses on movement disorders induced by antiepileptic drugs (AEDs) (first part), as well as by drugs used for treating movement disorders (second part). Seizures induced by drugs used for treating movement disorders will conclude this section (third part). Basal ganglia, epilepsy and movement disorders

Anatomic and physiological studies indicate that the basal ganglia are components of larger segregated motor circuits, which also involve parts of the cortex and thalamus (Albin et al., 1989; Alexander & Crutcher, 1990). Movement disorders appear to result from disturbances in the motor circuit, comprising pre- and postcentral sensorimotor fields, as well as the motor territories of the basal ganglia, the ventral anterior and ventrolateral thalamus (VA, VL). Cortical projections from the sensorimotor fields terminate largely in the post-commissural putamen, the motor portion of the striatum. Putaminal output is, in turn, directed toward motor portions of the internal segment of the globus pallidus (Gpi) and of the substantia nigra (SNr) of pars reticulata via two pathways: a ‘direct’ pathway from the putamen to motor portions of Gpi/SNr, and an ‘indirect’ pathway passing through the motor areas of the external pallidal segment (Gpe) and the subthalamic nucleus (STN). With the exception of excitatory (glutamatergic) projections between STN

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and Gpi/SNr, the intrinsic connections of the basal ganglia, as well as their outputs to thalamus are all inhibitory and GABAergic. More progress has recently been made in understanding the pathophysiological mechanisms underlying the major movement disorders of the basal ganglia origin. This group of disorders involves disruption of the delicate balance between the activity of the ‘direct’ and the ‘indirect’ pathways. Hypokinetic movement disorders (Parkinson’s disease) are thought to arise from a relative preponderance of activity of the indirect pathway, leading to an increase of inhibitory basal ganglia output to the thalamus. Conversely, hyperkinetic disorders (chorea, dystonia, myoclonus, tics) and akathisia are likely the result of shift of the balance towards the ‘direct’ pathway, leading to reduced basal ganglia output. Based on the observation of Fariello and Hornykiewicz (1979) that substantia nigra pars compacta (SNc) lesioning increases the convulsive threshold in rats, it has been suggested that basal ganglia circuits, particularly nigral output pathways, are involved in the pathophysiology of epilepsy. Since then, evidence has been accumulated to demonstrate the existence, in the central nervous system, of an endogenous mechanism that exerts an inhibitory control over different forms of epileptic seizures. Particularly, the substantia nigra and the superior colliculus have been described as the key-structures in this control circuit; inhibition of GABAergic neurons of the SNr results in suppression of seizures in various animal models of epilepsy (chemoconvulsant, Kindling, electroshock, genetic) (Iadarola & Gale, 1982; McNamara et al., 1983; Deransart et al., 1996). Pharmacological manipulations of both the direct and indirect pathways result in modulation of epileptic phenomena such as absence seizures. In particular, it is now believed that activation of the direct striato-nigral GABAergic pathway or inhibition of the indirect pathway, from the striatum through the GPe and the subthalamic nucleus, suppresses absence seizures through disinhibition of neurons in the deep and intermediate layers of the superior colliculus. Dopamine D1 and D2 receptors in the nucleus accumbens appear to be critical in these suppressive effects (Deransart et al., 1998). The role of SNr in the modulation of some seizures, is also demonstrated by the appearance of necrotic lesions in this anatomic structure following a prolonged status epilepticus, probably due to a massive metabolic activation (Ingvar et al., 1987). It is likely that SNr is involved in the control of cortical seizure susceptibility, regulating other structures, which are possibly involved in the generation and propagation of seizure. These experimental data have led to the conclusion that the SN may mediate some actions of antiepileptic drugs. In fact, microinjections into the SN of benzodiazepines and barbiturates protect rats against pilocarpine seizures, a model of limbic seizures (Turski et al., 1990). Other authors have suggested that both SNr and the SNc are involved in the control of seizure propagation (Ferraro

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et al., 1991). The availability of a neurotoxin with a selective activity on SNc dopaminergic neurons, MPTP, has allowed to demonstrate that, in lesioned animals, a protection against generalized convulsive seizure induced by chemical or electrical stimulation is possible, suggesting a role of dopaminergic mechanisms in seizure modulation (Fariello et al., 1987). In mice, the behavioural expression of epileptic seizures is greatly attenuated by MPTP treatment, without modification of the electrographic seizure pattern (Bonuccelli et al., 1994). This implies that the dopamine depletion induced by MPTP does not alter the epileptogenesis, but may alter the function of cerebral structures involved in the control of seizure motor expression. The negative epidemiological association between epilepsy and Parkinson’s disease that has been reported in the past, fits very well with these experimental data. On the other hand, parkinsonian symptoms improve transitorily after both generalized and partial complex seizures (De Angelis & Vizioli, 1984), and electroshock treatment has been proposed for treating PD. However, epileptic seizures are not a rare feature in other parkinsonisms, such as Wilson’s disease, neuroacanthocitosis and pallido-luysian degeneration. Interestingly, an early-onset phenotype of autosomal dominantly inherited frontotemporal dementia and parkinsonism (FTDP-17) in combination with epileptic seizures, has been recently described (Sperfeld et al., 1999). The most likely explanation of this clinically based incompatibility between parkinsonism and epilepsy, is that in idiopathic Parkinson’s disease patients, the nigro-striatal dopaminergic deficiency may reduce the clinical expression of the motor manifestation of seizures, but in parkinsonian syndromes, where lesions spread out of the nigro-striatal bundle, this apparent protection wanes. Movement disorders induced by AEDs (Tables 29.1, 29.2) AEDs can induce movement disorders through various pathogenic mechanisms and with various clinical expressions. AEDs-induced movement disorders include horea, tremor, dystonia, parkinsonism, myolonus, tics and akathisia. Many of these movement disorders disappear after withdrawal of the offending drug. Phenytoin (PHT)

Anticonvulsant induced-dyskinesia, chorea and dystonia are clinically similar to those induced by neuroleptic drugs (Chadwick et al., 1976). PHT is the antiepileptic drug most frequently associated with the development of movement disorders. This drug has been suggested to induce choreoathatosis, orofacial chorea, ballismus, dystonia, tremor, asterixis, and myoclonus (Harrison et al., 1993). In the mentioned review, 77 cases were reported until 1993; additional few cases have been reported more recently (Moss et al., 1994; Duarte et al., 1996; Koukkari et al., 1996).

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Table 29.1. AEDs-induced movement disorders

Drug

Movement Disorder

Phenytoin

Chorea Chadwick et al. (1976), Harrison et al. (1993), Shulman et al. (1996) 

Valproic acid

Evidence

Dystonia Chadwick et al. (1976), Moss et al. (1994)



Myoclonus Chadwick et al. (1976), Klawans et al. (1986)



Tremor Chadwick et al. (1976)



Parkinsonism Prensky et al. (1971), Goni et al. (1985)



Asterixis Chadwick et al. (1976)



Akathisia Chadwick et al. (1976)



Tremor Hyman et al. (1979), Karas et al. (1982), Karas et al. (1983)



Chorea Lancman et al. (1994)



Myoclonus Chadwick et al. (1976), Klawans et al. (1986)



Parkinsonism Armon et al. (1996)



Akathisia Riche et al. (1994)



Carbamazepine Dystonia Jacome (1979), Bradbury et al. (1982), Crosley & Swender (1979)



Chorea BimpongBula and Froescher (1982)



Myoclonus Wendland (1968), Aguglia et al. (1987)



Tics Neglia et al. (1984)



Note: Symbols: well documented; relatively well documented; anecdotal reports.

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Table 29.2. Other AEDs-induced movement disorders

Drug

Movement Disorder

Phenobarbital

Chorea Chadwick et al. (1976) Dystonia Lacayo and Mitra (1992)

Ethosuximide

Benzodiazepine

Lamotrigine

Gabepentin

Felbamate

Chorea Kirschberg (1975) Chorea Rosenbaum & De la Fuente (1979) Dystonia Stolarek and Ford (1990) Tics Lombroso (1999) Dystonia Verma et al. (1999) Chorea Buetefisch et al. (1996), Chudnow et al. (1997) Dystonia Bernal et al. (1999)

Chorea Kerrick et al. (1995) Dystonia Kerrick et al. (1995)

Evidence  



 

 

 

 

Symbols: well documented; relatively well documented; anecdotal reports.

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Abnormal involuntary movements (AIMs) usually occur in patients with high PHT plasma levels, but in 23% of the cases PHT levels were within the therapeutic range. Some 68% of the patients who developed AIMs were taking other AEDs in combination with PHT; the most common hyperkinesia observed is choreoathetosis (91%). There are two case reports in which a parkinsonian syndrome was induced after treatment with phenytoin, one in a child (Prensky et al., 1971) and one in an adult (Goni et al., 1985). Although the specific mechanism of PHT-induced movement disorders is unknown, it has been suggested that there is a disturbance in the functional equilibrium of the basal ganglia output systems, perhaps due to a differential effect of phenytoin on dopamine receptor subtypes or their associated second messenger systems. There is evidence that vulnerability to this effect is increased in the abnormal central nervous system (CNS). However, in only 12% of the patients structural lesion of the brain was identified (Gershanik, 1993). The cases presented by Harrison et al. (1993) represent the only two ones with radiographic evidence of a structural lesion of the thalamus, and involvement of the connections to the subthalamic nuclei is most likely implicated as an underlying abnormality. Valproic acid (VPA)

Tremor has been noticed as a side effect at variable doses and serum concentrations, and begins within 3 to 14 months after starting therapy (Price, 1976; Hyman et al., 1979; Karas et al., 1982). Up to 25% of patients on long-term VPA therapy with a daily dose greater than 750 mg suffer from tremor (Karas et al., 1982; Diederich & Goetz, 1998). Hyman et al. (1979) believed the tremor was similar to the benign essential type and occurred at dosages of 1 to 2 g/day, with serum levels of 34.9 to 154.3 g/ml. In three of their four patients, tremor did not appear until after 12 months of therapy, but 1 patient with a family history of tremor had tremor after only 3 months. Karas et al. (1982) found the tremor as early as 1 month. It was present and exacerbated by intentional positions, but also had prominent resting and postural components. Tremor usually appeared at doses greater than 750 mg/day, but blood levels did not reflect this relationship; tremor was present with VPA serum levels in the therapeutic range (35 to 102 µg/ml) and was reduced by decrease of valproate dosage. The majority of patients who develop a clinically significant tremor from VPA have responded to propranolol and, in some instances, treatment with amantadine or cyproheptadine have lessened tremor (Karas et al., 1983). VPA tremor could result from the interaction with anyone or all the neurotransmitters implicated in the tremor production: being GABA-mediated transmission,

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the possible target. The combination of VPA with lamotrigine may increase or precipitate the occurrence of tremor (Reutens et al., 1993). VPA may cause chorea in patients with severe epilepsy and brain damage (Lancman et al., 1994). In fact, three cases with severe brain damage, in whom chorea developed after long-term therapy with VPA associated with PHT, have been described. Chorea occurred after several years of valproate use and seemed to be dose related. The pathophysiology of VPA-induced chorea is unknown. Chorea can be induced by the injection of bicuculline, a GABA-antagonist, in the lentiform complex (Mitchell et al., 1989). Paradoxically, VPA action is partially GABAmediated (Fariello & Smith, 1989), and it has been reported to be useful in the treatment of refractory Sydenham chorea (Steinberg et al., 1987). Thus, VPA-induced chorea may be more likely to develop if VPA is taken together with phenytoin. A study in epileptic patients treated with VPA over 12 months demonstrated an insidious onset of parkinsonism (Armon et al., 1996). In this series, a remarkable 92% of patients had features of this syndrome. Almost all of them improved after discontinuation of the drug. Parkinsonism was associated with cognitive and hearing impairment, and it was speculated that this syndrome was due to overwhelming GABAergic activity and mitochondrial respiratory chain dysfunction (Armon et al., 1996). It is surprising that no previous or subsequent reports of VPAinduced parkinsonism–dementia syndrome have been published. Carbamazepine (CBZ)

Dystonia and chorea are the most common movement disorders associated with the use of CBZ. Jacome (1979) reported four cases who developed transient dystonia with doses exceeding 1000 mg/die, while Bradbury et al. (1982) noted dystonia in two patients with mildly elevated serum levels. Crosley and Swender (1979) described severe dystonia progressing to opisthotonus in three epileptic children. In addition to dystonia, Bimpong-Bula and Froesher (1982) observed CBZ-induced choreoathetosis, Weaver et al. (1988) reported five cases of CBZ-induced choreoathetosis after massive overdose of the drug. The pathophysiologic mechanisms underlying CBZ-induced hyperkinesias are not clear. A combination of altered dopaminergic and cholinergic function may play a role (Miyasaki & Lang, 1995). First, Wendland (1968) documented three cases who developed myoclonus. CBZ may exacerbate myoclonic seizures in patients with generalized epilepsy mostly in children. Tics have also been described with CBZ therapy (Neglia et al., 1984). Generally, these patients had Tourette’s syndrome with preexisting tics that were exacerbated following CBZ use. Other patients exhibiting new onset tics had prior diagnoses of

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Huntington’s chorea or Alzheimer’s disease. Only one patient without a preexisting movement disorder has been reported to have tics induced by CBZ (Neglia et al., 1984). It is postulated that CBZ causes tics through an enhancement of presynaptic release of dopamine by striatal neurons (Barros et al., 1986). It is therefore surprising that CBZ is the treatment of choice for paroxysmal kinesigenic choreoathetosis. Barbiturates and benzodiazepine

Patients who are treated with barbiturates, such as phenobarbital, can develop chorea (Lightman, 1978) and dystonia (Lacayo & Mitra, 1992). Benzodiazepines, such as diazepam, clorazepate, and lorazepam, rarely have been found to worsen or even to induce dyskinesias (Rosenbaum & De la Fuente, 1979). Acute dystonic reactions have been reported with the use of intravenous midazolam (Stolarek & Ford, 1990). Lamotrigine (LTG)

The administration of LTG to three children led to motor and vocal tics like those of Tourette’s syndrome (Lombroso, 1999). It is clear that such effects were dose related, disappearing once the drug was stopped or reduced. Although the occurrence of tourettism during LTG remains speculative, the potent inhibitory effect of the drug on presynaptic release of excitatory amino acids might alter the striatal dopamine uptake, inducing the development of tics. In a child, when 25 milligrams of LTG were added to VPA, nitrazepam athetosis was observed, and it subsided when the drug was halved (Buchanan, 1996). A case of blepharospasm was also reported during LTG therapy (Verma et al., 1999). Gabapentin (GBP)

The package insert for GBP indicates that 1.3% of patients in premarketing study reported ‘twitches’; movement disorders were reported in 0.3%, choreoathetosis in 0.1% (Reeves et al., 1996). Movement disorders associated with the use of GBP have been described: so far, three cases of chorea – of which one has been reported by Buetefisch et al. (1996) and two by Chudnow et al. (1997) – and four of dystonia – of which two by Reeves et al. (1996) and two by Bernal et al. (1999) – in epileptic patients have been reported. Felbamate (FBM)

Two children developed involuntary movements with FBM as an adjunct to their antiepileptic regimen (Kerrick et al., 1995). One exhibited choreoathetosis and the other an acute dystonic reaction; in both cases the symptoms resolved with no recurrence after FBM discontinuation.

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Vigabatrin (VGB)

Two cases, the first with akathisia and the second with severe hyperkinesia, associated with the introduction of VGB as additional therapy for intractable seizures, have been reported (Jongsman et al., 1991). In another study, a small number of patients with parkinsonian symptoms worsened on VGB (Grant & Heel, 1991). Movement disorders induced by drugs used for treating movement disorders The administration of drugs with agonistic or antagonistic effects upon striatal dopamine receptors (dopamine receptor-blockers – DRBs) or inhibiting dopamine storage and transport, used in the treatment respectively of parkinsonism, choreic dyskinesia, dystonia and tics, is frequently associated with the development of various types of movement disorders. In particular, neuroleptics can cause a gamut of movement disorders occurring acutely, subacutely, and chronically. The term ‘tardive’ is used to describe all persistent, occasionally reversible, abnormal involuntary movements caused by prolonged exposure to these types of drugs. DRB-induced movement disorders Acute syndromes

Acute dyskinesia composes a wide variety of phenomena that are mostly dystonic. DRB-induced acute dystonia affects face and neck and the more common clinical expressions are oculogyric crisis, and oromandibular dystonia. The onset is abrupt, and 90% of acute dystonia occurs within the first 5 days of drug assumption. Risk factors for the development of drug-induced acute dystonia include younger age, male gender. There may be spontaneous resolution, but mostly the use of parenteral injections of anticholinergic is needed to abate dystonia. Apomorphine and benzodiazepines are less potent alternative drugs. Two conflicting hypotheses have been proposed to explain the pathogenetic mechanism of drug-induced acute dystonia. One suggests a state of excess dopaminergic activity with increased release of dopamine and hypersensitivity of dopamine receptors as a net effect of neuroleptic-induced dopamine receptor blockade (the mismatch hypothesis). However, it is well accepted that the risk of developing acute dystonia relates to the neuroleptic potency, which is proportionate to its ability to block dopamine receptors. Hence, others have proposed that decreased striatal dopamine activity is the underlying pathophysiological explanation for acute dystonia (Miyasaki & Lang, 1995). This is in keeping with the observation that dopamine agonists can be useful in the treatment of acute dystonia. Elements of both hypotheses may be involved because D2 receptors are principally occupied by classical neuroleptics. The resulting increase in dopamine turnover may be expressed through greater

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activation of unblocked D1 receptors. Other neurotransmitters have been implicated in the pathophysiology of acute dystonia. These are based largely on clinical observation and the knowledge of intrinsic properties of specific neuroleptics. For example, neuroleptics, such as clozapine, with high anticholinergic activity have less propensity to induce acute dystonia. Additionally, anticholinergics quickly reverse the symptoms in most cases. Thus, it has been proposed that increased cholinergic activity results in dystonia, in keeping with the observation that cholinergic agonists can induce acute dystonia in animals confirms this. Some authors have invoked neuroleptic blockade of sigma receptors as the cause of acute dystonia. Studies of the role of g-aminobutyric acid (GABA) have yielded conflicting results. Similarly, assessments of drugs that affect the serotonergic system have provided little evidence for an important role of serotonin (Miyasaki & Lang, 1995). Subacute syndromes

This syndrome was firstly described by Steck (1954) in patients taking chlorpromazine. DRB-induced parkinsonism occurs in fewer than half of the treated patients, although the prevalence studies of parkinsonism give a wide range of 5% to 90% of treated patients, depending on neuroleptic potency, dose, population examined, and measurements applied (Diederich & Goetz, 1998). In patients at risk for DRB-induced parkinsonism, the syndrome develops within 1 month in 50% to 70% of the patients and within 3 months in 90% of the patients. It is difficult to predict which patients are maximally at risk for neuroleptic-induced parkinsonism and what is the maximal time of onset. Higher prevalence has been described for elderly and female patients. Onset is generally considered subacute, occurring after several days or weeks of drug exposure. Neuroleptic-induced parkinsonism can occur in the context of long-term drug treatment, when the dose of neuroleptic is increased. For this reason, tardive dyskinesia (see later), usually occurring months or years after antipsychotic drug use, can exist concomitantly with parkinsonism in instances in which the neuroleptic dose is increased. Clinical phenomenology of DRB-induced parkinsonism is indistinguishable from idiopathic Parkinson’s disease. Early reports claimed that this parkinsonism is more symmetric, has predominant bradykinetic features, and often lacks tremor. No unique syndromes are identified however, and asymmetric and tremor-dominant patients with DRB parkinsonism have been described. One sign that may be more frequent in DRB parkinsonism is a low-frequency, high-amplitude jaw tremor termed rabbit syndrome. Varying individual susceptibility suggests that affected patients may already suffer from subclinical parkinsonism, temporarily unmasked by pharmaceutical manipulation. The development of DRB-induced parkinsonism is usually dose-dependent for

DRB-induced parkinsonism

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Seizures and movement disorders precipitated by drugs

each drug, and seems to be related to the blockade of dopamine D2 receptors, and with the degree of D2 receptor occupancy in the striatum (Farde et al., 1992). Halogenate and piperazine phenothiazines, and butyrophenones, are the antipsychotics with the greatest likelihood of producing this complication (Grohmann et al., 1990). Although comparisons of absolute prevalence levels for parkinsonism and other movement disorders are difficult to make, the risk of developing these movement disorders with the newer atypical antipsychotics (clozapine, olanzapine, risperidone, sertindole, quetiapina) is lower than that of the typical ones (Egan et al., 1997). DRB-induced tremor It can be subacutely induced by DRBs and clears on drug withdrawal. Tremor is usually a low amplitude and high frequency postural tremor indistinguishable from essential tremor (Gabellini et al., 1989; Miller & Jankovic, 1990; Stacy & Jankovic, 1992). There have been reports of single cases of tongue tremor (Arblaster et al., 1993) and rubral-like tremor, which is characterized by a combination of rest and postural kinetic tremor with a peak of amplitude on attempting movement, in patients exposed to antipsychotic (Friedman, 1992). Tardive syndromes

The first description of an extrapyramidal syndrome drug-induced dates back to the 1953 Swiss symposium on chlorpromazine. The notion that tardive dyskinesia (TD) was uncommon persisted until studies in the late 1960s began to reveal relatively high prevalence rates and Faurbaie et al. (1964) were the first to propose the term ‘tardive dyskinesia’. General acceptance of the association of TD with longterm neuroleptic treatment came in the early 1970s. It was not until the late 1980s that serious epidemiologic studies were undertaken, showing prevalences varying between 0.5% and 65% (Wolf & Gautier, 1987). Epidemiological studies have uncovered a variety of risk factors that increase the chances of developing TD (Kane et al., 1985; Waddington, 1987; Morgerstern & Glazer, 1993). Demographic risk factors include increased age, psychiatric diagnosis (mood disorders have increased risk), and gender. Although the findings regarding genders are equivocal because initial studies suggested that females had increased risk, more recent reports found greater severity in young men than in young women (Yassa & Jeste, 1992). Treatment variables associated with increased risk include higher neuroleptic dose (Morgerstern & Glazer, 1993; Kane, 1995), and number of medication-free periods (Egan et al., 1994). Tardive syndromes can faithfully reproduce almost the entire spectrum of known abnormal involuntary movements of the hyperkinetic type (chorea, dystonia, tics, myoclonus). The movements in TD are somewhat different from those of typical chorea, in that they tend to be more patterned, repetitive and stereotypic.

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There is a controversy regarding terminology of these disorders on account of the peculiar nature of the movements observed in TD. The terms rhythmic chorea, tardive stereotypies and tardive akathisia have been used indistinctly to describe these movements (Lang, 1994; Jankovic, 1994; Sachdev, 1995). Tardive dystonia has been lately recognized as a clinical variant of TD (Burke et al., 1982). The repertoire of dystonic symptoms, seen after long-term neuroleptic treatment, is indistinguishable from the abnormal movements and postures seen in idiopathic dystonia. The affected population is usually younger (Burke et al., 1982; Gimenez-Roldán et al., 1985; Gardos et al., 1987). Dystonic symptoms may have a focal, segmental or generalized distribution as seen in idiopathic dystonia. The generalized forms of dystonia are not common in tardive syndromes. The body regions most commonly involved in TD are the neck (retrocollis), the cranial musculature (blepharospasm, oromandibular and pharyngeal dystonia), and trunk (opisthotonus). Motor and vocal tics following chronic neuroleptic treatment are occasionally seen as part of the tardive syndrome. This type of clinical presentation has been named tardive tourettism (Klawans et al., 1982). A few cases of tardive tourettism have been reported in the literature (Bharucha & Sethi, 1995). In a small number of cases myoclonus is the predominant feature of TD (Tominaga et al., 1987). The original publication reported prominent postural myoclonus in the upper extremities in 32 out of 133 patients treated with neuroleptic. A definitive understanding of the pathophysiology of neuroleptic-induced involuntary movements is lacking. The very number of theories offered to explain the basis of tardive dyskinesia is testimony to the absence of fundamental, unifying explanation for the propensity of neuroleptics to induce tardive dyskinesia. The classic explanation of the pathogenesis of tardive dyskinesia is the dopaminehypersensitivity theory proposed by Klawans et al. (1970). Considering the similarity between levodopa-induced dyskinesia and tardive dyskinesia, he suggested that chronic neuroleptic treatment produced supersensitive striatal dopamine receptors. The original version of this idea has been supplanted with the notion that D2 supersensitivity may be a necessary first step in a path that ultimately leads to the development of TD (Egan et al., 1997). Clozapine does not induce D2 supersensitivity at standard doses. As a result of deficiencies in the dopamine supersensitivity hypothesis, considerable attention has been focused on the GABA system (Mao et al., 1977; Gale, 1980). The idea that long-term neuroleptic treatment may have a toxic effect on the brain has led to many studies of evidence of neuronal injury. The neurotoxicity hypothesis is particularly engaging given the persistence of TD in some cases and the similarity between TD and degenerative disease of the basal ganglia, such as Huntington’s disease. Although stronger evidence is required, this hypothesis has led to trials of antioxidants as a treatment for TD: in fact, the development of atypical neuroleptics provides alternatives for the treatment of TD.

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These drugs have been shown to produce fewer TD than traditional neuroleptics (Borison et al., 1996; Tollefson et al., 1996; Beasley et al., 1996). Levodopa-induced dyskinesia

With advancing Parkinson’s disease and prolonged exposure to levodopa, more than 50% of patients will develop fluctuations in their motor response and druginduced involuntary movements (Marsden & Parkes, 1977; Hardy, 1989). A variety of dyskinesias can be seen, including chorea, athetosis, ballismus, myoclonus, dystonia and akathisia. Their relationship to levodopa dosage is often clear, falling under one of three temporal patterns: peak-dose, off-period, biphasic (onset and end-of-dose), and square wave dyskinesia (peak dose plus biphasic). Peak-dose dyskinesia most often consists of choreic movements involving the trunk and the extremities at time of peak effects (Nutt, 1990). Some 30% of patients additionally suffer from painful dystonic cramps, off-period dystonia, particularly involving the foot and leg at time of wearing-off of levodopa effects (Quinn, 1984). Another variety, biphasic dyskinesia, is linked to the phases of onset of waning of a motor response to an individual dose of levodopa; these forms also may contain prominent dystonic elements intermingled with jerky and ballistic limb movements (Muenter et al., 1977; Marsden et al., 1981; Marconi et al., 1994). In MPTP-exposed primates, dyskinesia is most readily provoked in animals with the most severe motor impairment (Crossman, 1990) associated with greater than 95% dopamine depletion (Schneider, 1989). Nigrostriatal degeneration, in and of itself, is insufficient to produce dyskinesia in response to levodopa. De novoparkinsonian patients do not develop dyskinesia immediately upon starting levodopa therapy. Similarly, MPTP-treated non-human primates develop dyskinesia only after a prolonged period of levodopa exposure (Clarke et al., 1987). Once established, dyskinesias persist and do not spontaneously disappear unless levodopa treatment is reduced with consequent increase in parkinsonism. In MPTP primates, treatment from the beginning with dopamine agonists, provoke few, if any, dyskinesias (Gagnon et al., 1990; Falardeau et al., 1988; Pearce et al., 1998, Grondin et al., 1996). The same has been observed for PD patients in a few studies (Rinne et al., 1998). However, this low propensity of dopamine agonists to induce dyskinesia is present only if there was not a previous exposition to levodopa sufficient to provoke the arising of dyskinesia. Many dopamine agonists reproduce dyskinesia when given to patients or MPTP primates already dyskinetic due to levodopa exposition. These observations indicate that levodopa is able to ‘prime’ a brain made vulnerable by preexisting nigrostriatal damage, and that this effect overlasts levodopa withdrawal, suggesting a learning phenomenon similar to kindling or long term potentiation. Moreover, a few studies have demonstrated that short-acting dopamine agonists are as capable as levodopa to provoke dyskinesia

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(Gomez-Mancilla & Bédard, 1992) and that the same agonists delivered by means of a minipump in a continuous infusion do not induce dyskinesia (Blanchet et al., 1995). Thus, it can be speculated that, due to its short plasma half-life, the pulsatile dopaminergic stimulation provided by levodopa is able to modify the postsynaptic compartment, sensitizing the denervated striatum. This sensitization does not occur if levodopa is administered in a more continuous way (Juncos et al., 1989); on the other hand, continuous levodopa infusion is able to reduce dyskinesia in advanced PD patients (Schuh & Bennett, 1993; Mouradian et al., 1990). In conclusion, levodopa and striatal denervation are the two principal contributing factors for the development of dyskinesia, through a sensitization phenomenon at the striatal level. After being primed, this sensitization, may enlarge the spectrum of drugs able to induce dyskinesia, making dopamine agonist similar to levodopa in that property. The sensitization of striatal dopamine neurons is caused by the prolonged denervation together with reduced presynaptic buffer capacities (reduced storage capacity). Thus, exogenous levodopa is metabolized to dopamine but cannot be adequately stored so that it floods the hypersensitive postsynaptic receptors and induces dyskinesia (Nutt et al., 1992). From the practical point of view, these data encourage the use of dopamine agonists instead of levodopa in the early treatment of PD patients. The manipulation of other neurotransmitter systems, once sensitization has been established, gives far from positive results, thus making the early use of dopamine agonists and the subsequent association of low levodopa dose an imperative therapeutic choice. In advanced PD patients, the partial or total substitution of levodopa with a high dose dopamine agonist, is a strategy now under scrutiny, after the positive results obtained in an open investigation (Facca & Sanchez-Ramos, 1996). Seizures induced by drugs used for the treatment of movement disorders Among agents used for movement disorders, some may exert anticonvulsant effects, others may show proconvulsant effects. Dopamine is the neurotransmitter much deeply involved in the mechanism of action for a large portion of drugs used for treating movement disorders. Recently, other neurotransmitters such as GABA, glutamate and adenosine entered in the field, but few clinical data have been collected so far. Traditionally, dopamine has been regarded as being anticonvulsant, though there might be an opposite side to dopamine’s action. The discovery of multiple dopamine receptor families (D1 and D2), mediating opposing influences on neuronal excitability, heralded a new era of dopamine–epilepsy research. The traditional anticonvulsant action of dopamine was attributed to D2 receptor stimula-

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tion in the forebrain, while the advent of selective D1 agonists with proconvulsant properties revealed for the first time that dopamine could also lower the seizure threshold from the midbrain (Starr, 1996). A reduction in dopaminergic tone is usually proconvulsant. Thus, D2 receptorblocking agents have been shown to attenuate anticonvulsant action of dopamine agonists, to potentiate the range and severity of most seizure-promoting stimuli, and to be epileptogenic in their own right. Dopaminergic drugs Levodopa

The precursor of dopamine is still considered by many authorities the gold standard of PD therapy; however, about 20 years ago direct-acting dopamine agonists were introduced in clinical practice, and their role in therapeutics of PD is largely measured. Levodopa has a variable effect on epileptic symptomatology. It has been claimed to be anticonvulsant in cases of post anoxic myoclonus (Lhermitte et al., 1972) and to curtail intention myoclonus (Cools et al., 1975). Epilepsy characterized by eyelid myoclonus, evolving into complex partial seizures or generalized convulsions, was also reported to be briefly suppressed by a combination of levodopa/carbidopa (Morimoto et al., 1985). However, some forms of epilepsy may be exacerbated by levodopa. Two cases of levodopa-induced seizures have been reported. Menassa et al. (1991) reported a case of myoclonic epilepsy induced by levodopa treatment and Yoshida et al. (1993) described a 68-year-old woman with parkinsonism who showed cortical myoclonus enhanced by levodopa, developing into generalized seizures. Dopamine agonists

The anticonvulsant effects of the prototypical mixed dopamine D1/D2 receptor stimulant apomorphine is similar to that of levodopa. In fact, apomorphine is particularly effective in suppressing action myoclonus (Van Woert & Sethy, 1975) and reflex seizures caused by sensitivity to light (Anlezark et al., 1981) but some simple and complex partial seizures, as well as some generalized non-reflex seizures, are either unresponsive to apomorphine or are exacerbated by it (Del Zompo et al., 1983; Marrosu et al., 1983). The effects of apomorphine on epileptic activity are indicative of what happens when both types of dopamine receptors are stimulated simultaneously. The prominent D2-stimulant action of the other dopamine agonists, such as bromocriptine, lisuride, pergolide, manifests itself as a seizure protection. Bromocriptine combined with selegiline in patients suffering from Lafora’s disease

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induced a marked reduction in the frequency of generalized convulsive seizures and myoclonic jerks (Mauro et al., 1986). In animal studies, lisuride markedly suppressed seizures produced with cobalt (Fargio & McQueen, 1979), pilocarpine (Al-Tajir & Starr, 1991) and kindling (Löscher & Czuczwar, 1986). Moreover, Obeso et al. (1983) found that lisuride diminished spontaneous and stimulusevoked jerking in six patients with cortical reflex myoclonus. Pergolide produces seizure protection only in the pilocarpine models (pilocarpine (Al-Tajir & Starr, 1991)). Unlike lisuride, pergolide also stimulates D1 receptors (Walters et al., 1983), which may well counterbalance the beneficial effects of D2 stimulation in seizure tests. However, in a clinical study, Gatterau et al. (1990) found that pergolide gives complete relief from temporal lobe epilepsy. Antidopaminergic drugs Classical neuroleptics

Clinical experience not only indicates in psychiatric patients, with no previous history of seizures, tranquilized with reserpine, the emergence of epileptic symptoms (Snead, 1983), but also the worsening of a preexisting epileptic condition (Laird et al., 1984). Most early information about the effects of dopamine receptor blockade on seizure expression has come from studies with the phenothiazine chlorpromazine and with the butyrophenone haloperidol. Chlorpromazine may actually provoke seizures in epileptic patients and in patients with organic brain damage (Arushanjan, 1976). The convulsions are often of grand mal type and are seen both with clinical dose levels and overdose (Kalinowsky & Hippius, 1969). Butyrophenones were also found to be proconvulsant (Lipka & Lathers, 1987). EEG measurements revealed that haloperidol stimulated spontaneous epileptic discharges in patients with no previous history of the condition (Logothetis, 1967). The same drug potentiated epileptic responses induced by intermittent flickering light in receptive psychiatric patients (Borenstein et al., 1982), and there are many other examples of neurolepticenhanced epilepsy (Anlezark et al., 1981). This proconvulsant effect is not restricted to the so-called typical neuroleptics, but occurs with atypical neuroleptics as well. Atypical neuroleptics

Clozapine, used in the management of dopaminergic psychosis and tremor in Parkinson’s disease (Golbe & Sage, 1995; Bonuccelli et al., 1997), of tardive dyskinesias (Gupta et al., 1999), and Huntington’s disease (Bonuccelli et al., 1995) lowers the seizure threshold dose-dependently (Jann et al., 1993). Its relatively weak dopamine receptor blocking ability, combined with selectivity for mesolim-

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bic dopamine receptors and reduced affinity for striatal dopamine receptors, accounts for its minimal extrapyramidal effects and may explain its epileptogenic potential (Baldessarini & Frankenburg, 1991). Clozapine may induce seizures in patients without risk factors for epilepsy (Haller & Binder, 1990, Devinsky et al., 1991). Devinsky et al. (1991) reporting on 1418 US patients exposed to clozapine before marketing, found a seizure frequency of 2.8% and predicted a cumulative 10% risk of seizures after 10 years of therapy. The risk seemed dose dependent, with the highest rate of seizures occurring in patients taking over 599 mg/day. Wilson and Claussen (1994) found seizures in 10% of 100 schizophrenic patients taking clozapine. In contrast with the previous study, the median clozapine dose at the time of seizure was only 237 mg/day. Bak et al. (1997) reported a series of cases of myoclonus associated with clozapine medication. In conclusion, seizures are a serious adverse effect of clozapine treatment, which tend to occur more frequently during initiation and titration of the drug and at doses greater than 599 mg/d. Patients with a prior history of epilepsy are more likely to have seizures at low doses of clozapine and should have their doses increased more slowly, under careful observation. Recently, two reports indicated that another atypical neuroleptic, olanzapine, may induce seizures. In the first report, Wydersky et al. (1999) described a case of fatal status epilepticus associated with the use of olanzapine; in the second, Lee et al. (1999) reported the case of a 31-year-old woman with multiple psychiatric and medical disorder, including generalized seizure disorder, who experienced seizure activity when switched from haloperidol to olanzapine. Other drugs used for treating movement disorders

Among the other antiparkinsonian drugs, selegiline, an irreversible inhibitor of MAO type B., exerts anticonvulsant efficacy in kindling model of epilepsy (Löescher & Hönack, 1995). Amantadine, a glutamate antagonist, that has been used in the treatment of Parkinson’s disease from 1969 (Schwab et al., 1969), has showed some benefit in refractory convulsive, myoclonic, absence and akinetic seizures in children (Shields et al., 1985) and in refractory generalized epilepsy in adults (Drake et al., 1991). Memantine, another recently developed NMDA-antagonist, also appears to exert anticonvulsant properties in the guinea pig hippocampal slice preparation (Apland & Cann, 1995). Among anticholinergic agents currently used in the management of parkinsonism and other movement disorders, biperiden, trihexyphenidyl and benztropine, show antimuscarinic and mild antinicotinic properties. They exert anticonvulsant effects in seizures induced by the organophosphorus compounds (Liu, 1996) and prevent nicotine-induced seizures (Gao et al., 1998).

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Steroid responsive motor disorders associated with epilepsy Brian G.R. Neville Neurosciences Unit, University College of London Medical School, The Wolfson Centre, London, UK

Introduction Although epilepsy syndromes have been primarily defined by their seizures, the pervasive additional impairments, particularly cognitive and behavioural, are increasingly recognized as being integral to the condition, e.g. cognitive and autistic regression in West syndrome. Landau–Kleffner syndrome (LKS) could hardly be described without the cognitive impairments. Motor impairments have been largely ignored from descriptions of epilepsy syndromes. Such motor phenomena are, however, common. This chapter summarizes the data on five patients with epilepsy-related movement problems that were present over long periods and were quite unrelated to individual seizures. Such impairments, which are present over time, are designated epileptic encephalopathies. They were all responsive to cortico-steroids which were used by analogy with their use in other epileptic encephalopathies, particularly West syndrome and Landau–Kleffner syndrome. The intention in treating these disorders with cortico-steroids is that such drugs are highly effective antiepileptic agents, rather than that they have any other modes of action, but this statement is open to challenge. The potential reversibility of such neurological impairments, which we would usually regard as evidence of fixed brain lesions in association with epilepsy, is of great theoretical interest, since it points to different pathophysiological mechanisms for the production of classical neurological signs (Neville, 1999). C A S E R E P O R T 1 L A N DA U – K L E F F N E R SY N D R O M E W I T H G A I T A P R A X I A ( N E V I L L E & B OY D , 19 9 5 ) The first child developed complex partial seizures at the age of 5.6 years with rolandic characteristics and, over a period of 8 weeks, she lost all speech and comprehension. Right limb

Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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B.G.R. Neville motor seizures also occurred with prolonged disuse of the right arm and she had a sustained dystonic posture of the right arm for 3 days (above the head with flexed elbow and hand open). Sometimes, the right leg would give way when put to the ground. However, the most obvious motor impairment was the development of a grossly apraxtic gait which was slow, broad based, high stepping and which only allowed simple walking. There were also some problems with chewing. Non-verbal skills were preserved. The response to 6 weeks of 2 mg/kg/day of prednisolone was dramatic with full restoration of motor skills and most language functions. EEG abnormalities were mainly L fronto-temporal with normal MR imaging. C A S E R E P O R T 2 D E V E LO P M E N TA L MYO C LO N I C AC T I O N DYSTO N I A ( N E V I L L E & B OY D , 19 9 5 ) This girl had a primary inability to walk. Her parents’ first attempt to get her to stand or walk were accompanied by showers of myoclonic jerks of the left leg and sometimes of the right leg. During attempted walking, dystonic postures of the legs appeared (extension of the right leg and great toe and inversion of the left foot and knee flexion), as well as myoclonic jerks. A diagnosis of paroxysmal kinesigenic choreoathetosis was suggested but there was no family history. The manifestations were very early and there was no response to carbamazepine. The EEG showed vertex spikes and slow waves, which were increased by tactile stimulation of the fingers and feet. She was given prednisolone at 23 months for asthma and first walked a week after the course had started. Immediately after this her gait was stifflegged and broad based with a slapping quality, back kneeing and sudden collapses occurred. A further course of prednisolone resulted in a near normal gait. Although her cognitive development appeared to be normal at this early stage, it was later clear that she had moderate global learning difficulties but not the profile of Landau–Kleffner syndrome. A further course of corticosteriods was given for a deterioration in gait and was totally effective in restoring a normal gait. MR imaging was normal. C A S E R E P O R T 3 E X E R C I S E - I N D U C E D ST E R O I D D E P E N D E N T DYSTO N I A , ATA X I A A N D A LT E R N AT I N G H E M I P L EG I A A SSO C I AT E D W I T H E P I L E P SY ( N E V I L L E E T A L . , 19 9 8 ) This young lady was followed to the age of 20 years. There was no relevant family history. She had primary cognitive impairment with verbal IQ 71, performance 54 and full-scale 62. She walked unsteadily at 1.8 years, having walked around the furniture at 0.8 years and lost this skill temporarily with the onset of seizures. Her gait remained ataxic, the upper limbs showed a cerebellar type intention tremor and she had slurred and scanning speech. Outdoor walking was accompanied by collapses. Tone in the limbs was normal with brisk deep tendon reflexes and flexor plantar responses. From the age of 5 years she developed dystonia after walking for 10–20 minutes. She would feel insecure, her right foot would turn in and the leg stiffen followed by the right leg and she would fall and could not walk again for about 10–20 minutes and when starting to walk again within 30 minutes the dystonia

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Steroid responsive motor disorders would rapidly recur. 1.5 mg/kg prednisolone for 10 days with 25 days weaning allowed her to walk without dystonia or falls. A second course was associated with rapid (2 days) resolution of ataxia, speech impairment and dystonic falls and seizures. All signs returned on withdrawal of prednisolone. She had about ten episodes from the age of 9 years of dense flaccid hemiparesis mainly but not always right-sided lasting about 1 hour associated with confused speech. She had minor right parietal white matter abnormality on MR. She developed epilepsy from 8 months with focal and generalized seizures and frequent atypical absences. The EEG showed multifocal abnormalities with some right parietal emphasis. A large number of metabolic investigations including for mitochondrial disease were negative. C A S E R E P O R T 4 G E N E R A L I Z E D DYSTO N I A A N D A P R A X I A A SSO C I AT E D W I T H M I N O R E P I L E P SY This girl was normal until the age of 2.3 years when she developed dystonia of the left leg, which spread to involve the right leg over a period of 6 months. Her arms became shaky with obvious dystonic posturing and although her left arm appeared to be the worst she changed from a right to a left-hand preference. She was at her worse at the age of 5.6 years, when walking was only just possible because of severe dystonia. Intellectual and bulbar functions were preserved. During the course of this illness she had four clinical seizures, which consisted of generalized jerks of the arms and legs with eye rolling in which she was unresponsive; she sweated in the attacks and cried on recovery. Some brief absences were also noted. EEGs and MR imaging were normal. L

Dopa had no effect. Prednisolone was given in a dose of 2 mg/kg and a dramatic

improvement was noticed from the second day in both walking and arm function and after 1 week there was only minor turning of the left leg and residual incoordination of the hands. As the dystonia receded, a major problem with motor organization became apparent with marked difficulty with gesture imitation (apraxia). Unfortunately, she relapsed on corticosteriod withdrawal and, although a second course produced improvement, she could not be maintained on low or intermittent therapy but some apparent improvement was sustained on lamotrigine and sodium valproate. I showed her to David Marsden who agreed that she had the clinical picture of typical torsion dystonia. C A S E R E P O R T 5 STA R T L E AT TAC K S W I T H ATA X I A A N D DYS P R A X I A This young lady walked at 18 months having shuffled on her bottom. Her coordination was never very good and when first seen aged 8 years she had slurred and scanning speech, broken eye following, normal tone and power, dysdiadochokinesis and a jerky intention tremor. She had marked difficulty with gesture imitation (hand praxis). Her main problem from about 6 years was startle episodes particularly to touch, e.g. catching her toe, or unexpected sounds when her legs would collapse, she would fall, remain conscious but be very upset. EEG showed a very marked abnormality with frequent multifocal discharges but without a clear response to tactile stimulation. Apart from the falls, no seizures were

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B.G.R. Neville reported. MR imaging was normal. Cognitive functions were in the low average range. A large number of different antiepilepsy drugs were used with some inconsistent reports of improvements in startles and coordination. A course of 100 mg of prednisolone daily for 1 week followed by 200 mg weekly was being given. This was associated with a marked reduction in startle attacks, much clearer speech, faster walking and better coordination, but she still had a mild intention tremor. It was agreed that, although there was a clear response, corticosteriods could not be used long term because of side effects.

In summary, these five children and young adults had the following features. Epilepsy in five but varying from trivial/subclinical to moderate severity without there being any limiting specific characteristics: five showed apraxia four had dystonia with it being purely on action in two two had cerebellar ataxia one had aphasia three had moderate learning difficulties three suffered collapses all five were female. All showed a clear response to corticosteriods, which was not necessarily a useful long-term therapeutic option, but in two the clinical response was much more extended than the course of treatment. These patients pose both simple and complex questions. Is this a rare phenomenon? Although they have been regarded as rare if not unique cases, it could be that we have tended to overlook the motor components of epilepsy syndromes. For example, the frequently unsteady and simple gait of people with Lennox–Gastaut syndrome is rarely mentioned in textbook descriptions. Our group’s experience of Landau–Kleffner syndrome supports the contention that such phenomena are not so rare. In data from a paper in preparation on 30 children with centro-temporal spikes and language regression, 13 showed moderate motor dysfunction, 6 showed severe dysfunction and 3 maximal motor regression. Motor and cognitive regression tended to occur at the same time. The motor components were amongst the most responsive to corticosteroids. What might the pathophysiology be? Epileptic encephalopathies are quite common. For example, in so-called ‘benign’ rolandic epilepsy children commonly have a continuing and symptomatic language

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processing disorder (Staden et al., 1998). Thus the potential for epilepsy syndromes to be associated with dysfunction of cerebral cortical systems should be clear from both benign and malignant epilepsy syndromes. Although in LKS we have used subclinical status epilepticus as our likely final common pathway for this disorder and evidence of hypometabolism and hypoperfusion as markers for the site of cortical dysfunction, these have not been studied rigorously. In my experience, socalled Todd’s paresis and changes in laterality are quite common in L.K.S., suggesting that it has a particular propensity for dysfunctioning cortical systems. We may be wrong in expecting to find a discrete area of cortex like, for example, the supplementary motor area as the ‘site’ of these motor phenomena. Epilepsy tends to engage motor, sensory and cognitive aspects of function as is again well illustrated in the seizures seen in benign rolandic epilepsy, i.e. bulbar sensory and motor phenomena and cognitive arrest. There are hints in these patients that when they try to engage a cortical system to speak or walk, this tends to provoke dysfunction or actual seizures, which would be an unkind trick for the developing brain to be playing! There seems no doubt that these types of epilepsy are a particular risk of the immature brain. The notion that epileptic encephalopathies are in some way related to the normal developmental processes of dendritic reorganization has not been explored. At this stage, it may be more important to frame the question than to expect there to be a ready answer. What is the significance for traditional localization-based neurology? It might not seem so surprising that apraxia could be induced by a cerebral cortical based functional disorder, but for cerebellar ataxia and particularly dystonia to be ‘caused by’ cortical discharges if that is what is happening is a greater problem for traditional neurology. This was the issue that I discussed with David Marsden at our combined motor clinic without a solution being apparent. The simplest explanation is that the balance of input to motor pathways by cortical and subcortical systems is disturbed and produces a picture identical to that of a cerebellar or basal ganglia lesion. Although we often refer to motor phenomena in seizures as being dystonic when it is usually a single tonic posture that is sustained, the phenomena in some of these patients are those of true torsion dystonia. We should now be very wary of assuming that neurological signs in children with normal high-quality modern scanning in the presence of epilepsy are evidence of untreatable brain damage that happens to be beyond the resolution of our scanners. The ‘functional’ impairments associated with epilepsy may be much commoner than we have suspected. We may do our patients a considerable service by reframing epilepsy as a group of disorders with chronic impairments, including motor, rather than as primarily a paroxysomal disorder.

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R E F E R E N C ES

Neville, B.G.R. (1999). Reversible disability associated with epilepsy. Brain and Development, 21, 83–5. Neville, B.G.R. & Boyd, S.G. (1995). Selective epileptic gait disorder. Journal of Neurology, Neurosurgery and Psychiatry, 58, 371–3. Neville, B.G.R., Besag, F.M.C. & Marsden, C.D. (1998). Exercise-induced steroid-dependent dystonia, ataxia and alternating hemiplegia associated with epilepsy. Journal of Neurology, Neurosurgery and Psychiatry, 65(2), 241–4. Staden, U., Isaacs, E., Boyd, S.G., Brandl, U. & Neville, B.G.R. (1998). Language dysfunction in children with Rolandic epilepsy. Neuropaediatrics, 29, 1–7.

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Drugs for epilepsy and movement disorders Lucio Parmeggiani1, Renzo Guerrini2 and Brian Meldrum3 1

Institute of Child Neurology and Psychiatry, University of Pisa, Italy Neurosciences Unit, Institute of Child Health, The Wolfson Centre, London, UK 3 Institute of Psychiatry, King’s College Hospital, London, UK 2

Introduction This chapter is intended as an overview of the different antiepileptic drugs (AED) that can also be used to treat movement disorders and of the rationale for their use. There are two main sections: the first reports in alphabetic order AEDs with a wellestablished use in both fields (epilepsy and movement disorders); the second contains other AEDs that have a less defined use profile in movement disorder treatment, because of their recent introduction or their narrow spectrum of action. The aim is, whenever possible, to highlight the mechanisms of action that can be shared by the drugs in the treatment of both epilepsy and movement disorders. Acetazolamide Acetazolamide (AZM) is a sulfonamide that inhibits carbonic anhydrase, an enzyme responsible for conversion of carbon dioxide and water to bicarbonate (Roblin & Clapp, 1950). Its use in epilepsy has a long history but remains limited (Bergstron et al., 1952; Ramsey & De Toledo, 1997). On the contrary, AZM is highly effective in treating episodic ataxias as serendipitously discovered in a patient misdiagnosed with periodic paralysis (Griggs et al., 1978). Epilepsy

Although several reports have claimed the efficacy of AZM as an AED, most of these studies were performed before the adoption of the International Classification of the Epilepsies (Commission, 1989) and it is therefore difficult to determine clearly what types of epilepsies respond to the drug. In partial epilepsies, different open studies indicate more than 50% seizure Renzo Guerrini, Jean Aicardi, Frederick Andermann and Mark Hallett, editors. Epilepsy and Movement Disorders. © 2002 Cambridge University Press. All rights reserved.

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reduction in 25% to 52% of patients, with a minority of them being seizure free. However, no controlled trials were performed (Lombroso & Forsythe, 1960; Chao & Plumb, 1961; Forsythe et al., 1981; Oles et al., 1989). These studies included both children and adults who received AZM as adjunctive or sole therapeutic agent for periods ranging from a few months to 3 years. Idiopathic generalized epilepsies such as juvenile myoclonic epilepsy (JME), childhood absence epilepsy and epilepsy with generalized tonic–clonic seizures, seem to respond better to AZM with a rate of seizure control ranging from 45% to 83%. In JME, AZM does not prove superior to valproic acid (VPA) but can be used as adjunctive therapy, particularly in patients with severe VPA-induced side effects (Ramsey & De Toledo, 1997). AZM seems to be effective in treating catamenial seizures. An intermittent treatment for 5–7 days around the menstrual period was reported to be highly effective in a limited number of patients, but there is no consistent evidence of benefit following this regimen (Poser, 1974; Ramsey & De Toledo, 1997). Movement disorders

Different forms of periodic ataxias respond to AZM treatment. The drug is particularly effective in familial episodic ataxia type 2 (EA2), an autosomal dominant disorder due to mutation of the calcium channel CACLNA4 gene on chromosome 19p and characterized by interictal down-beating nystagmus and episodes of paroxysmal ataxia (Ackerman & Clapham, 1997). A dose ranging from 250 to 500 mg/day usually resolves the episodes (Bouchard et al., 1984; Calandriello et al., 1997). AZM is also effective in some patients with episodic ataxia type 1 (EA1) (Brunt & Van Weerden, 1990), an autosomal dominant disorder due to a mutation in the gene coding for the potassium channel Kv1.1 on chromosome 12p (Griggs & Nutt, 1995). EA1 is characterized by brief (seconds to minutes) episodes of paroxysmal ataxia, triggered by startle and exercise and may be associated with epilepsy in some cases (Zuberi et al., 1999). Patients present with interictal myokymia, i.e. twitching of small muscles about the eyes and in the hands. Several other disorders due to mutations in ion channels respond to AZM, including hyperkalemic periodic paralysis (HYPP), paramyotonia congenita (PMC), hypokalemic periodic paralysis (HOKPP) and atypical myotonia congenita (aMC). In particular HYPP, PMC and aMC are allelic disorders, due to a mutation of a sodium channel gene on chromosome 17q, while HOKPP is due to a mutated calcium channel gene on chromosome 1q (OMIM, 2000). Mechanisms of action

AZM is a carbonic anhydrase inhibitor with anticonvulsant effect in different animal models of epilepsy (Ramsay & De Toledo, 1997). The mechanism producing its antiepileptic activity is not fully elucidated.

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AZM acts on carbonic anhydrase that is exclusively located in neuroglia citosol. The enzyme regulates intracellular Cl content through a cellular pump, exchanging extracellular Cl for intracellular HCO3 . The drug can decrease HCO3 and increase pH, enhancing intraneuronal CO2 concentration. The described metabolic changes reduce in turn pH and K in the interstitial fluid (Rho & Sankar, 1999). Neuronal excitability can finally be decreased because of extracellular reduction of K (Schwartzkroin, 1994) or increase of H, that can either block NMDA receptors or enhance GABAA activity (Traynelis & Cull-Candy, 1990; Krishek et al., 1996). The reason why AZM is effective in paroxysmal movement disorders remains speculative. In EA2, the only evidence is the presence of an elevated pH level in the cerebellum that can be corrected by AZM treatment, as demonstrated by magnetic resonance spectroscopy (Bain et al., 1992). Some metabolic effect produced by AZM, such as respiratory alkalosis or metabolic acidosis, can be partially responsible for its efficacy in periodic paralysis (Griggs & Nutt, 1995). Benzodiazepines Benzodiazepines (BDZs) are a class of compounds with a broad spectrum of activity: sedative-hypnotic, anxiolytic, muscle relaxant and antiepileptic (Macdonald, 1995). The majority of BDZs in clinical use are 1,4-benzodiazepines and only clobazam (CLB) is a 1,5-BDZ (Rho & Sankar, 1999). The rapidity of action and the efficacy on different seizure types make BDZs first line drugs for treatment of status epilepticus. We will review only BDZs that have been used to treat both epileptic seizures and movement disorders. Epilepsy

Some BDZs are primarily used to treat status epilepticus (diazepam and lorazepam) while others are mostly used in chronic treatment (clonazeapm, clobazam). Diazepam (DZP)

This drug is effective against either generalized or partial status epilepticus with a control rate ranging from 60% to 88% (Schmidt, 1995). DZP is administered intravenously or intrarectally. Seizures usually stop by 10 minutes from administration. Response failure can occur in presence of a progressive disease such as acute infectious encephalopathies, severe cerebral anoxia or infarction (Delgado-Escueta & Enrile-Bacsal, 1983). Clonazepam (CZP)

CZP can be used as an adjunct in different epilepsies. It is effective in children with intractable absence seizures in association with VPA (Mireles & Leppik, 1985).

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Combined therapy with VPA or ethosuximide can be useful in children with epilepsy with continuous spike-and-wave activity during slow sleep (Yasuhara et al., 1991). In JME, CZP can prevent myoclonic jerks, but it is less effective on generalized tonic–clonic seizures. Some patients who no longer have warning myoclonic jerks, but continue to experience generalized tonic–clonic seizures may experience severe injuries (Resor & Resor, 1990). Patients suffering from progressive myoclonus and epilepsy can find benefit from a combined treatment with CZP and VPA (Iivanainen & Himberg, 1982). In therapy-resistant generalized epilepsies such as Lennox–Gastaut syndrome, West’s syndrome and other undefined generalized symptomatic epilepsies, the efficacy of CZP remains controversial. Some reports show immediate beneficial effects, but long-term treatment does not produce satisfactory results (Sato & Malow, 1995). The efficacy of CZP on partial seizures is less established. A combined therapy with CZP and carbamazepine (CBZ) or VPA is claimed to control seizures that were resistant to monotherapy (Sato & Malow, 1995). However, a single double blind trial showed a similar efficacy of CZP and CBZ in partial epilepsies (Mikkelsen et al., 1981). Neonatal convulsions can be controlled by i.v. CZP (Andre et al., 1991). A single dose of CZP can be used to treat different forms of status epilepticus, ranging from generalized tonic–clonic to absence status (Sato and Malow, 1995). Clobazam (CLB)

This is a highly effective AED as demonstrated by several add-on, either placebo controlled or open studies (for review, see Shorvon, 1995). The spectrum of activity is wide, because both partial and generalized epilepsies in adults and children respond to CLB. In particular, patients with Lennox–Gastaut syndrome seem to respond very well to the drug, making it a BDZ of first choice in this form of epilepsy (Péchadre et al., 1981). As pointed out since the very first clinical trial, CLB can rapidly exert a potent antiepileptic effect, but its efficacy fades away in around half of the patients after a month of treatment (Gastaut & Low, 1979). CLB as well as CZP have proven effective in treating reflex epilepsies and, in particular, startle-induced epilepsies that are usually resistant to other AEDs (Aguglia et al., 1984). In this peculiar form of epilepsy, patients usually present with a monolateral or bilateral startle reaction, followed by monolateral or bilateral tonic spasm (Aguglia et al., 1984). It has been hypothesized that the proprioceptive input due to the startle reaction activates an epileptogenic cortical focus producing the motor seizure (Bancaud et al., 1975).

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Lorazepam (LZP)

This is effective in treating partial or generalized status epilepticus in around 80% of patients (Homan & Treiman, 1995). Compared to DZP, LZP presents more favourable kinetics, maintaining an effective plasma concentration for at least 18 hours after a single i.v. dose (Comer & Giesecke, 1982). LZP, used in a few patients to stop postanoxic myoclonic status proved to be effective (Vincent & Vincent, 1986). The chronic use of LZP in epilepsy has scarcely been addressed. Two placebo-controlled, add-on studies have been performed, including patients with both partial and generalized pharmacoresistant epilepsies (Moffett & Scott, 1984; Walker et al., 1984). LZP appeared to be superior to placebo in reducing seizure frequency. However, the number of patients treated was low (32 considering both studies) and the duration of treatment was brief (8 weeks) to completely assess the efficacy of LZP as AED for chronic treatment. Movement disorders

CZP is one of the most active drugs to treat different forms of myoclonus in addition to its effectiveness in epileptic myoclonus. It is the medication of choice in essential myoclonus (Pappert & Goetz, 1995). Posthypoxic myoclonus is usually treated with serotonergic drugs, but CZP in combination with VPA and piracetam can sometimes prove useful (Pappert & Goetz, 1995). CZP may offer symptomatic relief in segmental myoclonus, which is poorly responsive to drug treatment (Jankovic & Pardo, 1986). Various forms of idiopathic dystonic syndromes either focal or generalized may respond to CZP or DZP treatment. Benefit from BDZ treatment is observed in 14–16% of patients. Although duration of effectiveness is not fully documented, it is advisable to try BDZ when other drugs fail, since some patients may dramatically improve (Green, 1995). BDZs have been used to treat essential tremor for a long time, but their efficacy is limited (Koller, 1995). On the other hand, CZP is the drug of choice in kinetic predominant tremor and orthostatic tremor (Heilman, 1984). Chorea can respond to GABAergic agents, such as BDZ, but they are not as effective as antidopaminergic drugs (Feigin et al., 1995). Several reports and some controlled studies have stressed the efficacy of CZP in tic disorders and in particular in Tourette’s syndrome (Kurland & Trinidad, 1995). In comparison to haloperidol, CZP seems to be more effective in patients with a family history of tic disorders (Merikangas et al., 1985). Finally, paroxysmal non-kinesigenic dyskinesia can respond to CZP treatment. In particular, patients with long-lasting attacks and secondary forms seem to show a better response (Demirkiran & Jankovic, 1995).

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Mechanism of action

The principal molecular target of benzodiazepines as AED is the GABAA receptor. A specific benzodiazepine recognition site has been identified in the receptor, activation of which produces an increased frequency in Cl channel opening without changing mean open time or conductance (Twyman et al., 1989). The effect of benzodiazepines and barbiturates on the Cl channel is therefore different (see mechanism of action of phenobarbital (PB) and primidone (PRM)). At high concentration, comparable to those reached to treat status epilepticus, diazepam can block voltage-gated sodium channels and calcium channels (Rho & Sankar, 1999). The effect of BDZ, CZP on GABA receptors in particular, can explain their efficacy in treating myoclonus (Pappert & Goertz, 1995). In cortical reflex myoclonus, CZP can reduce the amplitude of somatosensory-evoked potentials acting on the afferent side of the loop, producing myoclonic jerks. However, its effectiveness on reticular myoclonus also suggests multiple pharmacological actions (Obeso et al., 1989). The mechanisms responsible for the efficacy of benzodiazepines in other movement disorders are less clearly understood. Carbamazepine CBZ is a 5-carbamyol-5H-dibenz[b,f]azepine, that presents a tricyclic structure similar to anti-depressive agents, such as imipramine or chlorimipramine (Faigle & Feldmann, 1995). Since its efficacy in epilepsy was first demonstrated in Europe in the early 1960s (Lorge, 1963; Muller, 1963; Bonduelle et al., 1964), it has become one of the most widely used AEDs. Its use in movement disorders is limited to the treatment of paroxysmal kinesigenic dyskinesia and non-hereditary chorea. Epilepsy

CBZ is a first-line antiepileptic drug of first choice for partial and secondarily generalized tonic–clonic seizures (Wilder & Rangel, 1987; Mattson, 1997). CBZ is used with similar efficacy in treating partial and secondarily generalized seizures in children (Dodson, 1987). Among the different epileptic syndromes, autosomal dominant nocturnal frontal lobe epilepsy [ADNFLE] shows a striking response to CBZ (Scheffer et al., 1995; see Chapter 7 by Tinuper et al. for details). Cryptogenic, symptomatic localization-related epilepsies and idiopathic benign epilepsies of childhood respond well to the drug (Lerman & Kivity-Ephrain, 1974). CBZ is not effective and can eventually worsen absence, myoclonic and atonic seizures in children and adults (Liporace et al., 1994; Guerrini et al., 1998a). In

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particular, monotherapy with CBZ poorly controls patients with JME, who can sometimes experience seizure worsening or even enter status epilepticus, while on the drug (Grünewald et al., 1992). The mechanism producing seizure worsening is not clear, but CBZ treatment institution is associated with an increase in generalized spike-and-wave abnormalities before actual seizure worsening takes place (Snead & Hosey, 1985; Liporace et al., 1994; Talwar et al., 1994). Epileptic negative myoclonus can be worsened by CBZ in children presenting atypical benign rolandic epilepsy (Guerrini et al., 1998a). CBZ has also been reported to exacerbate other epilepsy syndromes associated with frequent spikeand-wave activity, such as Landau–Kleffner syndrome and epilepsy with electrical status epilepticus during sleep (Marescaux et al., 1990). Movement disorders

CBZ can be effective in treating non-hereditary chorea (Roig et al., 1988). The efficacy of the drug in suppressing the movement disorder is, however, inferior to dopamine antagonists (Feigin et al., 1995). CBZ can be successfully used in treating paroxysmal kinesigenic dyskinesia (Wein et al., 1996; Hwang et al., 1998) and tonic spasms of multiple sclerosis (Shibasaki & Kuroiwa, 1974). Low doses (100–200 mg/day) are usually effective. In paroxysmal kinesigenic dyskinesia, CBZ equals phenytoin and proves to be superior to valproate (Hwang et al., 1998). Response to CBZ is also reported in dystonic patients, the majority of whom present with Segawa variant of dystonia. (Geller et al., 1974; Garg, 1982; Green, 1995). Drug efficacy appears, however, inferior to that observed with dopamine. Cerebellar tremor is reported to improve on CBZ in patients with multiple sclerosis or cerebrovascular disease. Reduction of tremor is appreciable by the 15th day after the start of treatment and lasts for at least 12–24 months (Sechi et al., 1989). Finally, patients with Steinert’s disease can find improvement of myotonia on CBZ treatment. The applied doses are similar to those used in epilepsy (Sechi et al., 1983). A variety of movement disorders can be induced by CBZ. These include chorea, dystonia, myoclonus and asterixis and usually appear in patients with neurologic deficit treated with toxic levels of the drug. Reduction of drug intake is normally associated with disappearance of the drug-induced movement disorder (Pellock, 1987). Mechanisms of action

CBZ is effective in treating seizures induced by maximal electroshock in experimental animals, while it is ineffective against clonic seizures following administration of threshold doses of pentylenetetrazol (Theobald & Kunz, 1963). This

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experimental evidence supports the clinical observation that CBZ is effective in treating partial and secondarily generalized, but not absence seizures (Mattson, 1997). Antiepileptic efficacy of CBZ seems to depend on a marked reduction of sustained high-frequency repetitive neuronal firing (SRF) (Mattson, 1997). The site of action is probably the voltage-dependent sodium channel. Once developed, inhibition lasts for several hundred milliseconds, suggesting a shift of Na channels to an inactive state from which recovery is delayed (McLean & Macdonald, 1986a). This mechanism of action partially overlaps that of phenytoin which, in any case, presents a stronger slowing effect on sustained high-frequency repetitive neuronal firing (Macdonald, 1997). Data collected from dentate granule cells from resected hippocampi of patients with pharmacoresistant temporal lobe epilepsy, did not confirm the action of CBZ on SRF, which probably explains the intractable nature of the epilepsy (Reckziegel et al., 1999). Macdonald (1989), published an extensive review of CBZ mechanism of action. Other mechanisms seem to play a role in CBZ antiepileptic action. In particular, its synaptic action on excitatory aminoacid receptors, on GABA and on adenosine or monoamine systems have been investigated without gathering consistent proofs (Mattson, 1997). Recently, CBZ was found to inhibit neuronal nicotinic acetylcoline receptor (nAChR), causing a channel blockade by steric hindrance. This inhibition was increased threefold in nAChR mutation observed in ADNFLE, providing evidence for the spectacular efficacy of the drug in this particular type of epilepsy (Picard et al., 1999). The reason for CBZ efficacy in movement disorders and particularly in paroxysmal kinesigenic choreathetosis is less defined (Wein et al., 1996). Different authors claim that the exquisite sensitivity of paroxysmal kinesigenic choreathetosis to AEDs is an indirect demonstration of its epileptic nature (Fahn, 1994). Patients presenting both epilepsy and paroxysmal kinesigenic choreathetosis or a family history of epilepsy (Hwang et al., 1998), and a single patient with epileptic activity recorded directly from the supplementary motor cortex during an attack (Lombroso, 1995), corroborated the former hypothesis. However, recent papers showed the possible association of paroxysmal dyskinesia and epilepsy and linked the disorder to chromosome 16p (Szepetowski et al., 1997; Guerrini et al., 1999; Bennett et al., 2000). A chanellopathy can be the cause of both of these forms of epilepsy and paroxysmal dyskinesias, possibly explaining the response to CBZ (Guerrini et al., 1999; Bennett et al., 2000). CBZ can increase GABA level or decrease glutamatergic activity, restoring the disrupted interplay between basal ganglia and cerebral cortex and explaining its efficacy in movement disorder treatment (Feigin et al., 1995).

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Phenobarbital and primidone PB was discovered in 1912 and is the oldest anticonvulsant drug in clinical use. It is safe, effective, and inexpensive, but sedative side effects and disturbance in cognitive functions limit its use (Cramer & Mattson, 1995). Moreover, in children PB can paradoxically induce insomnia and hyperkinetic behaviour (Ounsted, 1955; Wolf & Forsythe, 1977). PB and especially primidone (PRM), have been successfully used to treat essential tremor (Koller, 1995) Epilepsy

PB is widely used in the treatment of partial seizures as well as generalized tonic–clonic seizures in all age groups (Mattson et al., 1985; Mitchell & Chavez, 1987; Schmidt et al., 1986). PRM has the same spectrum of efficacy, but presents a higher incidence of side effects and is therefore less tolerated (Mattson et al., 1985). The efficacy of PB and PRM is comparable to CBZ and PHT to treat secondarily generalized seizures, but inferior to CBZ and PHT in treating partial seizures (Mattson et al., 1985). In children, PB can even worsen absence seizures (Wilder & Bruni, 1981). PB in association with VPA and clonazepam has proved superior to PRM and PHT or CBZ in treating patients with Unverricht–Lundborg disease (Iivanainen & Himberg, 1982). In the pre-VPA era, PRM and PB were the first-choice drugs for JME. Both drugs are reported to control generalized tonic–clonic seizures and myoclonus in 67% to 82% of treated patients. PRM treatment was associated with a higher number of seizure-free patients (Resor & Resor, 1990). PB administration has also been used to prevent febrile seizure recurrence (Faero et al., 1972). A particular use of PB is in neonatal seizures and in status epilepticus. PB is the drug most frequently chosen in the treatment of neonatal seizures. Its efficacy is comparable to that of PHT. Both drugs, however, can only control seizures in less than 50% of neonates (Painter et al., 1999). The preference of pediatricians for PB is thus not based on its proven superiority but on a greater familiarity with the drug. PB is effective in convulsive status epilepticus. Intravenous load (100 mg/min) until reaching a dose of 10 mg/kg has been demonstrated to suppress clinical convulsive activity within 10 minutes in 89% of patients. The efficacy of PB is comparable to that of PHT or diazepam, but use of benzodiazepines (diazepam or lorazepam) as a first-line AED to treat status epilepticus is preferred because of faster action (Schaner et al., 1988; Painter & Gaus, 1995).

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Movement disorders

Since the early 1980s, efficacy of PB and particularly of PRM in treating tremor has been established (Baruzzi et al., 1983; O’Brien et al., 1981). Usually doses of PRM between 375 and 750 mg/day are effective and their efficacy is still observed at 12month follow-up (Sasso et al., 1990). PB appears to be less effective at doses comparable to those used for epilepsy (Baruzzi et al., 1983). PRM action is not merely due to its conversion to PB, but probably depends on a direct activity of the drug itself or of an unrecognized metabolite (Sasso et al., 1991; Koller, 1995). PB has been used to treat blepharospasm/oromandibular dystonia in a small number of patients, but has not been noted to produce improvement (Marsden, 1976). PB and PRM are effective in treatment of cortical reflex and action myoclonus. In particular, PRM has been used at doses ranging from 325 to 750 mg/day in association with VPA, clonazepam or piracetam reaching a control of myoclonus lasting for 1 to 6 years (Obeso et al., 1989). Mechanisms of action

Basic mechanisms of selective antiepileptic action of PB are not fully understood. Much evidence points towards modulation of the inhibitory postsynaptic actions of GABA. PB interacts with GABAA-receptor complex, enhancing chloride currents and, at supratherapeutic dose, directly activating the receptor (Prichard & Ransom, 1995). Open time of GABA-activated single channel is increased, but opening frequency and conductance are not affected. This mechanism of action differentiates barbiturates from benzodiazepines that act by increasing opening frequency and conductance of GABA channel (Twyman et al., 1989). In animal models of absence seizures, benzodiazepines and PB are found to act on different thalamic nuclei, giving a probable reason for scarce efficacy of barbiturates in this condition (Hosford et al., 1997). PB inhibition of glutamatergic transmission (via the AMPA receptor) may contribute to explain its antimyoclonic action (Meldrum et al., 1983; Prichard & Ransom, 1995). However, efficacy of PRM and PB in cortical myoclonus can be mediated by an enhanced GABAergic activity (Obeso et al., 1989). Both drugs are effective in producing a clear-cut decrement of action and reflex myoclonus, but they do not affect the afferent pathway via somatosensory cortex, as demonstrated by unchanged amplitude of SEPs (Obeso et al., 1989). Decrease in GABA levels is found in the CSF in animal models of myoclonus and in patients with post-anoxic myoclonus and progressive myoclonus epilepsy (Enna et al., 1979; Airaksinen & Leino, 1982; Patel & Slater, 1987). Other possible sites of PB action are voltage-gated Ca2 channels and at very high

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concentrations, voltage-gated Na channels with a consequent reduction of SRF (Rho & Sankar, 1999). The latter mechanism seems to explain the efficacy of high concentrations of PB on generalized tonic–clonic status epilepticus (Macdonald, 1989). Phenytoin PHT is the most commonly used AED in North America (Wilder, 1995). It was developed in 1938 (Merritt & Putnam, 1938). Possible cosmetic side effects have reduced the use of the drug in children and young women. The use of PHT in movement disorders is limited to the treatment of paroxysmal dyskinesia. Epilepsy

As supported by its action in animal models, PHT is a drug of choice for partial and secondarily generalized seizures. Partial epilepsies respond equally well to CBZ and PHT (Mattson et al., 1985). CBZ, however, presents fewer side effects and is better tolerated (Troupin et al., 1977). In idiopathic generalized epilepsy, PHT can control tonic–clonic seizures (Wilder et al., 1983). In JME, some evidence supports the efficacy of PHT in treating generalized tonic–clonic seizures, but the possible aggravation of absence seizures and the inefficacy on myoclonus make it a second choice drug (Resor & Resor, 1990; Wilder, 1995). Treatment of infantile spasms and Lennox–Gastaut syndrome with PHT is not satisfactory. The drug can actually aggravate progressive myoclonus and epilepsy (PME) and worsen cerebellar symptoms often present in PME patients (Eldridge et al., 1983). PHT is effective in controlling neonatal seizures (Painter et al., 1999). Convulsive status epilepticus can be treated with PHT i.v. infusion (Wilder, 1995). PHT can be responsible for seizure worsening through different mechanisms (see Chapter 29 by Dulac and Bonucelli for details). Movement disorders

PHT has shown some effectiveness in treating paroxysmal kinesigenic choreoathetosis. Usually low doses are effective in adults while children may require doses in the antiepileptic effective range (Homan et al., 1980; Hwang et al., 1998). Other forms of paroxysmal dyskinesia do not respond so well to PHT or other AEDs (Demirkirian & Jankovic, 1995). Chorea or dystonia can occur in epilepsy patients receiving chronic PHT therapy (see Chapter 29 by Dulac and Bonuccelli for details). Usually the movement disorder is present when the plasma level of the drug is high and tends to subside as

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soon as it is reduced. A common cause of acute onset of this side effect is observed after parenterally loading of PHT to treat status epilepticus. Patients with cerebral lesions are more prone to be affected (Dravet et al., 1980; Miyasaki & Lang, 1995). The mechanism responsible for AED-induced hyperkinesias remains unclear, but a block of dopamine receptors is hypothesized for PHT (Sethi et al., 1990). Parkinsonism has been observed in rare cases during PHT treatment (Mendez et al., 1975; Miyasaki & Lang, 1995), while it is known that PHT can decrease the response to levodopa in patients with Parkinson’s disease. Mechanism of action

PHT like CBZ causes a voltage-, frequency- and use-dependent block of Na channels, that produces a reduction of SRF (De Lorenzo, 1995). The drug preferentially binds to the inactive state of the Na channels, limiting SRF. Depolarisation increases the susceptibility to block off the channels, which are therefore more easily inactivated during seizures than at rest. Other possible mechanisms of action include inhibition of neurotransmitter release and re-uptake, in particular glutamate (Potter et al., 1991) and inhibition of calcium-dependent calmodulin kinase (De Lorenzo, 1995). The latter mechanism suggests regulation of protein phosphorylation by PHT, which can therefore alter many different cellular processes (Rho & Sankar, 1999). Valproate Burton (1882) first synthesized this short chain fatty acid in 1882. It was not clinically used until Meunier and coworkers (1963) fortuitously discovered its anticonvulsant activity. The first clinical trials of VPA were reported in 1964 (Carraz et al., 1964). VPA was marketed for the treatment of epilepsy in France in 1967 and in the United States in 1978. VPA is particularly effective in the treatment of myoclonus. Epilepsy

Since its first clinical use, VPA has been rapidly established worldwide as a major AED against several types of seizures. It was soon recognized as a highly effective first-line drug in idiopathic generalized epilepsies: absence, generalized tonic–clonic, and myoclonic seizures (Jeavons et al., 1977). Childhood absence epilepsy responds equally well to VPA and ethosuximide (ESM) with a mean 89% of treated patients being seizure free (Callaghan et al., 1982; Sato et al., 1982; Bourgeois, 1995). A high percentage of patients with generalized tonic–clonic seizures treated with VPA is seizure-free (Bourgeois, 1995). VPA is the drug of choice for treating JME and benign myoclonic epilepsy of infancy (Resor & Resor, 1990;

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Timmings & Richens, 1992; Bourgeois, 1995). In progressive myoclonus epilepsy, VPA in association with clonazepam and PB can be effective (Iivanainen & Himberg, 1982). Some clinical trials found similar efficacy between CBZ and VPA in treating partial or secondarily generalized seizures in an adult population (Richens et al., 1994; Heller et al., 1995). These trials involved a population with a broad spectrum of epileptic disorders. In more selective studies, CBZ proved to be superior to VPA in controlling partial and secondarily generalized seizures (Mattson et al., 1992). VPA remains, however, a useful alternative if CBZ fails (Bourgeois, 1995). VPA can be used in prophylactic treatment of febrile seizures (Bourgeois, 1995). Movement disorders

VPA is useful in the treatment of myoclonus. Its effects are likely to be mediated by action at multiple sites within the central nervous system. Successful management of severe cortical myoclonus may require a combined therapy with two or three AEDs. For example, VPA has been used in association with clonazepam and PRM in the treatment of action myoclonus (Obeso et al., 1989; Berardelli et al., 1998). In Sydenham chorea, VPA proved to be effective with clinical improvement in 80% of patients during the first week of treatment (Dhanaraj et al., 1985; Daoud et al., 1990). Paroxysmal dyskinesias can be treated with VPA, but the efficacy of the drug is inferior to CBZ and PHT (Hwang et al., 1998). Hemichorea/hemiballism due to cerebrovascular lesions can respond to VPA (Lenton et al., 1981, Chandra et al., 1982), but the efficacy of the drug is debated (Lang, 1985; Sethi & Patel, 1990). A common side effect of VPA is postural tremor. It is found in 20–25% of patients receiving the drug and can start shortly after treatment initiation or even 1 year later. There is no correlation between severity of tremor and plasma level of the drug. Patients who find tremor disabling can be treated with propanolol (Miyasaki & Lang, 1995). Some patients treated with VPA either as monotherapy or in association with other AEDs can insidiously develop a syndrome characterized by hearing impairment, parkinsonism and dementia. The side effect is observed in children and adults and is completely reversed by drug withdrawal (Alvarez-Gomez et al., 1993; Sasso et al., 1994; Armon et al., 1996). The biochemical mechanism subtending the adverse reaction remains unclear; it could be due to a VPA-induced increase of GABAergic activity in globus pallidus, as observed in patients with Parkinson’s disease (Maneuf et al., 1994). Another possible explanation is VPA-induced, mitochondrial respiratory chain dysfunction, similar to that observed in Parkinson’s disease (Armon et al., 1996) (see Chapter 29 by Dulac and Bonuccelli).

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Mechanisms of action

VPA reduces SRF in animal models and decreases Na inward currents in voltage clamp experiments (McLean & Macdonald, 1986b; Zona & Avoli, 1990). These data support inhibition of voltage-gated Na-channel, as further demonstrated by reduction of peak conductance and delay of recovery from inactivation, observed in cultured rat hippocampal neurons. However, it is unknown if this mechanism plays any role in clinical therapy, because it is only active at supratherapeutic concentration (Van den Berg et al., 1993). Several effects on the GABAergic system have been ascribed to VPA, but the experimental evidence is not totally convincing. In particular VPA inhibits the enzyme GABA-transaminase and activates the biosynthetic enzyme glutamic acid decarboxylase, but these effects are observed at supratherapeutic concentrations (Rho & Sankar, 1999). The effect of VPA on the GABAergic system may explain its efficacy in treating cortical myoclonus (Obeso et al., 1989). Experimental studies have shown that VPA can increase GABA levels in striatum and substantia nigra, enhancing GABAergic synaptic transmission (Löscher & Schmidt, 1980; Löscher, 1981). The action of VPA on basal ganglia could explain its efficacy in the treatment of chorea and hemiballism and can be completely independent from that produced on the cortex to control epilepsy. Other possible mechanisms imply inhibition of NMDA-evoked depolarization and blockade of T-type Ca2 channels (Kelly et al., 1990; Gean et al., 1994). Other drugs Ethosuximide (ESM)

This is a substituted succinimide whose antiepileptic properties have been known since 1958 (Zimmerman & Burgmeister, 1958). Several open and double-blind control studies proved the efficacy of ESM in treating absence seizures and its weak or absent effect on generalized tonic–clonic seizures and partial seizures (Sherwin, 1995). Recently, a series of papers pointed out the efficacy of ESM in treating epileptic negative myoclonus (Oguni et al., 1998; Capovilla et al., 1999). ESM is not used to treat other movement disorders. Actually, a pilot study on Parkinson’s disease patients showed that it is ineffective in reducing resting tremor (Pourcher et al., 1992). ESM is effective in the threshold pentylenetetrazol model, corresponding with its antiabsence effect. It seems to exert its antiepileptic effect antagonizing lowthreshold T-type Ca2 channels in the thalamus (Coulter et al., 1989) and possibly exerting inhibition on GABAB thalamic receptors (Rho & Sankar, 1999). Absence seizures are probably produced by a phase-locked oscillation between excitatory

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and inhibitory neuronal networks located in the cortex and the thalamic nuclei (Snead, 1995). A similar mechanism can be involved in generation of epileptic negative myoclonus (see Chapter 12 by Guerrini et al., for details) and has been invoked to explain response to ESM with a clear reduction of resting tremor in the MPTP monkey model (Gomez-Mancilla et al., 1992). Gabapentin (GBP)

Originally synthesized as a GABA analogue, its mechanism of action remains speculative because it has not been proven to interact with either GABAA or GABAB receptors (Rho & Sankar, 1999). GBP is effective in treating partial epilepsies in both children and adults (Chadwick, 1995; Korn-Merker et al., 2000). Generalized epilepsies characterized by absence or myoclonic seizures do not seem to respond to GBP (Chadwick et al., 1996). Rare reports highlight the possible emergence of movement disorders such as dystonia, ataxia, chorea or myoclonus in patients receiving therapeutic dose of GBP to treat epilepsy (Chundnow et al., 1996; Reeves et al., 1996; Steinhoff et al., 1997). GBP is widely used to treat pain syndromes, psychiatric disorders and movement disorders such as restless leg syndrome, essential tremor and tardive dyskinesia (Magnus, 1999). In restless leg syndrome, different authors report a consistent reduction of symptoms in the majority of patients treated with doses of GBP ranging from 300 to 2400 mg/day (Mellick & Mellick, 1996; Alder, 1997). A recent randomized placebo-controlled comparative trial using GBP and propanolol in patients with essential tremor showed that both drugs are comparably effective (Gironell et al., 1999). Finally GBP has been used successfully to treat antipsychotic-induced tardive dyskinesia in psychiatric patients and to improve rigidity and bradykinesia in Parkinson’s disease (Olson et al., 1997; Hardoy et al., 1999). GBP does not affect GABA reuptake or synthesis but can produce an increased GABA turnover in specific brain areas, which is possibly responsible for its antiepileptic activity (Löscher et al., 1991). GABAergic activation is supposed to play a key role in movement disorder control. In particular, an alteration in GABA circuitry is hypothesized to explain essential tremor (Gironell et al., 1999) and GABA mimetic drugs have been used successfully to treat tardive dyskinesia (Tamminga et al., 1979). Finally, GBP can modulate glutamic acid release by interacting with the alpha2/delta subunit of a voltage-sensitive calcium channel, as recently observed in animal models (Dooley et al., 2000). The resulting attenuation of glutamate release can selectively reduce the hyperexcitability of neocortex and hippocampus where high-density calcium channel alpha2/delta subunits have been detected and where an excessive glutamatergic neurotrasmission has been hypothesized in generation of epileptic seizures (Dooley et al., 2000).

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Lamotrigine (LTG)

This was originally developed as an inhibitor of the enzyme dihydrofolate reductase, following some experimental evidence showing that folic acid can produce epileptogenic foci and the hypothesis suggesting that antifolate agents can be used as anticonvulsants (Hommes & Obbens, 1972). The efficacy of LTG as an AED, however, proved to be completely independent from its weak antifolate activity (Leach et al., 1995). LTG inhibits excessive release of excitatory amino acids blocking the voltage dependent sodium channels (Rho & Sankar, 1999). The mechanism of action is similar to CBZ and PHT, but the spectrum of activity is broader for LTG that demonstrates a higher selectivity for sodium channels (Lang et al., 1993). Moreover, efficacy of LTG in modulation of voltage-gated calcium currents has also been demonstrated (Grunze et al., 1998). Different clinical trials have showed that LTG is effective against partial as well as generalized epilepsies in adults (Leach et al., 1995). In children, some evidences pointed to the use of the drug in resistant absence and other generalized seizure types associated with idiopathic generalized epilepsies (Farrell et al., 1997) and seizures associated with the Lennox–Gastaut syndrome (Motte et al., 1997). However, efficacy of LTG in pharmacoresistant childhood partial epilepsies has gradually been established (Duchowny et al., 1999; Parmeggiani et al., 2000). LTG has not been found beneficial in severe myoclonic epilepsy, whose multiple seizure types may be aggravated by the drug (Guerrini et al., 1998b). A recent report on a single patient indicates that low doses of LTG may improve paroxysmal kinesigenic dyskinesia (Pereira et al., 2000). There is no additional evidence, that LTG can be effective in treating movement disorder. Actually, some reports showed the possible appearance of tourettism (Lombroso, 1999) or blepharospasm (Verma et al., 1999) after LTG therapy. A possible mechanism for movement disorders induced by LTG can be based on its inhibition of excitatory amino acids in the basal ganglia, leading to local alteration in dopamine uptake (Lombroso, 1999). Levetiracetam (LEV)

This is a pyrrolidone derivative, recently approved in the European Union and Argentina and marketed in USA and Switzerland since spring 2000. LEV has proven to be effective in animal models of partial as well as generalized seizures (Bialer et al., 1996; Gower et al., 1992). Three double-blind, add-on, placebo controlled trials in 904 adults with pharmacoresistant partial epilepsies showed that LEV (dose 1000–3000 mg/d) reduced seizure frequency by at least 50% in 27.7% to 41.3% of patients (Cereghino et al., 2000; Ben-Menachem & Falter, 2000; Shorvon et al., 2000). There was a relation between dose increment and increased seizure control with 5.6% of patients becoming seizure free (8% with the highest dose of 3000

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mg/d). Single oral dose of LEV ranging from 250 to 1000 mg has been demonstrated to suppress completely IPS-evoked photoparoxysmal response in 6 out of 12 photosensitive patients (Kasteleijn-Nolst Trenite et al., 1996). Very little data exist in children, but a preliminary report points to a good response as add-on treatment in partial epilepsies (Glauser et al., 1999). Data on efficacy of LEV on movement disorders are scarce. However, some preliminary reports support its efficacy in treating myoclonus in progressive myoclonus and epilepsies and posthypoxic myoclonus (Genton & Gelisse, 2000). LEV seems to exert an action similar to Piracetam, but it is effective at much lower doses. Two patients in the study by Kasteleijn-Nolst Trenite et al. (1996) had a clear reduction of myoclonus, they presented along with photosensitivity. Similar results have been found in patients with pharmacoresistant JME (Smith & Betts, 1998). Studies in animal models of paroxysmal dystonia show that LEV administered at high doses has an antidystonic effect (Löscher & Richter, 2000). LEV is well tolerated. Most commonly reported adverse effects in clinical trials were somnolence, asthenia, dizziness (15%). LEV appears to be a unique AED whose mechanisms of action remain unknown. In animal models, LEV administration protects against development of kindling and seizure induced by pilocarpine and kainic acid, but is ineffective in MES and PTZ test (Bialer et al., 1999; Klitgaard et al., 1998). It had been supposed that its pharmacological activity in epilepsy and movement disorders was due to a change in GABA metabolism and turnover, possibly as a result of its postsynaptic effects. There was no direct effect on GABA synthesizing enzyme glutamic acid decarboxylase (GAD) or degrading enzyme, GABA aminotransferase. LEV did not affect the GABA-ergic system in an in vivo study using mouse brain (Löscher et al., 1996; Sills et al., 1997). However, LEV possesses no significant affinity for GABA, benzodiazepine, glycine, adenosine or excitatory amino acid receptors and for Ca2, K or Cl channels (Perucca, 1999). Piracetam (PIR)

This was developed as a ‘nootropic’ drug capable of improving higher cerebral functions (Tacconi & Wurtman, 1986), but it has also proved to be very effective in treating myoclonus (Genton et al., 1999). The efficacy of PIR is prominent in patients with cortical myoclonus of different etiology (Obeso et al., 1988; Van Vleymen & Van Zandijcke, 1996). Very high doses, ranging from 7 to 45 g/day are necessary in order to achieve control of myoclonus (Genton et al., 1999). The onset of action is within 24 hours. PIR is very well tolerated and remains usually effective, even if it shows some tolerance effect after the first few weeks of treatment (Genton et al., 1999). In Unverricht–Lundborg disease and other progressive myoclonus epilepsies (PME), PIR can sometimes produce spectacular results (Koskiniemi et al.,

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1998). In any case, its efficacy is more marked in less severe forms (Genton et al., 1999). PIR can be used in other disorders featuring myoclonus and epilepsy such as Angelman syndrome (Guerrini et al., 1996). Mechanism of action of PIR remains obscure. PIR has no effect on brain neurotransmitters (Tacconi & Wurtman, 1986). PIR reduced the amplitude of somatosensory-evoked potentials, that can be interpreted as an inhibition on the afferent pathway producing the cortical reflex myoclonus (Obeso et al., 1989). Tiagabine (TGB)

This increases GABA level by inhibition of its reuptake in the synaptic cleft (Sommerville, 1997), through a high selective binding to transporter GAT-1 (Borden et al., 1994). Different add-on, double-blind trials have shown the efficacy of TGB in treating adults and children with partial and secondarily generalized seizures (Sommerville, 1997). The use of TGB in treating movement disorders is very limited. A pilot study in 14 children with spastic quadriparesis and intractable epilepsy has shown that TGB can reduce both seizure frequency and spasticity (Holden & Titus, 1999). Coadministration of haloperidol and TGB has proven effective in inhibiting oral dyskinesias in rats (Gao et al., 1994). However, TGB has never been used to treat tardive dyskinesias in humans. Possibly, the increase of GABA level is responsible for TGB efficacy against spasticity and drug-induced dyskinesias. Vigabatrin (VGB)

This is an irreversible inhibitor of the enzyme GABA transaminase, principle catabolic agent of GABA (Jung & Palfreyman, 1995). VGB increases whole brain GABA by 200–300% producing a 50% seizure protection in different animal models (BenMenachem, 1995). Since 1984 several add-on either uncontrolled or placebo-controlled studies have proven the efficacy of VGB in partial epilepsies with a mean seizure frequency decrease ranging from 37% to 54% (Kälviäinen et al., 1995). Similar results have been achieved in children (Dulac et al., 1991). Recent monotherapy studies comparing VGB with CBZ in newly diagnosed children or adults showed that VGB is slightly less effective than, or as effective as, CBZ, but better tolerated (Chadwick et al., 1999; Gobbi et al., 1999; Zamponi & Cardinali, 1999). VGB shows high efficacy in treatment of infantile spasms as demonstrated by different studies either on a short- or long-term basis (Vigevano & Cilio, 1997; Appleton et al., 1999; Granstrom et al., 1999). In particular VGB is more effective than ACTH in treating infantile spasms symptomatic of tuberous sclerosis and other cerebral malformations (Vigevano & Cilio, 1997). In other generalized epilepsies, VGB efficacy is less

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clear (Michelucci & Tassinari, 1989). Some children can eventually present exacerbation of atypical absences, tonic and myoclonic seizures during VGB therapy (Guerrini et al., 1998a). The recent observation that chronic VGB intake is associated with irreversible, concentric visual field defects in around 40% of patients, has greatly limited the use of the drug (Kälviäinen et al., 1999). The use of VGB in movement disorders is limited to treat tardive dyskinesia and as a spasmolytic drug (Tamminga et al., 1983; Jaeken et al., 1991). In a placebocontrolled study, VGB administered at 3 g/day reduced tardive dyskinesia in schizophrenic patients, previously treated with neuroleptics (Tamminga et al., 1983). In patients presenting spasticity due to metabolic disorders, 25–100 mg/kg/day in two divided doses of VGB was effective as a spasmolytic agent (Jaeken et al., 1991).

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Index

When they fall on a page not covered by the text reference, figures are indicated by ‘(fig.)’ and tables by ‘(table)’. acetazolamide for epilepsy 517–18 mechanisms of action 518–19 for movement disorders 518 acetylcholine receptor mutations, nocturnal frontal lobe epilepsy 8, 106–7, 439–40 acquired bilateral opercular lesions 252–3 alternating hemiplegia of childhood (AHC) 379–80 clinical findings atypical forms 385–6 clinical course 384–5 paroxysmal features 380–3 permanent abnormalities 383–4 differential diagnosis 387, 388t electrophysiology 386 laboratory findings 386 neuroimaging 386–7 possible etiology 389–90 treatment 387–9 Alzheimer’s disease, cortical myoclonus 180–1 Angelman syndrome cortical myoclonus 173–4, 175f, 182 GABAA receptor 3 subunit knockout mouse model 19–22 role of 17–19 angiomas and Sturge–Weber syndrome 393–4 pathophysiology 398–401 animal models of epilepsy, GAERS rat 6–8 of genetic reflex epilepsy Fayoumi chicken 30–2, 33f Papio papio 33f, 34–5, 36f rodents 32, 34 of paroxysmal dyskinesias 129–31

548

antidopaminergic drugs, seizures from 492–3 antiepileptic drugs acetazolamide 517–19 benzodiazepines 519–22 carbamazepine 522–4 drug-induced movement disorders barbiturates 481t, 484 benzodiazepines 481t, 484 carbamazepine 480t, 483–4 ethosuximide 481t felbamate 481t, 484 gabapentin 481t, 484 lamotrigine 481t, 484 and pathophysiology of movement disorders 477–9 phenytoin 479, 480t, 482 valproic acid 480t, 482–3 vigabatrin 485 drug-induced myoclonus 198–9 ethosuximide 530–1 gabapentin 531 lamotrigine 532 levetiracetam 532–3 phenobarbital and primidone 525–7 phenytoin 527–8 piracetam 533–4 and seizure worsening barbiturates 467–8 benzodiazepines 468 carbamazepine 468–71 drug intoxication 465–7 ethosuximide 471–2 gabapentin 472 lamotrigine 472 mechanisms of drug intoxication 475–6

549

Index mechanisms of specific drug effects 476–7 phenytoin 472–3 troxidone 473 vagabatrin 473–5 valproic acid 473 tiagabine 534 valproate 528–30 vigabatrin 534–5 audiogenic reflex epilepsies 29–30 animal models 30–4 classification 40–2 automatisms (stereotypies) in children see epileptic stereotypies in children autosomal dominant benign adult familial myoclonic epilepsy genotype 426t, 436 phenotype 435–6 autosomal dominant cortical reflex myoclonus and epilepsy 182–3 autosomal dominant juvenile myoclonic epilepsy see juvenile myoclonic epilepsy (JME) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) see nocturnal frontal lobe epilepsy autosomal dominant partial epilepsy with variable foci (ADPEVF), genetics 427t, 440 autosomal recessive idiopathic myoclonic epilepsy of infancy, genotype and phenotype 426t, 432 autosomal recessive rolandic epilepsy, genetics 427t, 440–1 baboon (Papio papio), genetic reflex epilepsy 33f, 34–5, 36f barbiturates drug-induced movement disorders 481t, 484 and seizure worsening 467–8 basal ganglia abnormalities in dystonia 119 and movement disorders, drug effects 477–9 benign epilepsy with centrotemporal spikes (BECTS) 260–3 benign familial infantile convulsions, genetics 424, 425t benign familial neonatal convulsions (BFNC) 290 genotype 425t, 430–1 phenotype 429–30 potassium channel mutations 8–10, 456–7 benign idiopathic neonatal convulsions (BINC) 289–90 benign myoclonus of early infancy 189–90, 343

clinical findings early series 349–51 recent series 343–7 differential diagnosis 347–8 benign neonatal sleep myoclonus (BNSM) 290–1 benign paroxysmal torticollis of infants (BPT) 127–8 benign rolandic epilepsy with centrotemporal spikes genotype 427t, 441–2 phenotype 441 benzodiazepines drug-induced movement disorders 481t, 484 for epilepsy 519–21 mechanisms of action 522 for movement disorders 519–21 and seizure worsening 468 calcium channel mutations in animal model of epilepsy 6–8 and channelopathies 457–8 carbamazepine drug-induced movement disorders 480t, 483–4 for epilepsy 522–3 mechanisms of action 523–4 for movement disorders 523 and seizure worsening 468–71 cerebellar dysfunction in progressive myoclonus epilepsies 242–3 cerebellar lesions and facial seizures clinical features 269–71, 272–4t neuroimaging 272–4t, 275 pathology 272–4t, 275–6 cerebral palsy clinical imitators of 353–4 definition 353 epilepsy in clinical features and classification 355–6 differential diagnosis 354 prognosis 356–7 risk factors 354–5 channelopathies 453–4 benign familial neonatal convulsions (BFNC) 8–10, 456–7 calcium channel mutations 457–8 epileptogenic neuronal excitability changes 1–4 episodic ataxia type 1 (EA-1) 456 episodic choreoathetosis/spasticity 459–60 generalized epilepsies 6–8

550

Index channelopathies (cont.) generalized epilepsy with febrile seizures plus (GEFS) 10, 454–5 nocturnal frontal epilepsy 8 paroxysmal dystonic choreoathetosis 459 paroxysmal kinesigenic choreoathetosis (PKC) 458–9 potassium channel mutations 456–7 sodium channel mutations 454–5 childhood absence epilepsy (CAE) 426t, 428–9, 436–7 chorea mollis, in Sydenham chorea 364–5 chorea, Sydenham chorea see Sydenham chorea clobazam for epilepsy 520 mechanism of action 522 clonazepam for epilepsy 519–20 mechanism of action 522 for movement disorders 521 congenital bilateral opercular lesions 254–9 cortical myoclonus and Alzheimer’s disease 180–1 and Angelman syndrome 182 autosomal dominant cortical reflex myoclonus and epilepsy 182–3 clinical findings 168 and corticobasal degeneration 180 and epilepsia partialis continua 181–2 epileptic negative myoclonus 178–9 and Huntington’s disease 181 induction mechanisms 169–73 and Lennox–Gastaut syndrome 185, 187, 188f mechanisms of spread 176–7 neurophysiologic findings 168–9 and postanoxic encephalopathy 179 and progressive myoclonus epilepsies 179–80 rhythmic/arrhythmic recurrence 173–6 and severe myoclonic epilepsy 183–5 treatment 198 cortical perisylvian developmental disorders 254–8 cortical reflex myoclonus and epilepsy, autosomal dominant 182–3 corticobasal degeneration, cortical myoclonus 180 dentatorubral–pallidoluysian atrophy (DRPLA) 453 diazepam for epilepsy 519 mechanism of action 522 for movement disorders 521

dopamine receptor-blockers (DRBs) DRB-induced movement disorders acute syndromes 485–6 levodopa-induced dyskinesia 489–90 subacute syndromes 486–7 tardive syndromes 487–9 dopaminergic drugs, seizures from 490–2 drug-induced movement disorders, in neonates 297–8 dyskinesia, paroxysmal see paroxysmal dyskinesia dystonia clinical features 111–13 from dopamine receptor-blockers 485–6 episodic dystonic posturing in neonates 296 physiology 113–14 motor cortex abnormalities 115–19 sensory dysfunction 114–15 treatment 119–20 early infantile epileptic encephalopathy (EIEE) 288–9 early myoclonic encephalopathy (EME) 191–3, 288 encephalopathies, in children and periodic spasms 307–8 case reports 308–14 semiology and differential diagnosis 314–16 and sleep starts 307–8 case reports 314 semiology and differential diagnosis 316–17 encephalopathy, and Sydenham chorea 365 epilepsia partialis continua (EPC) clinical features 217 cortical myoclonus 181–2 definition and pathophysiology 211–14, 215t etiology 214, 216–17, 218–19t investigations 217, 220 reversible operculum syndrome 259–60 treatment 220–1 epilepsy genes allele enrichment in affected populations 443–4 discovery of epilepsy alleles 444 evolutionary old/young genes 442–3 see also genetic epilepsies epileptic automatisms in children see epileptic stereotypies in children epileptic encephalopathies, steroid-responsive, motor disorders see motor disorders, steroid-responsive epileptic myoclonus see myoclonus epileptic negative myoclonus clinical features 78–9

551

Index definition and background 78 neurophysiology and neuroimaging 80–2 epileptic spasms see periodic spasms epileptic stereotypies in children clinical features and differential diagnosis 319–21 clinical study 321–5, 326f definition 319 as epileptic manifestations 328–32 intracranial video-EEG monitoring 325–8, 329f epileptic syndromes with cortical myoclonus 179–87 with myoclonus of unclear neurophysiologic characterization 191–6 with primary generalized epileptic myoclonus 187–91 episodic ataxia type 1 (EA-1), potassium channel mutations 428t, 456 episodic choreoathetosis/spasticity, genetics 459–60 episodic dystonic posturing and tonic events, in neonates 296 ethosuximide drug-induced movement disorders 481t for epilepsy 530–1 and seizure worsening 471–2 facial seizures, of cerebellar origin clinical features 269–71, 272–4t neuroimaging 272–4t, 275 pathology 272–4t, 275–6 familial febrile seizures, genetics 424, 425t familial infantile convulsions and choreoathetosis, genetics 424, 425t familial operculum syndrome and rolandic epilepsy 258–9 familial spastic paraparesis and epilepsy, genetics 428t Fayoumi chicken model, of genetic reflex epilepsy 30–2, 33f febrile seizures, genetics 424, 425t felbamate, drug-induced movement disorders 481t, 484 fixed encephalopathies, myoclonus in 193 focal status epilepticus, reversible operculum syndrome 259–60 Foix–Chavany–Marie syndrome (FCMS) see opercular epilepsies with oromotor dysfunction frontotemporal dementia with parkinsonism-17, epilepsy in 428t

functional magnetic resonance imaging (fMRI), of motor cortex applications 48–50 interpretation analysis of data 53–4 as increase in blood flow 52–3 location of activation 50–2 overview 47–8 GABAA receptors 3 subunit and Angelman syndrome 17–19 knockout mouse 19–22 structure and function 15–17 GABAergic drugs, and seizure worsening 476 gabapentin 531 drug-induced movement disorders 481t, 484 and seizure worsening 472 GAERS rat (genetic absence rat from Strasbourg), and calcium channel mutations 6–8 gastroesophageal reflux, in neonates 296 generalized epilepsies and calcium channel mutations 6–8 genetics 423–9 autosomal dominant benign adult familial myoclonic epilepsy 435–6 autosomal dominant juvenile myoclonic epilepsy 426t autosomal recessive idiopathic myoclonic epilepsy of infancy 426t, 432 benign familial neonatal convulsions 425t, 429–31 childhood absence epilepsy 426t, 436–7 generalized epilepsy with febrile seizures plus (GEFS) 425t, 431–2 juvenile myoclonic epilepsy, autosomal dominant 432–5 juvenile myoclonic epilepsy, autosomal recessive 435 generalized epilepsy with febrile seizures plus (GEFS) genotypes 425t, 431–2 phenotypes 431 sodium channel mutations 10, 454–5 generalized epileptic myoclonus benign myoclonic epilepsy of infancy 189–90 clinical and electrophysiologic findings 187 juvenile myoclonic epilepsy 190–1 myoclonic–astatic epilepsy 191, 192f, 194–5f genetic epilepsies allele enrichment in affected populations 443–4

552

Index genetic epilepsies (cont.) channelopathies see channelopathies differential diagnosis from movement disorders 421–3 discovery of epilepsy alleles 444 evolutionary old/young genes 442–3 generalized epilepsies see generalized epilepsies genetic reflex epilepsy see genetic reflex epilepsy partial epilepsies 427t, 438 autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) 438–40 autosomal dominant partial epilepsy with variable foci (ADPEVF) 440 rolandic epilepsies 440–2 genetic reflex epilepsy animal models Fayoumi chicken 30–2, 33f Papio papio 33f, 34–5, 36f rodents 32, 34 classification 40–2 human syndromes photogenic paroxysmal manifestations 37–8 somatosensory paroxysmal manifestations 38–9 types of 29–30 glycine receptor mutation, in startle disease 153–5 hemifacial seizures, of cerebellar origin clinical features 269–71, 272–4t neuroimaging 272–4t, 275 pathology 272–4t, 275–6 hereditary geniospasm, genetics 134 Huntington’s disease, cortical myoclonus 181 hyperekplexia see startle disease (hyperekplexia) hypnagogic jerks see sleep starts hypnic jerks see sleep starts idiopathic epilepsies, as channelopathies see channelopathies idiopathic (generalized) epilepsies see generalized epilepsies idiopathic generalized epileptic myoclonus see generalized epileptic myoclonus idiopathic partial epilepsies see partial epilepsies infantile spasms syndrome genetics 424, 425t intermittent light stimulation and genetic reflex epilepsy animal models 30–5 classification 40–2 human syndromes 37–8

ion channels and channelopathies acetylcholine receptor 8 calcium channels 6–8 potassium channels 8–10 sodium channels 10 molecular structure 4–5 and neuronal excitability 1–4 irreversible opercular syndrome acquired bilateral opercular lesions 252–3 congenital bilateral opercular lesions 254–9 jitteriness, in neonates 292 juvenile myoclonic epilepsy (JME) autosomal recessive 435 differential diagnosis from movement disorders 421–3 genotypes 426t, 433–5 phenotypes 432–3 primary generalized epileptic myoclonus 190–1 Kojewnidow’s syndrome see epilepsia partialis continua (EPC) Lafora disease 229–30 myoclonus in 240f lamotrigine 532 drug-induced movement disorders 481t, 484 and seizure worsening 472 Landau–Kleffner syndrome 511–12 Leigh syndrome, genetics 453 Lennox–Gastaut syndrome, cortical myoclonus 185, 187, 188f lethargic mouse, calcium channel mutations 458 levetiracetam 532–3 levodopa levodopa-induced dyskinesia 489–90 seizures from 491 lorazepam for epilepsy 521 mechanism of action 522 magnetic resonance imaging, functional (fMRI) see functional magnetic resonance imaging (fMRI) magnetoencephalography (MEG) and epilepsy 63–4 and neural plasticity 71–2 physiological background 59–60 and stroke 67–9

553

Index MERRF syndrome (myoclonus epilepsy and ragged red fibres) 230–1 metabolic disorders, and neonatal movement disorders 297–8 mitochondrial cytopathies, genetics 451–2 mitochondrial encephalopathy, and progressive myoclonus epilepsy 230–1 motor cortex abnormalities and dystonia 115–17, 118f and epilepsy 118–19 basal ganglia abnormalities in dystonia 119 functional magnetic resonance imaging (fMRI) analysis of data 53–4 applications 48–50 as increase in blood flow 52–3 location of activation 50–2 overview 47–8 motor disorders, steroid-responsive case reports 511–14 pathophysiology 514–15 prevalence 514 motor dysfunction from epileptic activity in sensorimotor cortex 77 case reports 87–90 epileptic negative myoclonus (ENM) 78–82 frequent paroxysmal discharges 85–7 partial atonic seizures (PAS) 82–5 movement disorders antiepileptic drug-induced barbiturates 481t, 484 benzodiazepines 481t, 484 carbamazepine 480t, 483–4 ethosuximide 481t felbamate 481t, 484 gabapentin 481t, 484 lamotrigine 481t, 484 phenytoin 479, 480t, 482 valproic acid 480t, 482–3 vigabatrin 485 differential diagnosis from epilepsy 421–3 from dopamine receptor-blockers (DRBs) 485 acute syndromes 485–6 levodopa-induced dyskinesia 489–90 parkinsonism 486–7 tardive syndromes 487–9 tremor 487 in neonates see neonatal movement disorders role of basal ganglia, drug effects 477–9 myoclonic–astatic epilepsy, primary generalized epileptic myoclonus 191, 192f, 194–5f

myoclonus clinical neurophysiology 167–8 cortical myoclonus and Alzheimer’s disease 180–1 and Angelman syndrome 182 autosomal dominant cortical reflex myoclonus and epilepsy 182–3 clinical findings 168 and corticobasal degeneration 180 and epilepsia partialis continua 181–2 epileptic negative myoclonus 178–9 and Huntington’s disease 181 induction mechanisms 169–73 and Lennox–Gastaut syndrome 185, 187, 188f mechanisms of spread 176–7 neurophysiologic findings 168–9 and postanoxic encephalopathy 179 and progressive myoclonus epilepsies 179–80 rhythmic/arrhythmic recurrence 173–6 and severe myoclonic epilepsy 183–5, 186f syndromes with 179–87 definition and classifications 165–7 drug-induced 198–9 epileptic negative myoclonus 78–82 idiopathic (primary) 187 neurophysiological characterization 199–200 primary generalized and benign myoclonic epilepsy of infancy 189–90 and idiopathic generalized epilepsies 187 and juvenile myoclonic epilepsy 190–1 and myoclonic–astatic epilepsy 191 in progressive myoclonus epilepsies 237, 239–42 reticular reflex myoclonus 196–8 in startle disease 155–7 treatment 198 of unclear neurophysiologic characterization 191–6 early myoclonic encephalopathy 191–3 epilepsy with myoclonic absences 193–4 fixed encephalopathies 193 myoclonus epilepsy and ragged red fibres (MERRF) 230–1 myoclonus epilepsy in infancy, as genetic reflex epilepsy 39 negative myoclonus 178–9 neonatal movement disorders benign familial neonatal convulsions (BFNC) 290

554

Index neonatal movement disorders (cont.) benign idiopathic neonatal convulsions (BINC) 289–90 benign neonatal sleep myoclonus (BNSM) 290–1 classification 280–2 difficulties with 286–8 and EEG findings 282–6, 287f diagnostic problems 279–80, 298–9 drug and metabolic factor induced 297–8 early infantile epileptic encephalopathy (EIEE) 288–9 early myoclonic encephalopathy (EME) 288 episodic dystonic posturing and tonic events 296 and excitatory/inhibitory neurotransmission 280 gastroesophageal reflux 296 non-seizure disorders 290 shuddering attacks 291–2 startle disease 293–5 tremulousness and jitteriness 292 neuraminidase, defects of, and progressive myoclonus epilepsy 233–4 neurodegenerative disorders, with epilepsy and movement disorders dentatorubral–pallidoluysian atrophy (DRPLA) 453 Leigh syndrome 453 mitochondrial cytopathies 451–2 neuroleptics, seizures from 492–3 neurological disorders, with cortical myoclonus 179–81 neuronal ceroid lipofuscinoses 231–3 neuronal excitability, epileptogenic activity 1–4 nocturnal frontal lobe epilepsy 97–8 acetylcholine receptor mutations 8, 106–7, 439–40 in children 104, 106 clinical features 99–101 case report 101–4, 105f genetics 106–7 genotypes 427t, 439–40 history 98–9 phenotypes 438–9 obsessive–compulsive symptoms, and Sydenham chorea 361–2 ocular symptoms, in Sydenham chorea 366 ocular tics, in children 333–5 opercular epilepsies with oromotor dysfunction classification 251–2, 253t irreversible opercular syndrome acquired bilateral opercular lesions 252–3 congenital bilateral opercular lesions 254–9

reversible operculum syndrome BECTS-like epilepsy with brain lesions 262–3 benign epilepsy with centrotemporal spikes (BECTS) 260–2 focal status epilepticus and epilepsia partialis continua 259–60 opsoclonus-myoclonus syndrome, in children 337–9 Papio papio, genetic reflex epilepsy 33f, 34–5, 36f parkinsonism, from dopamine receptor-blockers 486–7 paroxysmal choreoathetosis and spasticity, genetics 133 paroxysmal downgaze, in infants 337 paroxysmal dyskinesia animal models 129–31 classification 125 clinical features benign paroxysmal torticollis of infants (BPT) 127–8 paroxysmal exertion-induced dyskinesia (PED) 127 paroxysmal hypnogenic dystonia (PHD) 127 paroxysmal kinesigenic dyskinesia (PKD) 125–6 paroxysmal non-kinesigenic dyskinesia (PNKD) 126 paroxysmal tonic upgaze of infants 128–9 co-occurrence with epilepsy 407–8 genetic association 410–16 differential diagnosis 408–10 genetics 131–2 hereditary geniospasm 134 paroxysmal choreoathetosis and spasticity 133 paroxysmal exercise-induced dyskinesia (PED) 133–4 paroxysmal kinesigenic choreoathetosis (PKC) 133 paroxysmal non-kinesigenic dyskinesia (PNKD) 132–3 pathophysiology 129 paroxysmal dystonic choreoathetosis, genetics 459 paroxysmal exercise-induced dyskinesia (PED), genetics 133–4 paroxysmal exertion-induced dyskinesia (PED), clinical features 127 paroxysmal eye movements, non-epileptic associated disorders 334t ocular tics in children 333–5

555

Index opsoclonus-myoclonus syndrome in children 337–9 paroxysmal downgaze in infants 337 paroxysmal tonic upgaze of infants 335–7 paroxysmal hypnogenic dystonia (PHD), clinical features 127 paroxysmal kinesigenic choreoathetosis (PKC) as genetic reflex epilepsy 39 genetics 133, 458–9 paroxysmal kinesigenic dyskinesia (PKD), clinical features 125–6 paroxysmal non-kinesigenic dyskinesia (PNKD) clinical features 126 genetics 132–3 paroxysmal tonic upgaze of infants 335–7 clinical features 128–9 partial atonic seizures (PAS) clinical features 83–4 definition and background 82–3 differential diagnosis 84–5 neurophysiological characterization 84 partial epilepsies 438 genetics 427t autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) 438–40 autosomal dominant partial epilepsy with variable foci (ADPEVF) 440 autosomal recessive rolandic epilepsy 440–1 benign rolandic epilepsy with centrotemporal spikes 427t, 441–2 periodic spasms 307–8 case reports 308–14 semiology and differential diagnosis 314–16 phenobarbital for epilepsy 525 mechanisms of action 526–7 for movement disorders 526 phenytoin drug-induced movement disorders 479, 480t, 482 for epilepsy 527 mechanisms of action 528 for movement disorders 527–8 and seizure worsening 472–3 photogenic reflex epilepsies 29–30 animal models 30–5 classification 40–2 human syndromes 37–8 piracetam 533–4 postanoxic encephalopathy 179 potassium channel mutations

benign familial neonatal convulsions 8–10, 430–1, 456–7 episodic ataxia type 1 (EA-1) 456 Kv1.1 channel knockout 456 primary generalized epileptic myoclonus see generalized epileptic myoclonus primidone for epilepsy 525 mechanisms of action 526–7 for movement disorders 526 progressive myoclonus epilepsies 227 cerebellar dysfunction 242–3 cortical myoclonus 179–80 differential diagnosis 234–5 disorders causing Lafora disease 229–30 myoclonus epilepsy and ragged red fibres (MERRF) 230–1 neuronal ceroid lipofuscinoses 231–3 sialidoses 233–4 Unverricht–Lundborg disease 228–9 myoclonus 237, 239–42 rare causes 234 seizure types 235–7, 238f reticular reflex myoclonus clinical findings 196 neurophysiologic findings 196–8 reversible operculum syndrome BECTS-like epilepsy with brain lesions 262–3 benign epilepsy with centrotemporal spikes (BECTS) 260–2 focal status epilepticus and epilepsia partialis continua 259–60 rheumatic fever, and Sydenham chorea 359–60 rolandic epilepsies, genetics 427t, 440–2 seizures from antidopaminergic drugs 492–3 from dopaminergic drugs 490–2 in neonates see neonatal movement disorders partial atonic seizures 82–5 in progressive myoclonus epilepsies 235–7 in Sydenham chorea 366 worsening of with antiepileptic drugs barbiturates 467–8 benzodiazepines 468 carbamazepine 468–71 drug intoxication 465–7 ethosuximide 471–2 gabapentin 472

556

Index seizures (cont.) worsening of with antiepileptic drugs (cont.) lamotrigine 472 mechanisms of drug intoxication 475–6 mechanisms of specific drug effects 476–7 phenytoin 472–3 troxidone 473 vagabatrin 473–5 valproic acid 473 sensorimotor cortex magnetoencephalography (MEG) and epilepsy 63–4 and neural plasticity 71–2 physiological background 59–60 and stroke 67–9 motor dysfunction from epileptic activity 77 case reports 87–90 epileptic negative myoclonus 78–82 frequent paroxysmal discharges 85–7 partial atonic seizures 82–5 transcranial magnetic stimulation (TMS) and epilepsy 64–7 and movement disorders 67 and neural plasticity 71–2 paired TMS 61–3 physiological background 60–1 and stroke 69–71 sensory dysfunction, in dystonia 114–15 severe myoclonic epilepsy (SME), cortical myoclonus 183–5, 186f shuddering attacks, in neonates 291–2 shuddering, motor manifestations in early infancy see benign myoclonus of early infancy sialidoses 233–4 sleep starts 307–8 case reports 314 semiology and differential diagnosis 316–17 sodium channels mutations, generalized epilepsy with febrile seizures plus (GEFS) 10, 431–2, 454–5 somatosensory stimulation and genetic reflex epilepsy 29–30 animal models 34–5 classification 40–2 human syndromes 38–9 spastic paraparesis and epilepsy, genetics 428t startle disease (hyperekplexia) 38–9 clinical presentation 151–3 cortical excitability 157–8 differential diagnosis 159–60 genetics 153–5

in neonates 293–5 pathophysiology 155–7 treatment 158–9 startle-provoked epileptic seizures (SPES) clinical features 144–5 EEG findings 147 etiology 145–6 ictal semiology 146–7 neuroimaging 148 prevalence 145 provocative stimuli 146 surgical treatment 148 startle response in neonates 292–3 normal startle reflex 141–2 complexity of 144 physiological studies 142–4 stereotypies in children see epileptic stereotypies in children steroid-responsive motor disorders case reports 511–14 pathophysiology 514–15 prevalence 514 stroke magnetoencephalography (MEG) 67–9 transcranial magnetic stimulation (TMS) 69–71 Sturge–Weber syndrome paroxysmal attacks epileptic seizures 394–5 transient motor attacks 395–8 pathophysiology 398–401 treatment 401–3 vascular abnormalities 393–4 subacute necrotizing encephalomyopathy 453 Sydenham chorea clinical features and diagnosis 360–1 duration of disorder 364 neurologic signs and symptoms 362–4 psychiatric symptoms 361–2 unusual/atypical signs and symptoms 364–6 differential diagnosis 366–8 electrophysiology 370–1 epidemiology 359 etiology 360 laboratory investigations 368–9 neuroimaging 369–70 treatment 371–2 tardive syndromes, from dopamine receptorblockers (DRBs) 487–9

557

Index temporal lobe partial epilepsy, genetics 427t, 438 tiagabine, for epilepsy and movement disorders 534 tics, in Sydenham chorea 365–6 tottering mouse, calcium channel mutations 457 transcranial magnetic stimulation (TMS) and epilepsy 64–7 in movement disorders 67 and neural plasticity 71–2 paired TMS 61–3 physiological background 60–1 and stroke 69–71 tremor, from dopamine receptor-blockers (DRBs) 487 tremors, in neonates 292 troxidone, and seizure worsening 473

Unverricht–Lundborg disease (ULD) 228–9 myoclonus 241f seizures 236f vagabatrin, and seizure worsening 473–5 valproate/valproic acid drug-induced movement disorders 480t, 482–3 for epilepsy 528–9 mechanisms of action 530 for movement disorders 529 and seizure worsening 473 vigabatrin 534–5 drug-induced movement disorders 485